Hematopoietic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma

May 1, 2003

High-dose myeloablative therapy with autologous or allogeneicstem cell rescue is an effective treatment strategy for non-Hodgkin’slymphoma (NHL), but NHL is much less likely to stay in remission afteran autologous transplant than after an allogeneic transplant. Thebenefit of undergoing an autologous transplant earlier in the course ofthe disease, especially for patients who present with intermediate orhigh scores on the International Prognostic Index of risk factors, is stillunclear. The addition of immunotherapy, biologic modifiers, andantibody therapy such as rituximab (Rituxan) or radiolabeled antibodyto the autologous transplant are approaches undergoing evaluation.Historically, there has been a high regimen-related mortality rateassociated with myeloablative allogeneic transplant that has made thisapproach a less appealing option for therapy. The use of nonmyeloablativeallogeneic transplants as treatment for NHL is less well studiedand remains to be defined.

F

or clinicians, the most practicalway to approach the treatmentof non-Hodgkin's lymphomais based on the clinical behaviorof the disease. Hematopoieticstem cell transplantation (HSCT) hasbeen the backbone of the therapeuticoptions for treating aggressive (intermediate-and high-risk) disease thathas relapsed or does not respond toinitial therapy. Its role in the treatmentof indolent lymphomas has beenmore commonly applied in patientswith multiply relapsed or refractorydisease. In some cases, such as chemotherapy-sensitive, relapsed aggressiveNHL, HSCT results in a durableremission and is superior to conventionalsalvage therapy.[1,2] Theremay be a role, however, for an earlierHSCT in patients with poor prognosticfactors at the time of initialdiagnosis. In this review, we will summarizethe treatment of indolent andaggressive NHL with HSCT and commenton the evolving role of newhematopoietic stem cell transplant-based therapies.

Indolent Non-Hodgkin'sLymphoma

The role of HSCT in treating indolentlymphoma has been limitednot only by the heterogeneity of thedisease and its chronicity with manylong-term survivors, but also by highrates of transplant-related mortalitywith allogeneic HSCT and high ratesof relapse after autologous HSCT.

Autologous Transplants


Autologous transplants in thissetting have an observed regimenrelatedtoxicity rate that is similar tothat seen with other HSCT-treateddiseases. In most cases, the regimenrelatedmortality rate is about 5% to10%. However, most published studiesreport a continual relapse rate withno obvious plateau in the survivalcurves. Thus, autologous HSCT isnot curative therapy for the majorityof indolent lymphomas treated withcurrent regimens.[3,4] Relapses arethought to be due to both the inabilityto eradicate the tumor cells and tumor contamination of the infusedstem cell product.

In Vitro Purging inAutologous Transplantation


Numerous groups, includingFreedman et al,[5] have reported thatpatients who receive autologousgrafts that are not contaminated withlymphoma cells by polymerase chainreaction (PCR) analysis have a statisticallyhigher initial disease-freesurvival rate, compared to patientswith PCR-contaminated stem cells.As a result, considerable effort hasgone into studying the best way topurge grafts of tumor contaminantcells. The earliest such studies centeredon positive selection of CD34cells. Other approaches have focusedon tumor elimination by antitumorantibodies and complement or chemotherapyexposure with drugs suchas 4-hydroperoxycyclophosphamideor mafosfamide.Initially, improved disease-freesurvival was reported in patients whounderwent autologous bone marrowpurging with a cocktail of anti-B cellmonoclonal antibodies.[6] Greaterthan a 3 log depletion of follicularlymphoma cells was achieved, andno lymphoma cells could be detectedin 50% of treated patients. Patientswho had PCR-detected residual lymphomacells in their stem cell productwere initially more likely torelapse posttransplant, with a relapserate of 39% (vs 5% in PCR-negativepatients) after a median follow-up of23 months (

