Radiography (2006) 12, 203e208

The role of stem cell transplantation in themanagement of Non-Hodgkin’s lymphoma

Irene Foster*

Centre for Radiographic and Medical Studies, Cranfield University RMCS, Shrivenham,Swindon SN6 8LA, UK

Received 21 January 2005; accepted 21 June 2005Available online 2 August 2005

KEYWORDSNon-Hodgkin’slymphoma (NHL);Stem celltransplantation;Autologous bonemarrowtransplantation(AMBT);Peripheral blood stemcell (PBSC)transplantation;Allogeneictransplantation;Graft versus hostdisease (GvHD);Myelodysplasticsyndrome (MDS)

Abstract The role of stem cell transplantation has markedly improved the clinicaloutcomes of patients with aggressive and relapsed Non-Hodgkin’s lymphoma (NHL),and has now become the treatment of choice. This paper examines the evidencewhich is resulting in the changing trends in the management of NHL, in the use ofstem cell transplantation. Autologous bone marrow transplantation has been muchfavoured due to the reduced incidence of treatment related complications.Although allogeneic transplants have had equal success, its use has been hamperedby the increasing difficulty in finding suitably matched donors. The use ofperipheral blood stem cells continues to increase, although further research isrequired to improve the effects of priming and purging methods used in order toreduce the risk of myelodysplastic syndrome.ª 2005 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.

Introduction

Non-Hodgkin’s lymphoma (NHL) represents a di-verse group of malignancies, the cause of whichhas not been associated with any one single

* Tel.: C44 1793 785752; fax: C44 1793 785774.E-mail address: i.j.foster@cranfield.ac.uk

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aetiological factor. NHL is both chemosensitiveand radiosensitive, therefore responding well totherapy. Early stage disease is effectively managedby local radiotherapy, whilst patients with highgrade and intermediate disease have shown im-proved response rates with modern chemothera-peutic combination regimes. However, thisresponse rate does not constitute a cure, since

rs. Published by Elsevier Ltd. All rights reserved.

204 I. Foster

50e60% of patients with high grade disease arelikely to relapse.1

The dose of anti-tumour agents is largely de-termined by the toxicity to normal bone marrowtissue. Potentially, curative doses may be admin-istered if the patient could be salvaged by re-placement of progenitor cells. Supportive therapyof this nature would save the patient from iatro-genic death.2

Treatment regimes in NHL have been widelystudied, striving to improve the clinical outcomesof patients with relapsed disease. The role of bonemarrow transplantation has increased the proba-bility of success in achieving these aims.

Bone marrow transplantation

Bone marrow transplantation (BMT) has evolvedfrom a research procedure to an establishedtherapeutic modality.3 The basic concept of BMTunderpins the regimes of dose intensity. Higherdoses of radiotherapy, and/or chemotherapy maybe given, than would otherwise be possible.2

BMT is largely of three types: (i) autologoustransplants involve the use of the patients ownbone marrow; (ii) allogeneic transplants utilizedonor marrow, related or unrelated to the recipi-ent; and (iii) syngeneic transplants are reliant uponthe recipient having an identical twin as a donorand thus this type of BMT occurs to a lesser degree.

Promising results were reported from the earlyBMT studies conducted with leukaemic patients.The data gathered from these studies served asa springboard for the numerous clinical trials in BMTfor a myriad of malignancies which followed. Onesuch study in NHL was reported by Philip et al.(cited in Bolwell2). A group of patients who relapsedfollowing initial induction therapy, were givena further course of chemotherapy. Induction ther-apy which has a mortality rate of 20%, is largelybased on the CHOP regime consisting of cyclophos-phamide, doxorubicin, vincristine and predniso-lone. A second response deemed the patients‘sensitive relapse’. The patients were ‘resistantrelapse’ where no second response was achieved.Patients who were ‘sensitive relapse’ showed a 36%chance of complete remission in autologous bonemarrow transplantation (ABMT), versus the 14%for patients with ‘resistant relapse’. The outcomeappeared to be worse for patients with refractorydisease, who showed no significant initial response.2

Thus the patients treated while they were sensitiveto chemotherapy fared the best. Nademanee et al.4

also published very promising results for patientswith poor-risk aggressive lymphomas. Patients were

treated during first remission with ABMT. Disease-free survival at 3 years was 84%.

Other studies3,5 have employed similar means ofoptimising the patient’s status, with a view tofurther improving the clinical outcomes. Thesestudies demonstrate the importance of identifyingthe patients who are likely to do well and there-fore justify further intensive treatments. However,Lopez-Guillermo et al.6 suggest that many studieshave not given thought to the change in prognosticfactors which may occur following complete re-mission. The advantage of sensitive techniquessuch as polymerase chain reaction has increasedthe detection of residual disease in patients incomplete remission.7 Manipulation of biomedicaltools suggests prediction of non-favourable statusat an earlier stage of intervention and monitoringand thus a much improved outcome.

