Stem Cell Transplantation and Gene Therapy for HIV-Related Lymphomas

JOURNAL OF HEMATOTHERAPY amp STEM CELL RESEARCH 11765ndash775 (2002)copy Mary Ann Liebert Inc

State-of-the-Art Review

Stem Cell Transplantation and Gene Therapy for HIV-Related Lymphomas

AMRITA KRISHNAN JOHN ZAIA and ARTURO MOLINA

ABSTRACT

The treatment of patients with HIV-related non-Hodgkinrsquos lymphoma (NHL) and Hodgkinrsquos dis-ease (HD) is less successful than in the non-HIV setting in part due to the aggressive character ofthese lymphomas but also due to the underlying HIV infection High-dose therapy with stem celltransplantation has been used with success in the HIV-negative lymphoma setting for high-risk orrelapsed disease However for patients with HIV-NHL and HIV-HD ultimately the chance for long-term lymphoma-free survival also depends on successful control of the HIV infection Gene ther-apy approaches may provide the opportunity for this long-term control Herein we describe the useof high-dose chemotherapy with stem cell rescue in conjunction with current and future gene ther-apy approaches for the treatment of HIV-associated lymphomas

765

INTRODUCTION

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART)has changed the natural history of HIV infection by

improving immune function and thereby prolonging sur-vival by reducing the incidence of opportunistic infec-tions (12) However the effects of HAART on the inci-dence of AIDS-related non-Hodgkinrsquos lymphoma (NHL)and Hodgkinrsquos disease (HD) are less clear A Swiss HIVcohort study of 6636 HIV-infected individuals observeda dramatic decrease in the incidence of Kaposirsquos sarcoma(KS) in the HAART era but no significant change in theincidence of NHL (3) In contrast the US AIDS clini-cal trials group observed a decline in both KS and NHLduring the years of combination antiretroviral therapy al-though the effect on KS was more profound (4) Lastlya meta-analysis of 23 studies encompassing 47936 HIV-infected individuals from three continents demonstratedoverall a decline of HIV-related NHL in the period1997ndash1999 (5) Nonetheless the incidence of NHL in

HIV-infected individuals still remains far above the HIV-negative setting particularly in individuals with a priorAIDS diagnosis (6ndash8) The major factor affecting the in-cidence of AIDS-lymphoma appears to be the fact thatthe CD4 counts have increased due to antiretroviral ther-apy (8) Overall the relative risk of developing im-munoblastic lymphoma or large-cell lymphoma follow-ing an earlier diagnosis of AIDS is 627-fold and 145-foldincreased over the HIV-negative general population(389) Although HD is not considered an AIDS-defin-ing illness nonetheless the incidence of HD is also in-creased among the HIV-infected population (1011)

The best treatment for HIV-related lymphomas is asyet unknown For patients with relapsed HIV-relatedNHL or HD the optimum treatment options are even lessclear However with the advent of HAART and the sub-sequent improvement in immune function in HIV-in-fected individuals on combination antiretroviral therapythe use of transplantation including solid organ and pe-ripheral stem cell transplantation is being explored

Division of Hematology and Bone Marrow Transplantation and Department of Virology City of Hope National Medical Cen-ter Duarte CA 91010

(812ndash15) This review addresses three areas the back-ground rationale for use of high-dose chemotherapy inAIDS lymphoma the experience to date with autologousand allogeneic stem cell transplantation in this diseaseand the potential for the use of myeloablative and non-myeloablative therapy with stem cell transplantation asthe basis for gene transfer into stem cells as treatment forHIV infection

BACKGROUND

With the advent of HAART clinical characteristics ofHIV-NHL have changed The median CD4 lymphocytecount at lymphoma diagnosis has decreased reflectingthe fact that lymphoma is often a late manifestation ofHIV infection The pathologic spectrum of disease hasalso changed with a decrease in the prevalence of smallnoncleaved lymphoma and an increase in diffuse large-cell lymphoma (1718) HIV-related HD is also charac-terized by a different histopathologic predominance fromthe HIV-negative setting with the mixed cellularity sub-type predominating The median survival for both HIV-NHL and -HD remains poor and is far below that ob-served in the HIV-negative setting (1117)

Prognostic factors for HIV-NHL can be divided intothose reflecting the severity of the underlying HIV in-fection and those directly related to the lymphoma Anearly study by Levine and colleagues observed that per-formance status prior AIDS diagnosis and bone marrowinvolvement were strongly associated with shortened sur-vival (17) A more recent study from the same center fur-ther evaluated the significance of bone marrow involve-ment It revealed that factors associated with decreasedsurvival in marrow-positive patients included 50marrow involvement with lymphoma B symptoms andhigh-grade histologic type (20) The international prog-nostic index for lymphoma has also been applied to HIV-NHL and was found to be predictive of survival in threestudies (82122)

Early therapeutic approaches to HIV-related lym-phomas focused on reduction of chemotherapy dose in-tensity due to fears of further worsening the immunefunction in these individuals after administration of stan-dard dose regimens A randomized trial comparing low-dose M-BACOD (methotrexate bleomycin doxorubicincyclophosphamide vincristine dexamethasone) withstandard dose M-BACOD in conjunction with cytokinesupport was conducted by the US AIDS clinical trialgroup and the results further reinforced the early con-cept that higher-dose chemotherapy was not better Therewere no significant differences in overall survival anddisease-free survival between the low-dose and standard-dose groups and greater hematologic toxicity in the stan-dard-dose group although the median survivals of 31

and 35 weeks was far below that one would expect in theHIV-negative setting (23) However this study was per-formed before the widespread availability of protease in-hibitor-based therapy For patients with HIV-HD the useof standard-dose ABVD (adriamycin bleomycin vin-blastine dacarbazine) chemotherapy and growth factorsupport has been explored in a multicenter trial (24)Again the incidence of hematologic toxicity was highand median survival was poor at only 18 months Simi-larly the majority of these patients were not on HAARTIn contrast a study using concomitant HAART and a rel-atively new intense weekly multidrug regimen ldquoStanfordVrdquo showed higher remission rates and improved disease-free survival (25)

Several investigators have studied the efficacy of in-fusional chemotherapy either as initial treatment or forrelapsed HIV-NHL Sparano and colleagues reportedhigh response rates with cyclophosphamide doxorubicinand etoposide given in combination with single agent an-tiretroviral therapy (didanosine ddI) and more recentlywith HAART (2627) Although response rates were thesame in the group treated with concomitant ddI versusthose on HAART the median survival was higher in thegroup on HAART Investigators at the National CancerInstitute have utilized a dose-adjusted schedule ofEPOCH (etoposide vincristine doxorubicin cyclophos-phamide prednisone) in untreated patients Initial com-plete remission (CR) rates were 79 with as yet no re-lapse of lymphoma in the CR group (28) Of noteantiretroviral therapy was withheld until day 6 of the lastdose of chemotherapy due to concerns of drug interac-tions In that study the HIV viral load increased dra-matically by cycle four of chemotherapy in most patientsbut did return to pretreatment levels with the resumptionof antiretroviral therapy The treatment of relapsed dis-ease with the infusional regimen ESHAP (etoposide sol-umedrol Ara-C platinol) has shown promise with re-sponse rates of 54 and median survival of 7 months(2930) Future studies are addressing the role of mono-clonal antibody therapy with rituximab in conjunctionwith chemotherapy either for newly diagnosed disease orfor treatment of relapse (31) For relapsed HIV-HD theoptimal salvage regimen is even less clear and againcisplatinum-based salvage regimens have been used