P

In Vivo Purging inAutologous Transplantation
Recently, interest has focused onin vivo purging. Antibodies such asrituximab (Rituxan), given prior tohigh-dose chemotherapy, appear toincrease the sensitivity of lymphomacells to chemotherapy. Rituximab hasbeen studied by numerous investigators,in many cases administered withmobilization regimens for collectingperipheral blood stem cells (PBSC)in mantle cell and indolent NHLpatients.[10-12]In a small pilot study, Magini etal[11] showed that 93% of patientsreceiving rituximab with chemotherapyhad a PCR-negative stem cellgraft, compared to 40% of controlcases. When granulocyte colonystimulatingfactor (G-CSF, Neupogen)alone is used for mobilizationof PBSC with rituximab, two or moredoses of rituximab should be givenbefore PBSC collection to get theleast contaminated product. Thus,several groups have shown that rituximabcan render a stem cell productfree of contaminating tumor cellsby PCR while having no adverse effectson the collection of an adequatenumber of stem cells or on engraftmentposttransplant.Rituximab has also been administeredpost-HSCT. Brugger et al[13]treated patients with follicular andmantle cell NHL with four weeklydoses of rituximab after autologousHSCT. Following total-body irradiationand high-dose chemotherapy, thecomplete response rate was 44%, andafter the addition of rituximab to thetransplant regimen, this rate initiallyincreased to 57% and continued toimprove over time. By 1 year, it was88%, and by 2 years, all follicularNHL patients and 90% of mantle celllymphoma patients were in completeremission. Following high-dose therapy,48% of evaluable patients hadno evidence of disease by PCR. Immediatelyafter rituximab therapy,this parameter improved to 80%, andat 6 months posttransplant, it was100%. Leukopenia and infectionswere reported.Horwitz et al[14] studied the administrationof rituximab alone posttransplantin more aggressive NHLor transformed B cell NHL, reportinggrade 3/4 neutropenia in 9 of 20patients. Flinn et al[10] also reportedlate infection problems, with threedeaths in the first year posttransplantas well as neutropenia, disseminatedherpes zoster, and atypical mycobacterialinfections.Thus, rituximab therapy appearsto be deliverable with good results inthis setting. However, increasing evidencesuggests that some patients(at least 25% to 45%)[10,13,14] alsodevelop transient neutropenia aftertransplant, and there may be an increasedrisk of infection. Randomizedcontrolled studies of rituximabuse in an autologous transplant settingare lacking. In the future, otherantibodies such as CD22 and CD40will be similarly studied. It may bethat the most effective therapy willinvolve a combination of antibodies,similar to what has been reported forin vitro purging.

Targeted Therapy inAutologous Transplants


Another area of active researchhas been to give targeted therapy, ie,using radiolabeled antibody, combinedwith chemotherapy and followedby autologous stem cell rescue.This targeted radiotherapy is basedon the fact that hematologic malignanciesare sensitive to radiation. Inaddition, the antibody is not internalized,nor does it need to activate animmune response to generate an antitumoreffect. Based on the isotopetagged to the antibody and its penetration,the radiolabeled antibodydoes not need to reach every malignantcell for it to be effective.Different radiolabeled antibodiesto anti-CD20 have been used in an autologous transplant setting.[15-19]In a phase I/II study of iodine-131tositumomab (anti-CD20, Bexxar),etoposide, and cyclophosphamide(Cytoxan, Neosar), Press et al[17] reportedthat the maximum tolerated doseof the anti-CD20 monoclonal antibodywas 25 Gy, with etoposide, 60 mg/kg,and cyclophosphamide, 100 mg/kg.The reported time to engraftment andtoxicity data were similar to historicalresults with total-body radiation, etoposide,and cyclophosphamide therapy.Overall survival at 2 years was83%, and the progression-free survivalrate at 2 years was 68%. Approximately21% developed a humanantimurine antibody. The results havebeen encouraging, but which radioisotopeand regimen will prove to be themost effective and practical to deliverremains unknown.Many of the radiolabeled antibodystudies published to date have beenrestrictive in their eligibility requirements,for example, requiring noevidence of enlarged spleen and lowtumor burden of no more than500 cc. Randomized studies are neededto show an increased benefit inpatients, for example, with increasedsurvival and disease-free survivalassociated with the radiolabeled antibody-containing regimens. Longtermfollow-up is also needed toaddress the issue of whether secondarymalignancies are more likely tooccur with intensified radiolabeledtargeted therapy.