Autologous transplant

The most effective use of ABMT has been used inthe treatment of patients with relapsed disease,but has also been explored as a consolidationtherapy for patients in first remission who are athigh risk of relapse. The use of high dose chemo-therapy and ABMT rescue is associated with severemyelosuppression in the short term.8 Since muchof the toxicity of ABMT leads to infections duringneutropenic periods, the use of growth factorsduring these times, is to decrease the incidenceand duration of infections. Haemopoietic growthfactors are glycoproteins which act to promote stemcell production and differentiation. Successful post-transplant use of granulocyte colony-stimulatingfactor (G-CSF) and granulocyteemacrophage colo-ny-stimulating factor (GM-CSF) have been re-ported.2,3,9 The use of GM-CSF led to more rapidneutrophil engraftment2,3 whilst both G-CSF andGM-CSF accelerated the recovery of granulocytes9

which reduced the incidence of infection and lengthof hospitalisation.

The patients own bone marrow is mostly usedwhen suitable donors cannot be found. ABMT avoidsthe problems associated with graft versus hostdisease (GvHD), a major and potentially fatalcomplication, but is also thought to lose thebeneficial anti-tumour reaction associated withGvHD, referred to as graft versus lymphoma (GvL)effect. An additional perceived problem with ABMTis the potential contamination of the transfusedmarrow with tumour cells.10 However, Souhami andTobias1 believe that residual disease is more likelyto be in the patient than in the marrow. Purging ofthe bone marrow was a suggestive means of

Stem cell transplantation in NHL 205

addressing this issue. A variety of purging proce-dures are being used to eliminate residual tumourcells. One of these methods uses monoclonal-anti-bodies. Monoclonal-antibody purged autologousbone marrow administered to patients with indolentdisease proved to be beneficial10 in specific passivetargeting and thus selective removal of malignantcells from the harvested marrow.

However, Williams et al.11 suggest that thebenefits of purging are yet to be proved. Theyreviewed cases of purged and unpurged autologousbone marrow transplantation for NHL. They con-cluded that there was no significant improvementin survival rates for patients receiving purged bonemarrow as compared with unpurged.

Peripheral blood stem cell (PBSC) transplant isparticularly useful for patients who have meta-static disease in their marrow or have hypocellularmarrow, since bone marrow stem cells circulate inthe peripheral blood, thus providing an effectivealternate source of progenitor cells for harvest.

Another notable advantage is that it negates theneed for general anaesthesia and the discomforts ofbone marrow harvesting.2 It may well be that thesefactors are influencing the shift from ABMT to PBSC.3

More recently, cord blood stem cell transplantshave been used. Cord blood which is rich inhaemopoietic stem cells can be cryopreserved forlong periods of time. The attraction of cord bloodis that it is a by-product of pregnancy that wouldnormally be discarded. However, due to therelatively low numbers of stem cells, it does notprovide a viable option for adult use.10

Allogeneic transplant

The use of allogeneic bone marrow transplant hasalso increased within recent years. A retrospectivestudy conducted by Freytes et al.12 demonstratedlower rates of disease progression in patientsreceiving allogeneic stem cell transplant who re-lapsed following autologous transplant, but alsorecommend the use for patients in remission. Asmaller scale study13 confirmed this viewpointalthough also indicated the prophylactic use oftacrolimus and methotrexate for GvHD. Allogeneictransplants have an added complication of de-pendence upon histocompatibility matching be-tween recipient and donor. Close matching isessential since the transplanted marrow containsmany lymphocytes which mount an immunologicalresponse against the tissues of the host giving riseto GvHD.10 Myeloablation for allogeneic trans-plants have mostly been used12 but due to thetoxicity of this approach, nonablative regimens

have been developed.13,14 Nonablative regimenshave been used for low grade, relapsed andadvanced lymphoma with encouraging results inprogression free survival. The approach proved tobe better tolerated by patients, achieved engraft-ment and allowed development of GvL effect.14

This phenomenon was first suggested in 1991.15

Bishop15 examined databases to support this phe-nomenon and suggests that patients with chemo-sensitive disease may already be cured bymyeloablation and thus response may not beattributed to GvL effect. However, evidence ap-pears to suggest an element of this response inpatients with no relapse following unrelated allo-geneic transplants, but raises more questions withregard to graft contamination and the need forfurther study into alloreactivity toward NHL.