CHEMOTHERAPY ANDANTIRETROVIRAL THERAPY

The advent of effective protease inhibitor-based anti-retroviral therapy has raised the question Could survivalof AIDS lymphoma be improved by combining HAARTwith conventional dose chemotherapy There are bothadvantages and disadvantages to combining chemother-apy and anti-HIV therapy One possible advantage is that

KRISHNAN ET AL

766

viral suppression may limit the immune damage by HIVduring chemotherapy and may allow development of hostantitumor responses The potential disadvantage is thatpharmacokinetic interactions may affect the therapeuticindex of both the chemotherapeutic agents and the anti-retroviral drugs Recent trials have studied the interac-tions of chemotherapy and HAART Using the antiretro-viral regimen of lamivudine stavudine and indinavir inpatients with AIDS lymphoma receiving CHOP themean cyclophosphamide clearance was reduced withouta significant effect on toxicity and with no effect on in-dinavir clearance (32) A recent report evaluated thechanges in immune parameters and viral load during che-motherapy and HAART In patients maintained onHAART the viral load did not change significantly andCD4 counts returned to baseline values a few weeks af-ter completion of chemotherapy Last retrospective stud-ies from Europe comparing the use of chemotherapy priorto HAART and now in the era of HAART showed higherCR rates and longer disease-free survival when HAARTwas given concomitantly with chemotherapy (33)

STEM CELL TRANSPLANTATION IN HIV-RELATED LYMPHOMAS

As HAART has improved immune function in HIV-infected patients new approaches to the treatment ofHIV-NHL such as myeloablative chemotherapy withstem cell transplantation have been explored The initialexperiences with both allogeneic and autologous stemcell transplantation in HIV-infected individuals were no-table for multiple infectious complications (34) How-ever this was before the widespread use of HAARTMore recent experiences demonstrate that both stem celland solid organ transplantation is feasible in patients onHAART (1214153536) For instance in a recently re-ported case of liver transplantation in an HIV-infected in-dividual a patient was maintained on FK506 lamivu-dine stavudine and nelfinavir post-transplant and had anundetectable HIV viral load He did develop transient cy-tomegalovirus (CMV) antigenemia that responded toganciclovir therapy Of note he also had a petit mal sei-zure from high FK506 levels in part due to the inter-action of nelfinavir and FK506 This complication emphasizes the continued need for monitoring of phar-macokinetic interactions between HAART and chemo-therapy (12)

The feasibility of using autologously derived granulo-cyte colony-stimulating factor (G-CSF)-mobilized pe-ripheral blood progenitor cells from HIV-infected indi-viduals with lymphoma is based on several earlierinvestigations Firstly several investigators have demon-strated that primitive cells are not directly infected by theHIV virus (3738) In addition studies found that G-CSF

caused no significant changes in the HIV viral load anddemonstrated the clonogenic potential of CD341 Thy11

stem cells collected through apheresis from the HIV-in-fected patients (39) The ability to mobilize stem cellsmay in part be mediated by the use of antiretroviral ther-apy In patients started on HAART there has been a notedrise in white blood cell (WBC) and platelet counts as HIVviral loads decline In vivo studies document an increasein marrow mononuclear cells and functional improve-ment in progenitor cell and stem cell assays on HAART(40) A clinical trial from the US AIDS Clinical TrialsGroup found that there was an inverse relationship be-tween the baseline CD41 cell count and mobilizableCD341 cell counts These studies as well as studies fromthe City of Hope have demonstrated that HIV-infectedindividuals even patients with CD41 counts 200 cellsmm3 can mobilize adequate numbers of stem cells foruse in autologous rescue (3941)

In the HIV-negative setting a combination of high-dose chemotherapy and autologous stem cell transplan-tation is the optimal therapy for relapsed NHL and HD(42) This approach is also being explored for NHL pa-tients in first remission with high-risk disease as definedby the International Prognostic Index (43) Given the im-provement in immune function after initiation of HAARTin HIV-infected individuals investigators at the City ofHope have explored the use of stem cell transplantationwith the goal of improving the outcome in patients withpoor-risk HIV-associated lymphomas and have demon-strated the feasibility of mobilizing and engrafting autol-ogously derived peripheral blood progenitor cells fromthese patients (1415) Herein we update our experiencewith 15 patients with HIV-NHL or HD on HAART whoreceived chemotherapy and G-CSF (10 mgkg) for stemcell mobilization (16) (see Table 1) Twelve patients hadeither relapsed disease or were in partial remission (10NHL 2HD) and 3 with NHL were in first remission withhigh-risk features as defined by the International Prog-nostic Index A median of 9 3 106 CD341 cellskg werecollected Fourteen patients received CBV (cyclophos-phamide 100 mgkg ideal body weight BCNU 450mgm2 etoposide 60 mgkg adjusted body weight) and1 patient received fractionated total body irradiation(FTBI) 1200 cGy cyclophosphamide 100 mgkg idealbody weight and etoposide 60 mgkg adjusted bodyweight) as the conditioning regimen All patients weremaintained on HAART but 8 were intolerant of the reg-imen because of gastrointestinal toxicity Routine antibi-otic prophylaxis and supportive care measures were ad-ministered to all patients in a manner similar to theHIV-negative autologous transplant setting All 15 pa-tients engrafted and white cell engraftment defined as anabsolute neutrophil count greater than 500ml occurredat a median of 11 days which is a result similar to thatobserved in the HIV-negative transplant setting

TRANSPLANTATION IN HIV-RELATED LYMPHOMAS

767

Pre-engraftment infectious complications were similarto those in HIV-negative autologous transplants withGram-positive bacteremias predominating The most se-rious septic episode was in a patient with a culture-neg-ative febrile illness which manifested around the time ofengraftment as gastrointestinal bleeding skin erythemahypotension and hypoxia and for which he required sev-eral days of intensive care monitoring before recoveryOne patient developed an ldquoengraftment syndromerdquo con-sisting of a diffuse erythematous rash and high feversHe was treated with a brief course of prednisone (1 mgkgper day) and had rapid improvement Post-engraftmentcomplications in the first 2 years were primarily respira-tory and included lobar pneumonia in 1 patient and in-terstitial pneumonia in 2 patients between days 140 and60 without documented infection One patient developedan influenza-like syndrome with presumed bacterialpneumonia at 121 months for which he required tem-porary ventilatory support but achieved a full recoveryOne patient developed fever and neutropenia without adocumented source of infection at 5 months post trans-plant

Opportunistic infections were seen in 3 patients Anuncomplicated varicella zoster infection occurred at 2months in 1 patient not on acyclovir prophylaxis and thisinfection responded to high-dose acyclovir therapy An-

other patient developed CMV viremia and low-gradefevers at day 137 which responded promptly to ganci-clovir therapy One patient who stopped pneumocystisprophylaxis and antiretrovirals developed pneumocystispneumonia at 8 months and CMV retinitis at 17 monthsBoth infections were successfully treated Last 1 patientdeveloped asymptomatic CMV viremia at approximately3 months post-transplant that did not require treatment

Conditioning regimen-related complications were asfollows The oldest patient (age 68) developed a car-diomyopathy at day 110 and subsequently died withmultiorgan failure including three-fold increase inbilirubin levels (grade 3 toxicity) and 20-fold increasein liver transaminase levels (grade 4) above upper limitsof normal (ULN) Thirteen other patients had mild he-patic toxicity consisting of three-fold hyperbilirubine-mia and five-fold elevated transaminase levels (grades1ndash2 toxicity) above ULN and hypoalbuminemia Ten pa-tients developed mild mucositis Late toxicity was seenin 1 patient who presented with interstitial infiltrates atday 155 and was ultimately diagnosed with BCNU-re-lated pneumonitis after a negative bronchoalveolarlavage He responded well to oral prednisone therapy