Unique Problems WithAutologous Transplant


Unique issues arise with respectto transplanting low-grade lymphoma.Fludarabine (Fludara) is commonlyused as conventional therapyto treat the disease, and its use mayaffect the ability to mobilize stemcells.[20] Autologous transplants arealso problematic in this setting, giventhe high rate of secondary cancersreported, including myelodysplasticsyndrome (MDS)/acute myelogenousleukemia (AML), for which incidencerates are as high as 20%.[9,21]

Timing of Autologous Transplant


Recently, investigators haveplaced much emphasis on moving autologous HSCT up earlier in patientswith poor prognostic factors.Colombat et al[22] treated 29 patients,with 7 in first complete remissionat a median follow-up of 6 years.The overall survival was 64%, andthe actuarial event-free survival was55%. Tarella et al[23] treated 46 patientswith advanced low-grade NHL;17 had small lymphocytic lymphoma,29 had follicular lymphoma, and 10also had histologic transformation.Patients received tumor debulking bytwo courses of APO (doxorubicin[Adriamycin], prednisone, vincristine[Oncovin], methotrexate, asparaginase[Elspar], mercaptopurine [Purinethol])and two courses of DHAP(dexamethasone, high-dose cytarabine[Ara-C], cisplatin [Platinol]),sequential administration of highdoseetoposide, methotrexate, and cyclophosphamidewith stem cellharvest, and high-dose mitoxantrone(Novantrone) and melphalan (Alkeran)with PBSC infusion. Ten follicularlymphoma patients had ex vivopurging of stem cells. At a medianfollow-up of 4.3 years, the estimated9-year overall survival was 84% andprogression-free survival was 45%.Follicular lymphoma patients hadlonger survival without evidence ofdisease-59% vs 17% for small lymphocyticlymphoma patients. Theseresults indicate that there may belonger progression-free survival afterautologous transplant if it is partof the up-front therapy.Thus, we need to address the issueof whether a randomized study shouldbe conducted in patients with intermediateand high scores on the InternationalPrognostic Index (IPI) of riskfactors, comparing the addition of afront-line autologous HSCT after conventionaltherapy. Indeed, front-lineautologous transplant may be veryrelevant for the long-term benefit ofpatients. As oncologists, we tend totreat patients with multiple cycles ofdifferent therapeutic regimens andhave in the past relied heavily onalkylating agents. As we treat patientsmore intensely for longer periodsof time, we can expect to seemore secondary cancers-especiallyMDS/AML. The use of autologoustransplant upfront and the decreasing use of multiple regimens of therapyinitially may prolong the time to thedevelopment of MDS. If we conductsuch studies in the future, we need touse molecular correlating studies (eg,microarray assays) to help identifypatients that do benefit from upfronttransplants.

Immunotherapy andBiologic Modifier TherapyAfter Autologous Transplant


Indolent NHL may be a better targetfor immunotherapy approaches, inboth autologous and allogeneic settings.Several different approaches arebeing used to study the addition ofimmunotherapy to an autologoustransplant to reduce relapse rates.These strategies include treatmentwith immune stimulators such asdose-intensive interleukin-2 (IL-2,Proleukin) therapy,[24] IL-2-incubatedstem cells with sequentialIL-2,[25,26] and low-dose IL-2 withor without rituximab.[27] In indolentlymphoma, vaccination with idiotypespecificvaccines after transplant is analternative approach to be furtherstudied. Again, no randomized studieshave shown evidence of efficacywith immunotherapy in this setting,but the randomized Southwest OncologyGroup study of dose-intense IL-2after an autologous transplant is stillongoing. Other biologic modifierssuch as bcl-2 antisense for maintenancetherapy after autologous transplantalso need to be investigated.