Late hepatotoxicity was seen at 10 months post-trans-plant in 1 patient who developed three-fold increase inbilirubin and 20-fold elevation in transaminase levels

KRISHNAN ET AL

768

TABLE 1 AUTOLOGOUS STEM CELL TRANSPLANT PATIENTS WITH HIV-LYMPHOMA

UPN Diagnosis Disease status HAART Prior chemotherapy Status

202 NHL 1st REL Nf L S CHOP CR 36 mo203 HD 1st REL I L S CHOP IfosVP16 ESHAP CR 30 mo204 NHL 1st PR Nf L S CHOP ESHAP Relapsedeath 4 mo208 NHL 1st CR Nf Nv S CHOP ESHAP CR 24 mo209 HD 1st REL I L BOSE ABVD ESHAP CR 25 mo400 NHL 2nd CR Nf Nv L POG-8617 -9517 and -9317 Relapsedeath 4 mo405 NHL 1st PR I L S CHOP ESHAP RTX CR 26 mo406 NHL 1st CR R S Nv Sa CHOP CR 47 mo407 NHL 3rd CR E L S CHOP IfosVP16 RTX ESHAP CR 29 mo408 NHL 1st CR R S Sa CHOP CR 16 mo409 NHL 1st PR L A Nf CHOP ESHAP Death day 22410a NHL 1st PR L E Sa M-BACOD RTX ESHAP CR 18 mo411 NHL 1st REL S E Nf CHOP ESHAPRTX CR 11 mo412 NHL 1st PR S E L CAV AraCMTX CODOX-M CR 9 mo413 NHL 1st REL L E S CHOP ESHAP RTX CR 13 mo

Abbreviations CR complete response (remission) E efavirenz I indinavir IfosVP16 ifosfamideetoposide L lamivudineNf nelfinavir Nv nevirapine R ritonavir RTX rituxan S stavudine Sa saquinavir CHOP cyclophosphamide adriamycinvincristine prednisone ESHAP etoposide cytarabine cisplatinum prednisone BOSE bleomycin oncovin streptozocin etopo-side ABVD adriamycin bleomycin vincristinevinblastine dacarbazine POG-8617 cyclophosphamide adriamycin cytarabinePOG-9517 same plus methotrexate Ifos VP16 POG-9317 IfosVP16 methotrexate cytoarabine CAV cyclophosphamide 400mg vincritine 2 mg adriamycin 40ndash60 mg AraCMtx cytarabine methotrexate CODOX-M cyclosphamide vincristine adri-amycin methotrexate M-BACOD methotrexate bleomycin doxorubicin cyclophosphamide vincristine cytarabine dexam-ethasone

aAll subjects received autologous stem cell transplant after cyclophosphamide BCNU VP16 (etoposide) (CBV) status at 2-18-02 except UPN 410 received FTBI 1200cgy VP16 (etoposide) cyclophosphamide

This was ascribed to his antiretroviral regimen as hisliver function improved with the discontinuation of thesemedications

CD4 counts reached their nadir at a median of 45months in 8 patients who recovered their CD4 counts topretransplant levels by a median of 9 months One pa-tient who had the highest pretransplant levels did not re-cover his CD4 counts to that level Three patients werenot evaluable due to early death and 3 patients are notfar enough post-transplant to assess recovery from thenadir Of the 12 evaluable patients 7 had transient in-creases in their HIV viral load (VL) during the initial 2years following transplant The main reason for this risewas noncompliance with HAART in 6 patients One pa-tient however required multiple changes in his anti-retroviral regimen due to drug resistance The median vi-ral load has returned to undetectable levels in the majorityof these patients during the first 2 years of follow upHowever 1 patient during year 3 had a rise in his viralload in part due to medication noncompliance Three pa-tients died 1 of regimen-related complications and 2 ofrelapsed lymphoma The other 12 patients are alive andin remission with median follow-up of 243 months(range 86ndash473) (Fig 1)

Investigators from France have also explored the useof stem cell transplantation in HIV lymphomas (35

3644) Their initial series included 8 patients with eitherrelapsed or refractory HIV-associated lymphomas Sim-ilar to the City of Hope practice an attempt was made tokeep patients on HAART during the lymphoma therapyThus 7 of the 8 patients received HAART during the pe-riod of stem cell collection and throughout the transplantAdequate numbers of stem cells a median of 7 3 106

CD341 cellskg were collected from the 8 patients Onepatient died early post-transplant and was not evaluableThe others engrafted white blood cells at a median of 12days a time frame similar to the HIV-negative setting(36) These results were updated at the 2001 meeting ofthe American Society of Hematology and included 14 patients who have undergone autologous transplant 13of whom were treated with concomitant HAART (42)Six patients had HD 3 had Burkittrsquos type NHL 2 im-munoblastic NHL 1 lymphoblastic NHL and of note 1had a primary effusion lymphoma Two of these patientshad primary resistant disease and the remainder were be-tween their first and fourth relapse The conditioning reg-imen was high-dose chemotherapy alone in 6 patients andhigh-dose chemotherapy and TBI in 8 patients Two pa-tients developed CMV infection post-transplant that wasnot associated with organ-specific disease Two of 9 pa-tients with previously undetectable HIV viral loads hadan increase in viral load post-transplant However there


769

FIG 1 Progression-free survival Autologous stem cell transplant for HIV-related lymphoma (n 5 15) (16)

were no statistically significant differences in the viralload and CD41 count pre- and post-transplant for the 14patients Eight patients have died 6 from lymphoma 1from AIDS and 1 from a second tumor Six patients arealive with follow up ranging from 1 to 31 months Hencethis experience too confirms the feasibility of autologousstem cell transplantation in HIV-associated lymphomasand demonstrates that there are minimal increases in in-fectious complications over the HIV-negative transplantsetting In addition the experience of both studies of au-tologous stem cell transplantation for AIDS lymphomademonstrates that immune function can recover post-transplant in the majority of patients who are compliantwith HAART The high recurrence rate noted in theFrench study suggests that an earlier use of autologousstem cell transplantation may be necessary to producelong-term disease-free survival

GENE THERAPY FOR HIV INFECTION

This experience demonstrating the feasibility of stemcell mobilization and administration of myeloablativechemotherapy in HIV-positive individuals formed the ba-sis of trials at the City of Hope exploring the use of genetransfer into stem cells for autologous stem cell rescueas an adjunct to potent anti-HIV therapy The rationalefor this approach is based on the current limitations ofHAART Specifically many compliant patients do notrespond completely to HAART and in addition HAARTregimens are costly and can have unpleasant or toxic sideeffects (45ndash47) Also in spite of the fact that overall im-munity improves with therapy the increase in peripheralblood CD41 T cells often does not reflect new naiveCD41 cells but rather mobilization of committed CD41

cells from reserves (4849) Although some increases innaive cells may be seen over time specific immune func-tion may or may not improve (50ndash52) and thus despitecontinued objective improvement with therapy HIV-1persists (53ndash58) Furthermore of concern is the devel-opment of HAART-resistant strains of HIV-1 arising dur-ing therapy (59ndash64) Thus there is a need for new ther-apeutic options in treating HIV-infected individuals andmore specifically a need for therapies that are less toxicless expensive and less likely to lose efficacy over timeGene therapy might be one such therapeutic option

Hematopoietic stem cells (HSC) are attractive candi-dates for gene therapy because HSC proliferate rapidlyand produce numerous progeny of several lineagesThus the targeting of this self-renewing populationcould provide them and their progeny with a selectiveadvantage over nontransduced cells in the setting ofHIV infection by providing a reservoir of HIV-resistantcells (6566) Early studies of adenosine deaminase

(ADA) deficiency and other diseases showed that ge-netically engineered HSC may persist in the bone mar-row and that their derivatives may persist in the pe-ripheral blood for years (86768) However levels ofcell marking in large animals and in human clinical tri-als have generally been disappointing (67ndash69) Initialclinical trials have underscored the limitations of the useof stem cells and of the transduction methods (870)For example a significant limitation of retroviral genedelivery vectors for CD341 stem cell gene delivery isthat murine retroviruses cannot traverse the nuclearmembrane effectively and therefore require active celldivision for transduction This restriction can be ad-dressed by transducing cells ex vivo using cytokines tostimulate mitosis but this stimulation can induce celldifferentiation (70) Thus this process can result intransgene delivery to lineage-committed cells ratherthan to multipotent hematopoietic progenitor cells(87273) Furthermore retroviral vectors are prone tohave their promoters inactivated resulting in diminish-ing expression over time (65727374) Therefore lev-els of genetically modified cells have been well belowthe therapeutic range (71) Other vectors that apparentlydo not require CD341 cell division for transduction areadeno-associated virus (AAV) and lentiviruses (LV)AAV gene delivery to bone marrow progenitor cells hasbeen reported with varied results (75) The differencesin AAV gene delivery to CD341 cells may reflect widevariability in levels of AAV receptor and co-receptorsby CD341 cells (876ndash78) Gene delivery to HSC bylentiviruses has also been described These viral vectorsdo not require active cell division for effective trans-duction However they are still susceptible to promoterinactivation and thus declining transgene expressionwith time (79ndash81)

A diverse array of transgenes has been developed tosuppress HIV-1 functions These can be separated intotwo main typesmdashRNA elements and proteins The RNAtype used in clinical trials at the City of Hope is a ri-bozyme an RNA molecule that can cleave RNA at spe-cific sequences and can be designed to target HIV atcritical sites such as tat rev and gag (82ndash85) Thesegenes are critical for HIV integration and replication incells

In the City of Hope trial five volunteers (see Table 1UPN202-204208209) with AIDS lymphoma underwentautologous stem cell transplantation and received in ad-dition to unmanipulated stem cells selected CD341 cellstransduced with a retrovirus encoding ribozymes targetedto tat and rev This was a phaseIII study and hence theregimen-related side effects the CD4 counts and HIVRNA levels were followed Engraftment times were sim-ilar to the HIV-negative setting and no increase in regi-men-related toxicity was seen All of the patients were

KRISHNAN ET AL

770

maintained on HAART during the transplant periodHowever these patients did show a transient rise in HIVload immediately after the transplant which returned tobaseline within 10 months In addition the CD4 countsdecreased following transplantation and eventually roseabove baseline by 10ndash12 months post-transplant Thusthe gene manipulation appeared to be safe and did nothave deleterious long-term effects on the underlying HIVinfection

In terms of gene marking the 5 subjects with AIDSlymphoma undergoing CBV (cyclophosphamide BCNU[carmustine] etoposide [VP16]) conditioning beforestem cell transplantation showed a 10- to 50-fold increasein marked cells post-transplant as compared to priorhealthy HIV-infected volunteers who received trans-duced cells without myeloablative chemotherapy (86)However the durability of this engraftment was short-lived There was observable marking in multiple cell lin-eages during the first 6 months post-transplant but thisdeclined to minimum levels of detection over the next 6months The conclusion from this study was that theretrovirus system used did not efficiently transduce un-committed stem cells but only seemed to affect commit-ted progenitors either due to conditions of the transduc-tion or due to the viral vector or to both factors

Other centers have expanded upon the use of stem celltransplantation for treatment of HIV-related malignanciesin a variety of ways such as using syngeneic transplan-tation or nonmyeloablative conditioning regimens in con-junction with genetically modified allogeneic stem cells(8788) In the nonmyeloablative transplant experience2 patients with HIV infection and refractory hematologicmalignancies (primary refractory HD and secondarytreatment related acute myelogenous leukemia) weretreated with a cyclophosphamidefludarabine condition-ing regimen G-CSF-mobilized stem cells were collectedfrom HLA-matched sibling donors These cells wereCD341 selected and then split into two pools One poolwas transduced with either a transdominant Rev an HIVregulatory protein that was engineered to inhibit viralreplication through inhibition of Rev or a control vec-tor Of note HAART therapy was held 1 week prior tothe start of chemotherapy and then resumed when the pa-tient was able to tolerate oral intake The patients toler-ated the transplant procedure well and were dischargedday 19 and day 111 respectively on cyclosporin forgraft-versus-host disease (GVHD) prophylaxis Both pa-tients developed CMV antigenemia that responded totherapy One patient at day 1180 also developed centralnervous system toxoplasmosis Both also developedgrade II acute GVHD of the skin that required treatmentwith prednisone The patient with HD ultimately died ofrecurrent disease at 12 months post-transplant The pa-tient with secondary leukemia remains in remission with

limited chronic skin GVHD In terms of the underlyingHIV infection the HIV viral load remained undetectablefor the majority of follow up except for a brief periodwhere HAART was not taken due to nausea in 1 patientCD4 counts increased to levels above pretransplant lev-els in both patients Effects of gene marking were lesssuccessful Overall marking levels were low 001However the patient available for longer follow up (2years exact duration not reported) by report continues toshow evidence of gene marking There were no signifi-cant differences seen in marking for the anti-rev vectorand the control vector (88)

Despite the lack of long-term gene expression in theCity of Hope trial and the low levels of marking in theNIH trial the experiences demonstrate the feasibility ofusing chemotherapy followed by transplantation in HIV-positive patients with an underlying hematologic malig-nancy These initial experiences open the door for thepossibility for comparative gene-marking trials usingother gene transfer systems In addition the fact that theconditioning regimens were well tolerated opens the doorfor exploration of other conditioning regimens that arecurrently used in the HIV-negative transplant setting Thepresent models for upcoming trials incorporate a combi-nation of manipulated transduced cells in conjunctionwith unmanipulated cells for autologous rescue The rea-son for this is that there is no evidence that vector-trans-duced cells can result in long-term engraftment The NIHtrial used only transduced cells however this was in con-junction with a nonmyeloablative conditioning regimenand therefore host hematopoietic reconstitution was the-oretically possible if the donor cells failed to engraftHowever as we gain more experience with the long-termengraftment of transduced cells it should be possible totransplant only the transduced cells and use frozen un-transduced stem cells as back-up material following fullyablative transplant regimens

CONCLUSIONS

In summary HAART therapy has allowed us to exploremany new therapeutic applications for patients with HIVinfection and its related complications of HIV-related lym-phomas While the effects on lymphoma-free survival areas yet unproved the fact that the transplant procedures werewell tolerated and that long-term engraftment was achievedsuggests that the approach to treatment of relapsed or re-fractory lymphoma in HIV-positive patients should be sim-ilar to the HIV-negative setting Lastly these transplant mo-dalities allow the exploration of gene transfer systems thatmay positively impact the underlying HIV infection andhopefully someday be therapeutic for patients with pro-gressive HIV infection without malignancies