Myeloablative andNonmyeloablativeAllogeneic Transplants


Allogeneic transplants offer theadvantage of a "clean" stem cell productand a graft-vs-lymphoma effect.With a myeloablative allogeneictransplant, there is the risk of developinggraft-vs-host disease (GVHD)and a high regimen-related mortalityrate. International Bone MarrowTransplant Registry data for myeloablativeregimens shows a transplantrelatedmortality rate of 40% to 50%,with an event-free survival rate of49%. The high regimen-related mortalityrate has limited the use of myeloablativeallogeneic transplants. Itshould be noted, however, that there is a plateau in survival in these allogeneictransplant recipients. Becauseof the high associated upfront mortalityrate, myeloablative allogeneictransplants have never shown a survivaladvantage.In particular, patients with a historyof multiple therapeutic regimensalso seem to have an increased riskof complications. T-cell depletion orantithymocyte globulin (Thymoglobulin)therapy is being used by many centers to cut down on GVHD incidence,but these approaches usuallyresult in higher replase rates and maynot be the answer unless further manipulationsof the stem cell infusionallow us to safely and effectively separatethe cells that cause GVHD fromthose that provide the graft-vs-lymphomaeffect.The intent of myeloablative allogeneictransplant is to use high-dosetherapy to help eradicate the underlyingdisease, prevent graft rejection,and produce a graft-vs-lymphomaresponse to maintain disease control.In indolent NHL, a graft-vslymphomaeffect is documented bylower relapse rates after an allogeneictransplant and by the evidenceof tumor control by infusion of donorlymphocyte cells following amyeloablative transplant. Thus, if therisk associated with a myeloablativeallogeneic transplant can be lowered,the lower risk for disease progressionmay eventually lead to a superioroutcome. The source of donorstem cells appears to make a differencein initial mortality rates,with PBSC being superior to bonemarrow.[28]Alternatively, nonmyeloablativetransplants have been studied basedon the theory that the most importantpart of an allogeneic transplant is thedonor cell graft-vs-lymphoma effect.Khouri et al[29] treated 15 patients,11 of whom had engraftment of donorcells and 8 of the 11 who achieveda complete remission. Five of six patients(83.3%) with chemotherapysensitivedisease have survived,compared with two of nine (22.2%)with refractory or untested disease(

P

= .04). Thus, patients with lowertumor burden and chemotherapy-sensitivedisease may be more effectivelytreated with a nonmyeloablativeapproach and have the longest durationof responses. However, cautionis needed in selecting patients fornonmyeloablative therapy. In manydiseases, higher doses of radiationand chemotherapy have been associatedwith a reduced risk of relapse.[30] Nonmyeloablative therapyprobably needs to be consideredmainly in patients with a diagnosisthat is very sensitive to the graft-vslymphoma effect, older patients, andpatients with comorbid medical problems.Indolent NHL may be a goodtarget for reduced-intensity nonmyeloablativeallogeneic stem celltransplant.[31]Tandem transplants with autologoustransplant followed by nonmyeloablativeallogeneic transplant hasalso been studied.[32] In one trial, 11of 13 patients achieved a completeresponse postallograft, including 9patients with a partial response afterthe autograft. Seven also receivedadditional donor lymphocytes. Sevenpatients developed acute GVHD(grade 2-4) and two developed chronicextensive disease. Between 210and 340 days postallografting, 2 patientshave relapsed, 10 are alive,and 5 are in complete remission. Fivehave died-two from GVHD and progressivedisease, two from GVHDand infection, and one from diseaseprogression.