771

ACKNOWLEDGMENTS

This work was supported in part by United States Public Health Service Grants CA30206 CA33572AI38592 and grant MO1 RR-43 from the General Clin-ical Research Center branch of the National Center forResearch Resources National Institutes of Health AKis the recipient of a Lymphoma Research Foundation ofAmerica Fellowship Award AM is the recipient of anAmerican Cancer Society Clinical Oncology Career De-velopment Award The authors thank Sarah Cole andCelina Acedo for statistical support and Diana Garcia formanuscript preparation

REFERENCES

1 Navarro J J Ribera A Oriol M Vaquero J Rombu MBatlle A Flores Milla and E Feliu (2001) Influence ofhighly active anti-retroviral therapy on response to treat-ment and survival in patients with acquired immunodefi-ciency syndrome-related non-Hodgkinrsquos lymphoma treatedwith cyclophosphamide hydroxy doxorubicin vincristineand prednisone Br J Hemat 112909ndash915

2 Palella JrF KM Delaney AC Moorman MO Lovless JFuhrer GA Satten DJ Aschman and SD Holmberg (1998)Declining morbidity and mortality among patients with ad-vanced human immunodeficiency virus infection N EnglJ Med 338853ndash860

3 Ledergerber B A Telenti and M Egger for the Swiss HIVCohort Study (1999) Risk of HIV related Kaposirsquos sar-coma and non-Hodgkinrsquos lymphoma with potent antiretro-viral therapy Prospective cohort study Br Med J 31923ndash24

4 Rabkin C M Testa J Huang and J Von Roem (1999) Ka-posirsquos sarcoma and non-Hodgkinrsquos lymphoma incidenceTrends in AIDS Clinical Trial Group Study ParticipantsJAIDS 21S31ndash33

5 Beral V R Newton and G Reeves (2000) Internationalcollaboration on HIV and cancer JAIDS 23A8

6 Beral V T Peterman R Berkelman and H Jaffee (1991)AIDS associated non-Hodgkinrsquos lymphoma Lancet 337805ndash809

7 Cote TR RF Biggar PS Rosenberg SS Devasa C PercyFJ Yellin G Lemp C Hardy JJ Geodert and WA Blattner(1997) Non-Hodgkinrsquos lymphoma among people withAIDS Incidence presentation and public health burden IntJ Cancer 73645ndash650

8 Levine AM DT Scadden JA Zaia and A Krishnan (2001)Hematologic aspects of HIVAIDS American Society ofHematology Education Book Dec 7 pp 463ndash475

9 Van Dillen N KJ Roozendaal JW Mulder RHJ Van Oerset al (2001) Influence of highly active antiretroviral ther-apy (HAART) on the prevalence and outcome of AIDS re-lated non-Hodgkinrsquos lymphoma (ARL) Blood 98a1462

10 Hessol NA MH Katz JY Lin SP Buchbinder CJ Rubinoand SD Holmberg (1992) Increased incidence of Hodg-kinrsquos disease in homosexual men with HIV infection AnnIntern Med 117309ndash311

11 Levine AM (1998) Hodgkinrsquos disease in the setting of hu-man immunodeficiency virus infection J Natl Cancer Inst2337ndash42

12 Ragni MV SF Dodson SC Hunt FA Bontempo and JJFung (1999) Liver transplantation in a hemophilia patientwith acquired immunodeficiency syndrome Blood 931113ndash1114

13 Campbell P H Iland J Gibson and D Joshua (1999) Syn-geneic stem cell transplantation for HIV related lymphomaBr J Hematol 105795ndash798

14 Molina A A Krishnan A Nademanee R Zabner I Sniecin-ski J Zaia and SJ Forman (2000) High dose therapy andautologous stem cell transplantation for human immunode-ficiency virus associated non-Hodgkin lymphoma in the eraof highly active antiretroviral therapy Cancer 89680ndash689

15 Krishnan A A Molina J Zaia A Nademanee N Kogut JRosenthal D Woo and SJ Forman (2001) Autologousstem cell transplantation for HIV-associated lymphomaBlood 983857ndash3859

16 Krishnan A A Molina J Zaia D Vasquez D Smith S For-man (2002) Durable remissions in HIV-related lymphomawith autologous stem cell transplantation Am Soc Hem(submitted)

17 Levine A L Seneviratne B Espina A Wohl A Tulpule BNathwani and P Gill (2000) Evolving characteristics ofAIDS-related lymphoma Blood 134084ndash4090

18 Mathews GV M Bower S Mandalia T Powles MR Nel-son and BG Gazzard (2000) Changes in acquired immu-nodeficiency syndrome related lymphoma since the intro-duction of highly active antiretroviral therapy Blood962730ndash2734

19 Levine AM J Sullivan-Halley M Pike M Rarick CLoureiro and M Bernstein-Singer (1991) Human immu-nodeficiency virus related lymphoma Prognostic factorspredictive of survival Cancer 682446ndash2471

20 Seneviratne L BM Espina BN Nathwani JA Chan RKBrynes and AM Levine (2001) Clinical immunologicand pathologic correlates of bone marrow involvement in291 patients with acquired immunodeficiency syndrome-related lymphoma Blood 982358ndash2362

21 Thiessard F Morlat C Marimoutou S Laboyries J Rag-naud J Pellegriin M Dupon and F Davis (2000) Prog-nostic factors after non-Hodgkinrsquos lymphoma in patientsinfected with the human immunodeficiency virus Cancer881696ndash1702

22 Straus D J Huang M Testa A Levine and L Kaplan(1998) Prognostic factors in the treatment of human im-munodeficiency virus associated non-Hodgkinrsquos lym-phoma J Clin Oncol 163601ndash3606

23 Kaplan L D Straus M Testa JV Roenn BJ Dezube TPCooley and B Herndor (1997) Low dose compared withstandard dose M-BACOD chemotherapy for non-Hodg-kinrsquos lymphoma associated with human immunodeficiencyvirus infection N Engl J Med 3361641ndash1648

24 Levine AM P Li T Cheung A Tulpule J Von Roenn BNNathwani and L Ratner (2000) Chemotherapy consistingof DTIC with G-CSF in HIV infected patients with newlydiagnosed Hodgkinrsquos disease A prospective multi-institu-tional AIDS Clinical Trials Group Study (ACTG 149)JAIDS 24444ndash450

KRISHNAN ET AL

772

25 Spina M E Gabarre E Vaccher et al (2001) Feasibilityof integration of Stanford V chemotherapy with highly ac-tive anti-retroviral therapy and G-CSF in patients withHodgkinrsquos disease and HIV infection 5th InternationalAIDS Malignancy Conference April 23ndash25 2001 BethesdaMD p A24

26 Sparano J P Wiernik X Hu C Sarta E Schwartz and RSoiero (1996) Pilot trial of infusional cyclophosphamidedoxorubicin and etoposide plus didanosine and filgastrimin patients with human immunodeficiency virus-associatednon-Hodgkinrsquos lymphoma J Clin Oncol 143026ndash3035

27 Sparano J S Lee DH Henry et al (2000) Infusional cy-clophosphamide doxorubicin and etoposide in HIV asso-ciated non-Hodgkinrsquos lymphoma 4th AIDS MalignancyConference May 16ndash18 2000 Bethesda MD J AcquirImmune Def Synd 23A11

28 Little R D Pearson Steinberg P Elwood R Yarchoan andW Wilson (1999) Dose adjusted EPOCH chemotherapyin previously untreated HIV associated non-Hodgkinrsquoslymphoma (HIV-NHL) Proc Am Soc Clin Oncol 1810a(Abstract 33)

29 Bai JIA BM Espina A Tulpule W Boswell and AMLevine (2001) High dose cytosine-arabinose and cisplatinregimens as salvage therapy for refractory or relapsedAIDS-related non-Hodgkinrsquos lymphoma JAIDS 27416ndash421

30 Tulpule A BM Espina M Palmer J Schiflett P Gill andAM Levine (1997) Treatment of relapsedrefractoryAIDS-related lymphomas (AIDS-NHL) with high dose cy-tarabine (ARA-C)Cisplatin combination regimens Blood90 (Abstract 1525)

31 Barrett JC CA Linn RB Arani J Rosenberg and MN Saleh(1999) A pilot study of anti-CD20 MoAB rituximab inAIDS-associated non-Hodgkinrsquos lymphoma Blood94(10)258b (Abstract 4361)

32 Ratner L D Redden F Hamzeh A Levine W Harringtonand D Scadden (1999) Chemotherapy for HIV-associatednon-Hodgkinrsquos lymphoma (HIV-NHL) in combinationwith highly active antiretroviral therapy (HAART) is notassociated with excessive toxicity National AIDS Malig-nancy Conference 1999

33 Weiss R P Mitrou A Keikawus D Shurmann and D Huhn(2001) HIV related lymphoma HAART parallel to CHOPchemotherapy is safe and improves survival Blood 98a1463

34 Contu L G LaNasa M Arras A Pizzatti A Vacca C Car-cassi A Ledda R Boero S Orru A Pintus L Schivo GFaa V Costa and F Pitzus (1993) Allogeneic bone mar-row transplantation combined with multiple anti-HIV treat-ment in a case of AIDS Bone Marr Transpl 12669ndash671

35 Gabarre J V Leblond L Sutton N Azar M Jouan C Boc-cacio H Gonzalez F Charlotte M Gentilini and JL Binet(1996) Autologous bone marrow transplantation in re-lapsed HIV-related non-Hodgkinrsquos lymphoma Bone MarrTranspl 181195ndash1197

36 Gabarre J N Azir B Autran C Katlama and V Leblond(2000) High-dose therapy and autologous hematopoieticstem cell transplantation for HIV-1 associated lymphomaLancet 3551071ndash1072

37 Koka PS BD Jamieson DG Brooks and JA Zack (1999)

Human immunodeficiency virus type 1-induced hemato-poietic inhibition is independent of productive infection ofprogenitor cells in vivo J Virol 739089

38 Shen H T Cheng FL Preffer D Dombkowski MH Tomas-son DE Golan O Yang W Hofmann JG Sodroski ADLuster and DT Scadden (1999) Intrinsic human immuno-deficiency virus type-1 resistance of hematopoietic stemcells despite coreceptor expression J Virol 73728ndash737

39 Junker U JJ Moon I Sniecinski JA Zaia E Bohnlein andH Kaneshima (1996) HIV status and function of G-CSFmobilized peripheral blood hematopoietic stem cells fromasymptomatic HIV-1 infected individuals implications foranti-HIV gene therapy Blood 88271a

40 Isgro A I Mezzaroma A Aiuti L De Vita F Franchi FPandolfi C Alario F Ficara E Riva G Antonelli and FAiuti (2000) Recovery of hematopoietic activity in bonemarrow from human immunodeficiency virus type-1 in-fected patients during highly active antiretroviral therapyAIDS Res Hum Retroviruses 161471

41 Schooley RT J Mladenovic A Sevin S Chiu SA MilesRJ Pomerantz TB Campbell D Bell D Ambruso R WongA Landay RW Coombs L Fox M Kamoun and J Jacovini(2000) Reduced mobilization of CD341 stem cells in ad-vanced human immunodeficiency virus type-1 disease JInfect Dis 181148ndash157

42 Philip T C Gugliermi A Hagenbeek R Somers H Vander Lelie D Bron P Sonneveld C Gisselbrecht JY Cahnand JL Harousseau (1995) Autologous bone marrow trans-plantation as compared with salvage chemotherapy in re-lapses of chemotherapy sensitive non-Hodgkinrsquos lym-phoma N Engl J Med 3331540ndash1545

43 Nademanee A A Molina MR OrsquoDonnell A Dagis DSSnyder P Parker A Stein E Smith I Planas A KashyapR Spielberger H Fung KK Wong G Somlo K MargolinW Chow I Sniecinski N Vora KG Blume J Niland andSJ Forman (1997) Results of high dose therapy and au-tologous bone marrowstem cell transplantation in poor-risk intermediate and high-grade lymphoma InternationalIndex High and High-Intermediate Risk Group Blood903844ndash3852

44 Gabarre J S Choquet N Azar R Kobt et al (2001) Highdose chemotherapy (HDC) with autologous stem cell trans-plantation (AST) for HIV-associated lymphoma (Ly) Asingle center report on 14 patients (pts) Blood 98a2092

45 drsquoArminio Monforte A L Testa E Adorni E Chiesa T BiniGC Moscatelli C Abeli S Rusconi S Sollima C BallotaM Musicco M Galli and M Moroni (1998) Clinical out-come and predictive factors of failure of highly active anti-retroviral therapy in antiretroviral-experienced patients in ad-vanced stages of HIV-1 infection AIDS 121631ndash1637

46 Gulick RM JW Mellors D Havlir JJ Eron C GonzalezD McMahon DD Richmann FT Valentine L Jonas AMeibohm EA Emini and JA Chodakewitz (1997) Treat-ment with indinavir zidovudine and lamivudine in adultswith human immunodeficiency virus infection and prior an-tiretroviral therapy N Engl J Med 337734ndash739

47 Lucas GM RE Chaisson and RD Moore (1999) Highlyactive antiretroviral therapy in a large urban clinic Riskfactors for viroogic failure and adverse drug reactions AnnIntern Med 13181ndash87


773

48 Bucy RP RD Hockett CA Derdeyn MS Saag K SquiresM Sillers RT Mitsuyasu and JM Kilby (1999) Initial in-crease in blood CD41 lymphocytes after HIV antiretrovi-ral therapy reflects redistribution from lymphoid tissues JClin Invest 1031391ndash1398

49 Evans TG W Bonnez HR Soucier T Fitzgerald DC Gib-bons and RC Reichman (1998) Highly active antiretrovi-ral therapy results in a decrease in CD81 T cell activationand preferential reconstitution of the peripheral CD41 Tcell population with memory rather than naive cells Anti-viral Res 39163ndash173

50 Haase AT (1999) Population biology of HIV-1 infectionviral and CD41 T cell demographics and dynamics in lym-phatic tissue Annu Rev Immunol 17625ndash656

51 Martinon F C Michelet I Peguillet Y Taoufik P LefebvreC Goujard JG Guillet JF Delfraissy and O Lantz (1999)Persistent alterations in T-cell repertoire cytokine andchemokine receptor gene expression after 1 year of highlyactive antiretroviral therapy AIDS 13185ndash194

52 Zanussi S C Simonelli MT Bartolin M DrsquoAndrea CCrepaldi E Vaccher G Nasti D Politi L Barzan U Tirelliand P DePaoli (1999) Immunological changes in periph-eral blood and in lymphoid tissue after treatment of HIV-infected subjects with highly active anti-retroviral therapy(HAART) or HAART1 IL-2 Clin Exp Immunol 116486ndash492

53 Chun TW D Engel MM Berrey T Shea L Corey and ASFauci (1998) Early establishment of a pool of latently in-fected resting CD4(1) T cells during primaryHIV-1 in-fection Proc Natl Acad Sci USA 958869ndash8873