Chronic Graft-vs-Host Disease


Chronic GVHD will remain aproblem after a nonmyeloablativetransplant. It therefore behooves usto remember that in a myeloablativesetting, significant chronic GVHD isassociated with a 50% nonrelapsemortality rate.[33] The pathophysiologyof GVHD is poorly understoodand needs to be further studied. Theidentity of the antigenic targets forthe immune reactive cells have notbeen well clarified; nor is it clearwhich populations of cells mediatethe ongoing immune responses seenin chronic GVHD. In a coisogenicmurine model, T cells from donormice transplanted into mice with onlya three-amino acid difference in theirDr molecule developed chronicGVHD.[34]Some investigators believe thatrecipient alloantigens provide thestimulus for the graft-derived T cellsthat have already undergone selectionand maturation in the donor thymusenvironment, causing GVHD.Alternative explanations have includedflawed T-cell reconstitution, dominantautoantigens driving the system,and improper thymic selection of denovo donor cells undergoing maturationin the new host that does not result in tolerance. Many of our therapiesfor chronic GVHD, though, onlycontrol disease but do not delete thepathogenic clone.The incidence of GVHD appears tobe similar between nonmyeloablativeand myeloablative transplant recipients,although long-term follow-up islacking.[35] Older patients have decreasedthymus function, and thus, aswe age we generate an environmentmore conducive to the developmentof chronic GVHD. The preferredsource for nonmyeloablative transplantsstudies are PBSCs, which areassociated with a higher risk of developingchronic GVHD, a longer diseaseduration, and a greater amount of therapyrequired to treat GVHD.[36] Also,many nonmyeloablative transplantsdepend on additional donor lymphocyteinfusions for disease control. Ingeneral, 80% of patients who receivedonor lymphocytes and respond developGVHD. Better understanding ofgraft selection and the mechanism ofchronic GVHD, as well as alternativeapproaches to treating GVHD that donot affect lymphoma control, areneeded.

Optimizing AllogeneicTransplant Therapy


Interest is also beginning to focuson optimizing immune responsesagainst lymphoma cells in an allogeneictransplant. Numerous laboratoriesare studying the generation ofminor histocompatible antigen-specificclones to treat residual diseaseafter allogeneic transplant for a hematologicmalignancy. However, theconcept of using restricted antigenspecificT-cell clones as effectivetreatment after transplant may beflawed. The reason that the graft-vstumoreffect is so prominent in anallogeneic setting most likely is dueto its polyclonal recognition of tumorcells that results in disease control.Limited recognition of tumorcells by antigen-specific clones willmost likely lead to escape of recognitionof the tumor cells by variousmechanisms, and will not result ineffective long-term disease control.Further investigation of the abilityto amplify the polyclonal tumorresponse after an allogeneic transplant,to prevent relapse and to determinewhich patients require this intervention,needs to be undertaken.In addition, what is lacking in humansis the ability to separate thecells that cause GVHD from the cellsthat cause a graft-vs-tumor effect, andwe need to study the differences inthe antigen recognition repertoire ofthese cells.

Summary


The optimal therapy for indolentlymphoma and the timing of varioustransplant entities remains unclear. Itis conceivable that early autologoustransplant for patients with intermediateand poor IPI risk factors maymaximize survival and quality of life,with nonmyeloablative allogeneictransplants being left to later, whendisease recurs. Quality of life in patientswith chronic GVHD is poorlystudied in the setting of nonmyeloablativetransplants, and for patientswith indolent NHL, quality of life ismore of an issue early in the diseasethan disease eradication, thus makingthis type of approach an interestingone for investigation in futurerandomized trials.Indolent disease is more likely tobe a good target for nonmyeloablativeimmunotherapy than aggressivedisease that will quickly outgrow theability of the immune system to controlit. How much bulky low-gradeNHL tumor burden patients can haveat the time of nonmyeloablative transplantis still poorly defined, but commonsense and previous experiencewould argue that chemotherapy-sensitivedisease and a lower tumor burdenare associated with the bestlong-term outcomes.

Aggressive Non-Hodgkin'sLymphoma

Autologous Transplant


It is well established that in chemotherapy-sensitive relapsed aggressiveNHL, autologous HSCT resultsin durable remissions and is superiorto conventional salvage therapy.[1,2]Mantle cell NHL, although consideredan aggressive form of the disease,could probably be categorizedas both indolent and aggressive. In general, it is well accepted that anautologous transplant is reasonableconsolidation therapy for mantle cellpatients in first complete remission.In meta-analysis, the addition ofrituximab has also been shown toincrease overall and disease-free survivalwith limited follow-up, andthus, has become the standard of therapyto incorporate with an autologoustransplant in mantle cell patients.The addition of radiolabeled anti-CD20 to a cyclophosphamide and etoposideconditioning regimen hasresulted in encouraging initial responserates for patients with persistentmantle cell disease.[37]