54 Finzi D M Hermankova T Pierson LM Carruth C BuckRE Chaisson TC Quinn K Chadwick J Margolick RBrookmeyer J Gallant M Markowitz DD Ho DD Rich-man and RF Siliciano (1997) Identification of a reservoirfor HIV-1 in patients on highly active antiretroviral ther-apy Science 2781295ndash1300

55 Ho DD (1998) Toward HIV eradication or remission Thetasks ahead Science 2801866ndash1867

56 Natarajan V M Bosche JA Metcalf DJ Ward HC Laneand JA Kovacs (1999) HIV-1 replication in patients withundetectable plasma virus receiving HAART highly activeantiretroviral therapy Lancet 353119ndash120

57 Finzi D J Blankson JD Siliciano JB Margolick K Chad-wick T Pierson K Smith J Lisziewicz F Lori C FlexnerTC Quinn RE Chaisson E Rosenberg B Walker S GangeJ Gallant and RF Siliciano (1999) Latent infection ofCD41 T cells provides a mechanism for lifelong persis-tence of HIV-1 even in patients on effective combinationtherapy Nature Med 5512ndash517

58 Zhang H G Dornadula M Beaumont L Jr Livornese BVan Uitert K Henning and RJ Pomerantz (1998) Humanimmunodeficiency virus type 1 in the semen of men re-ceiving highly active antiretroviral therapy N Engl J Med3391803ndash1809

59 Jimenez-Nacher I R Rodriguez-Rosado P Anton V Sori-ano and J Gonzalez-Lahoz (1998) Virological failure andadherence to antiretroviral therapy in HIV-infected pa-tients Int Conf AIDS 12591 32350a

60 Ledergerber B M Egger M Opravil A Telenti B Hirschel

M Battegay P Vernazza P Sudre M Flepp H Furrer PFrancioli and R Weber (1999) Clinical progression andvirological failure on highly active antiretroviral therapy inHIV-1 patients a prospective cohort study Swiss CohortStudy Lancet 353863ndash868

61 Schapiro JM MA Winters J Lawrence and TC Merigan(1999) Clinical cross-resistance between the HIV-1 pro-tease inhibitors saquinavir and indinavir and correlationswith genotypic mutations AIDS 13359ndash365

62 Vandamme AM K Van Laethem and E DeClerq (1999)Managing resistance to anti-HIV drugs An important con-sideration for effective disease management Drugs 57337ndash361

63 Wit FW R van Leeuwen GJ Weverling S Jurriaans KNauta R Steingrover J Schuijtemaker X Eyssen D For-tuin M Weeda F de Wolf P Reiss SA Danner and JMLange (1999) Outcome and predictors of failure of highlyactive retroviral therapy One year follow-up of a cohort ofhuman immunodeficiency virus type 1-infected persons JInfect Dis 179790ndash798

64 Wei X SK Ghosh ME Taylor VA Johnson EA Emini PDeutsch JD Lifson S Bonhoeffer MA Nowak BH HahnMS Saag and GM Shaw (1995) Viral dynamics in humanimmunodeficiency virus type 1 infection Nature 373117ndash122

65 Richter J (1997) Gene transfer to hematopoietic cells-theclinical experience Br J Haematol 5967ndash75

66 Rosenzweig M DF Marks D Hempel J Lisziewicz andRP Johnson (1997) Transduction of CD341 hematopoi-etic progenitor cells with an anti-tat gene protects T-celland macrophage progeny from AIDS virus infection J Vi-rol 712740ndash2746

67 Dunbar CE M Cottler-Fox JA OrsquoShaughnessy S DorenC Carter R Berenson S Brown RC Moen J GreenblattFM Stewart SF Leitman WH Wilson K Cowan NSYoung and AW Nienhuis (1995) Retrovirally markedCD34-enriched peripheral blood and bone marrow cellscontribute to long-term engraftment after autologous trans-plantation Blood 853048

68 Van Beusechem VW A Kukler PJ Heidt and D Valerio(1992) Long-term expression of human adenosine deami-nase in rhesus monkeys transplanted with retrovirus-in-fected bone-marrow cells Proc Natl Acad Sci USA 897640ndash7644

69 Xu LC S Karlsson ER Byrne S Kluepfel-Stahl SWKessler BA Agricola S Sellers M Kirby CE Dunbar ROBrady AW Nienhuis and RE Donahue (1995) Long-termin vivo expression of the human glucocerebrosidase genein nonhuman primates after CD341 hematopoietic celltransduction with cell-free retroviral vector preparationsProc Natl Acad Sci USA 924372ndash4376

70 Kohn DB KI Weinberg JA Nolta LN Heiss C LenarskyGM Crooks ME Hanley AG Annett JS Brooks A El-Khoureiy K Lawrence S Wells K Shaw RC Moen J Bas-tian DE Williams-Herman M Elder D Wara T BowenMS Hershfield CA Mullen RM Blaese and R Parkman(1995) Engraftment of gene-modified umbilical cord bloodcells in neonates with adenosine deaminase deficiency Na-ture Med 11017ndash1023

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774

71 Dunbar CE and NS Young (1996) Gene marking and genetherapy directed at primary hematopoietic cells Curr Opin-ion Hematol 3430ndash437

72 Kerr WG (1998) Genetic modification of the hema-tolymphoid compartment for therapeutic purposes Hema-tol Oncol Clin NA 12503ndash518

73 von Kalle C H Glimm G Schultz R Mertelsmann and RHenschler (1998) New developments in hematopoieticstem cell expansion Curr Opinion in Hematol 579ndash86

74 Peterson R G Kempler and E Barklis (1991) A stem cell-specific silencer in the primer-binding region of a retro-virus Mol Cell Biol 111214ndash1221

75 Chatterjee S and KK Wong Jr (1996) Adeno-associatedvirus vectors for gene therapy of the hematopoietic systemCurr Topics Microbiol Immunol 21861ndash73

76 Ponnazhagan S P Mukherjee XS Wang K Qing DMKube C Mah C Kurpad MC Yoder EF Srour and A Sri-vastava (1997) Adeno-associated virus type 2-mediatedtransduction in primary human bone marrow-derivedCD341 hematopoietic progenitor cells donor variationand correlation of transgene expression with cellular dif-ferentiation J Virol 718262ndash8267

77 Qing K C Mah J Hansen S Zhou V Dwarki and A Sri-vastava (1999) Human fibroblast growth factor receptor1 is a co-receptor for infection by adeno-associated virus2 Nature Med 571ndash77

78 Summerford C JS Bartlett and RJ Somulski (1999) Al-pha Vb5 integrin a co-receptor for adeno-associated virus2 Nature Med 578ndash82

79 Poeschla EM F Wong-Staal and DJ Looney (1998) Effi-cient transduction of nondividing human cells by feline im-munodeficiency virus lentiviral vectors Nature Med 4354ndash357

80 Zufferey R D Nagy RJ Mandel L Naldini and D Trono(1997) Multiply attenuated lentiviral vector achieves effi-cient gene delivery in vivo Nature Biotechnol 15871ndash875

81 Miyoshi H KA Smith DE Mosier IM Verma and BE Tor-bett (1999) Transduction of human CD341 cells that me-diate long-term engraftment of NODSCID mice by HIVvectors Science 283682ndash685

82 Bai J S Gorantla N Banda L Cagnon J Rossi and RAkkina (2000) Characterization of anti-CCR5 ribozyme-transduced CD341 hematopoietic progenitor cells in vivoMolec Ther 1244ndash254

83 Bauer G P Valdez K Kearns I Bahner SF Wen JA Zaia

and DB Kohn (1997) Inhibition of human immunodefi-ciency virus-1 (HIV-1) replication after transduction ofgranulocyte colony-stimulating factor-mobilized CD341

cells from HIV-1 infected donors using retroviral vectorscontaining anti-HIV-1 genes Blood 892259ndash2267

84 Ojwang JO A Hampel DJ Looney R Wong-Staal and JRappaport (1992) Inhibition of human immunodeficiencyvirus type 1 expression by a hairpin ribozyme Proc NatlAcad Sci USA 8910802ndash10806

85 Sarver N EM Cantin PS Chang JA Zaia PA Landne DAStephens and JJ Rossi (1990) Ribozymes as potential anti-HIV-1 therapeutic agents Science 2471222ndash1225

86 Zaia JA JJ Rossi A Krishnan JI Ito D Castanotto S LiP Yam G Bauer D Selander S Csik JM Rossi H Li VBanh W Tseng S Sauter A Molina V Parker DJ Jolly ISniecinski SJ Forman and DB Kohn (1999) Autologousstem cell transplantation using retrovirus-transduced pe-ripheral blood progenitor cells in HIV-infected personscomparison of gene marking post-engraftment with andwithout myeloablative therapy Blood 942850a

87 Lane HC KM Zunich W Wilson F Cefal M Easter J Ko-vacs H Masur S Leitman HG Klein R Steis D Longoand AS Fauci (1990) Syngeneic bone marrow transplan-tation and adoptive transfer of peripheral blood lympho-cytes combined with zidorudine in human immunodefi-ciency virus (HIV) infection Ann Int Med 113512ndash519

88 Kang E M de Witte H Malech RA Morgan S Phang CCarter SF Leitman R Childs AJ Barrett R Little and JFTisdale (2002) Nonmyeloablative conditioning followedby transplantation of genetically modified HLA matchedperipheral blood progenitor cells for hematologic malig-nancies in patients with acquired immunodeficiency syn-drome Blood 99698ndash701

Address reprint requests toAmrita Krishnan MD

City of Hope National Medical Center1500 E Duarte Road

Duarte CA 91010

E-mail akrishnancohorg

Received February 22 2002 accepted April 8 2002


775

(812ndash15) This review addresses three areas the back-ground rationale for use of high-dose chemotherapy inAIDS lymphoma the experience to date with autologousand allogeneic stem cell transplantation in this diseaseand the potential for the use of myeloablative and non-myeloablative therapy with stem cell transplantation asthe basis for gene transfer into stem cells as treatment forHIV infection

BACKGROUND

With the advent of HAART clinical characteristics ofHIV-NHL have changed The median CD4 lymphocytecount at lymphoma diagnosis has decreased reflectingthe fact that lymphoma is often a late manifestation ofHIV infection The pathologic spectrum of disease hasalso changed with a decrease in the prevalence of smallnoncleaved lymphoma and an increase in diffuse large-cell lymphoma (1718) HIV-related HD is also charac-terized by a different histopathologic predominance fromthe HIV-negative setting with the mixed cellularity sub-type predominating The median survival for both HIV-NHL and -HD remains poor and is far below that ob-served in the HIV-negative setting (1117)

Prognostic factors for HIV-NHL can be divided intothose reflecting the severity of the underlying HIV in-fection and those directly related to the lymphoma Anearly study by Levine and colleagues observed that per-formance status prior AIDS diagnosis and bone marrowinvolvement were strongly associated with shortened sur-vival (17) A more recent study from the same center fur-ther evaluated the significance of bone marrow involve-ment It revealed that factors associated with decreasedsurvival in marrow-positive patients included 50marrow involvement with lymphoma B symptoms andhigh-grade histologic type (20) The international prog-nostic index for lymphoma has also been applied to HIV-NHL and was found to be predictive of survival in threestudies (82122)

Early therapeutic approaches to HIV-related lym-phomas focused on reduction of chemotherapy dose in-tensity due to fears of further worsening the immunefunction in these individuals after administration of stan-dard dose regimens A randomized trial comparing low-dose M-BACOD (methotrexate bleomycin doxorubicincyclophosphamide vincristine dexamethasone) withstandard dose M-BACOD in conjunction with cytokinesupport was conducted by the US AIDS clinical trialgroup and the results further reinforced the early con-cept that higher-dose chemotherapy was not better Therewere no significant differences in overall survival anddisease-free survival between the low-dose and standard-dose groups and greater hematologic toxicity in the stan-dard-dose group although the median survivals of 31

and 35 weeks was far below that one would expect in theHIV-negative setting (23) However this study was per-formed before the widespread availability of protease in-hibitor-based therapy For patients with HIV-HD the useof standard-dose ABVD (adriamycin bleomycin vin-blastine dacarbazine) chemotherapy and growth factorsupport has been explored in a multicenter trial (24)Again the incidence of hematologic toxicity was highand median survival was poor at only 18 months Simi-larly the majority of these patients were not on HAARTIn contrast a study using concomitant HAART and a rel-atively new intense weekly multidrug regimen ldquoStanfordVrdquo showed higher remission rates and improved disease-free survival (25)

Several investigators have studied the efficacy of in-fusional chemotherapy either as initial treatment or forrelapsed HIV-NHL Sparano and colleagues reportedhigh response rates with cyclophosphamide doxorubicinand etoposide given in combination with single agent an-tiretroviral therapy (didanosine ddI) and more recentlywith HAART (2627) Although response rates were thesame in the group treated with concomitant ddI versusthose on HAART the median survival was higher in thegroup on HAART Investigators at the National CancerInstitute have utilized a dose-adjusted schedule ofEPOCH (etoposide vincristine doxorubicin cyclophos-phamide prednisone) in untreated patients Initial com-plete remission (CR) rates were 79 with as yet no re-lapse of lymphoma in the CR group (28) Of noteantiretroviral therapy was withheld until day 6 of the lastdose of chemotherapy due to concerns of drug interac-tions In that study the HIV viral load increased dra-matically by cycle four of chemotherapy in most patientsbut did return to pretreatment levels with the resumptionof antiretroviral therapy The treatment of relapsed dis-ease with the infusional regimen ESHAP (etoposide sol-umedrol Ara-C platinol) has shown promise with re-sponse rates of 54 and median survival of 7 months(2930) Future studies are addressing the role of mono-clonal antibody therapy with rituximab in conjunctionwith chemotherapy either for newly diagnosed disease orfor treatment of relapse (31) For relapsed HIV-HD theoptimal salvage regimen is even less clear and againcisplatinum-based salvage regimens have been used

CHEMOTHERAPY ANDANTIRETROVIRAL THERAPY

The advent of effective protease inhibitor-based anti-retroviral therapy has raised the question Could survivalof AIDS lymphoma be improved by combining HAARTwith conventional dose chemotherapy There are bothadvantages and disadvantages to combining chemother-apy and anti-HIV therapy One possible advantage is that

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ACKNOWLEDGMENTS


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CONCLUSIONS



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ACKNOWLEDGMENTS


REFERENCES

























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CONCLUSIONS



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ACKNOWLEDGMENTS


REFERENCES

























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Duarte CA 91010




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CONCLUSIONS



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ACKNOWLEDGMENTS


REFERENCES

























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KRISHNAN ET AL

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Duarte CA 91010




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CONCLUSIONS



771

ACKNOWLEDGMENTS


REFERENCES

























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KRISHNAN ET AL

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Duarte CA 91010




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CONCLUSIONS



771

ACKNOWLEDGMENTS


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773

























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Duarte CA 91010




775

ACKNOWLEDGMENTS


REFERENCES

























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Documents

Stem Cell Transplantation and Gene Therapy for HIV-Related Lymphomas