Non-Mantle Cell NHL


Upfront autologous transplant, asoutlined by Cabellero et al,[38] hasbeen studied in diffuse large cellNHL. In this study, 42% of patientsreceived stem cell transplants in firstcomplete response, 19% in secondcomplete response, and 47% with activedisease. Moreover, 35% had diseasesensitive to chemotherapy, and12% had chemotherapy-refractorydisease. The estimated overall anddisease-free survival rates at 5 yearswere 53% and 43%, respectively, andthe transplant-associated mortalityrate was 11%. By multivariate analysis,the following variables significantlyaffected overall and diseasefreesurvival rates: the number ofregimens to reach first complete remissionand disease status at transplant.Total-body irradiation in conditioningregimens had an adverseeffect on survival and age-adjustedIPI scores also affected disease-freesurvival.However, in terms of transplantingnon-mantle cell, aggressive NHLpatients in first complete remission,the role of autologous HSCT remainscontroversial. Several recently publishedrandomized studies and prospectivetrials have compared upfrontHSCT to standard therapy in poorprognosispatients in first completeor partial remission.[39-43] Thesestudies differed in their design andconclusions.Gianni et al[39] reported muchearly toxicity in the transplant arm.Although differences could not be accurately measured due to thestudy's crossover design, event-freesurvival in the initial transplant armwas 76% compared with 49% in thenontransplant arm (

P

= .004). Haoiunet al[40] did not at first show anydifferences in overall or disease-freesurvival, but their retrospective analysisshowed that patients with an IPIscore of 2 or 3 who underwent HSCThad a better outcome, with a diseasefreesurvival rate of 55% vs 39%,and an overall survival rate of 64%vs 49% (

P

= .4) at 8 years. Kluin-Nelemans et al[42] compared eightcycles of CHOP (cyclophosphamide,doxorubicin HCl, vincristine, prednisone)to six cycles of CHOP plusBEAC (carmustine [BCNU], etoposide,cytarabine, cyclophosphamide)and found no difference in outcome.Most patients in the study by theEuropean Organization for Researchand Treatment of Cancer had favorableIPI scores. Other studies thatcontained a shortened induction regimenbefore transplant have failed toshow an advantage.Taken together, these resultswould seem to suggest that patientsneed to receive standard inductionchemotherapy for diffuse large cellNHL before an autologous transplant.Patients with poor IPI risk factors atinitial diagnosis of diffuse large cellNHL may benefit from front-lineHSCT. On the other hand, patientswho present with favorable IPI factorsshould not undergo an upfrontautologous HSCT, but rather, shouldwait until first relapse.With respect specifically to adultBurkitt's and Burkitt's-like NHL, aretrospective analysis of 117 patientsin Europe showed that 70 patientsreceived an autologous transplant infirst complete remission.[44] Themajor factor predicting for outcomeafter transplant was disease status attime of transplant. The 3-year actuarialsurvival was 72% for patients infirst complete remission, comparedto 36% for patients transplanted withchemosensitive relapse and 7% forchemorefractory disease. As moredose-intense therapy has become thenorm for treating newly diagnosedadult Burkitt's and Burkitt's-likeNHL, a randomized study comparing outcome after transplant in firstcomplete remission to these newerdose-intense regimens is needed.

Other AutologousTransplant Strategies


Tandem autologous transplantshave also been assessed to see if theywill increase response rates.[45] Theaddition of radiolabeled antibody,[17-19] immunotherapy (eg,dose-intense IL-2, IL-2-incubatedPBSC, IL-2 and rituximab, and rituximabalone), and antigen-specifictherapy (eg, Epstein-Barr virus-drivenT-cells clones) to conditioning regimensare also being studied. Biologicmodifiers such as bcl-2 antisense willalso be studied for maintenance therapyafter an autologous transplant.

Myeloablative andNonmyeloablativeAllogeneic Transplants


The role of myeloablative allogeneictransplant in aggressive NHLhas limitations similar to those discussedin the indolent NHL section.The lower relapse rates but still highmortality rates associated with myeloablativeregimens have limitedtheir use to patients whose stem cellscannot be collected for an autologoustransplant and patients withchemorefractory disease. Many physiciansbelieve that a total-bodyirradiation-containing allogeneic myeloablativeregimen for chemorefractorydisease may be more effectivethan a chemotherapy-only regimen.The use of nonmyeloablativetransplants in this setting has beenless studied. Aggressive non-mantlecell NHL may not be the best candidatefor nonmyeloablative therapy.Intermediate-grade NHL historicallyhas been thought to be only moderatelysensitive to an allogeneic graftvs-lymphoma effect. Allogeneictransplants have resulted in fewer relapsesthan an autologous or syngeneictransplant, but response to donorlymphocytes is less common and moretransient in intermediate NHL. Highgradelymphomas such as Burkitt's,Burkitt's like, and immunoblastic NHLappear to be more insensitive to a graftvs-lymphoma effect, as they grow rapidlyand may lack adequate ability to cause an immune response. Thus,high-grade NHL patients will benefitmore from a myeloablative allogeneictransplant than a nonmyeloablativeapproach and, if medically stable,should not be offered the nonmyeloablativetherapy.

Diffuse NHL


Diffuse NHL patients may be anappropriate group in which to studythe tandem transplant approach, withan autologous transplant first for tumorcontrol followed by a nonmyeloablativeallogeneic transplant. Theproblem remains, however, that atleast 35% of diffuse NHL patients infirst relapse with chemotherapy-sensitivedisease are cured with an autologoustransplant. To commit thesepatients to the risk of developingGVHD does not seem reasonable.What is needed is a better way todetermine which patients will remainin the cured group with an autologoustransplant. Certain indicators areinherently useful. For example, patientswho relapse and then respondto salvage therapy with a completeresponse are more likely to stay inremission after an autologous transplantthen patients with refractorydisease. Thus, a better understandingof tumor markers is needed. It ishoped that this will emerge from themany ongoing molecular studies (eg,involving microarray assays), so thatwe can differentiate the various diffuseNHL patients and determine whois most likely to remain in remissionafter an autologous transplant alone.Until then, it is more reasonableto study a strategy of offering allpatients with chemotherapy-sensitivediffuse NHL a standard autologoustransplant and offering patients withpersistent disease after the autologoustransplant (who have an HLAmatcheddonor) a nonmyeloablativetransplant. Positron-emission tomography(PET) evaluation post-autologoustransplant and PCR evaluationof bone marrow may help us determinewhich patients have persistentminimal disease that would benefitfrom a nonmyeloablative allogeneictransplant.We should not shortchange our patients and give in to the temptationto reduce the dose of the autologoustransplant conditioning regimen, ie,in favor of the nonmyeloablative allogeneicapproach. We do not knowhow to maximize the allogeneic effectin a nonmyeloablative approach.We need to study whether the use ofnatural killer cells, donor lymphocytessensitized to minor HLA tumorassociatedantigens, amplification ofthe polyclonal tumor response afteran allogeneic transplant, or vaccinationstrategies can improve the nonmyeloablativeapproach. Patients whoare in complete remission after anautologous transplant should be followedand offered allogeneic therapyonly at the time of diseaseprogression.

Conclusions

The role of HSCT in the treatmentof NHL is still evolving. Basic questionsabout when to incorporateHSCT early in the course of the diseaseremain unanswered. How to increasethe benefit of autologoustherapy through the addition of therapiessuch as immunotherapy, targetedradiolabeled antibody, antibodytherapy, and biologic modifiers hasyet to be established. Moreover, weneed to explore how to decrease thetoxicity of allogeneic transplants, tobetter control chronic GVHD, to determinewhich patients will benefitfrom a nonmyeloablative approach,and to maximize the allogeneic graftvs-lymphoma effect.

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