Harvesting stem cells

Harvesting of ABMT requires multiple aspirations ofthe iliac crests in an attempt to yield at least1 ! 108/kg of nucleated cells, over a period of1e2 h under general anaesthetic. This proceduremay be avoided if sufficient progenitor cells can beharvested by using the patient’s peripheral blood.2

The use of peripheral blood stem cells (PBSCs)for transplantation has increased in frequencyduring the past few years. This procedure involvesthe harvesting of peripheral stem cells at a seriesof collections, until a mononuclear cell yield of7 ! 108/kg.2 Yields have been shown to be en-hanced by chemotherapy prior to collection. Theaction of chemotherapy causes a surge of circu-lating PBSCs during the recovery stage of the whitecell nadir.2,10 This hypothesis was tested by Toet al. (cited in Bolwell2). Patients treated withcyclophosphamide showed marked increase in thenumber of granulocyteemacrophage cells. Thetime scale correlated with the white cell recovery.It was concluded that priming with cyclophospha-mide led to increased PBSC yields. Priming withVP-16 (etoposide) has also been used and shown tobe effective in the mobilization of PBSC.17 Similarincrease in yields resulted from the combined useof cyclophosphamide and GM-CSF prior to AMBTand GM-CSF on its own.

Late complications of treatment

Consideration of the toxic side effects of high dosechemotherapy has mostly been concentrated onearly effects due to short term follow up. Evidenceindicates that the most significant late complications

206 I. Foster

of treatment manifest as secondary leukaemia andmyelodysplastic syndrome (MDS).8 Toren et al.16

state that NHL is the primary tumour most prone toresult in a second malignancy and MDS. The causes ofthese complications are not clear, although there isfirm belief that the prolonged use of intensivechemotherapeutic drugs is a predisposing factor.8

Natural killer (NK) cell activity, characteristic ofinnate immunity, may be significantly depleted bysuch regimes. A functional immune system, in whichNK cells are intrinsically linked with cytokinesthrough a sequence of events, maximizes the de-struction of malignant cells.17 Depression of theseeffector cells thus impede the mechanism of cancerimmunosurveillance during an induced state ofimmunosuppression. Whilst Imai et al.18 support theclinical significance of NK cell activity, they alsosuggest that ‘there isno clearevidenceof associationbetween use of immunosuppressive drugs and in-creased risk of the more common cancers’ (page1795).

Other factors also thought to contribute to com-plications include older age at transplant, radiother-apy and low platelet count.19 Various studies haveindicated that MDS is a significant late complicationof ABMT.8,19e22 Large scale examination23 of latecomplications indicate that incidences may not be assignificant as previously reported. These claims arenot supported by Baker et al.24 who conducteda similarly large scale study. Their evidence suggeststhat patients receiving stem cell transplant have an8-fold increased risk of developing a new malignancythan expected in the general population. The mostsignificant risk noted within this cohort of patientswas a 300-fold higher increase in the incidence ofMDS and acute myeloid leukaemia (AML), thanexpected in the general population.

It was suggested that the incidence and time ofonset of MDS in transplant patients did not varysignificantly from non-transplant patients.9,23

However, a study conducted by Krishnan et al.19

indicated a strong association between the trans-plant and increased risk of MDS and AML. The riskwas further increased for patients receiving VP-16primed PBSCs. Miller et al.21 suggest that apartfrom the change in the bone marrow stromamicroenvironment, there is also increased endog-enous secretion of myeloid growth factors whichaccelerates the onset of MDS.

Morphological analysis of MDS following PBSCshowed two distinct forms: an aggressive form andan indolent form. Unlike the aggressive form, theindolent form does not necessarily lead to leukae-mic transformation.20

Allogeneic BMT is an accepted treatment mo-dality for primary MDS. Similar measures were

undertaken as a means of managing MDS followingauto-PBSC for NHL patients. All 13 patients died.20

Baker et al.24 suggest that the use PBSC may bea risk factor in the development of MDS, due topurging and growth factor mobilization. Theyfurther suggest that the cells harvested may bein a state of incomplete DNA repair followingchemotherapy priming when they are stimulatedto proliferate. There is also suggestion that sinceabnormal telomere lengths in stem cells arepresent in primary MDS and after PBSC, it ispossible that shortened telomeres from cytotoxicchemotherapy may provide an important link inthe prediction and management of MDS.20

AIDS related NHL

An increased incidence of intermediate and highgrade lymphoma amongst homosexual men wasnoted in the early 1980s. Burkitt’s lymphoma, a raredisease in the western world, but more commonlyappearing in equatorial Africa, was being presentedin 30e40% of NHL patients.25 The routine use ofanti-retroviral therapy has not only reduced thesignificance of opportunistic infections in patientswith autoimmune deficiency syndrome (AIDS), butalso appears to reduce the risk of developinglymphoma.26 AIDS patients are immunocompro-mised and thus susceptible to opportunistic infec-tions such as pneumocystis carnii, herpes simplex,varicella zoster and cytomegalovirus pneumonia.10

The management for this group of patients aremost confined to the use of low dose methotrexate,bleomycin, doxorubicin, cyclophosphamide, vincris-tine and dexamethasone (mBACOD regime).25e27

Holland et al. (cited in Northfelt and Kaplan27)reported the results of a study conducted in thetreatment of AIDS-NHL. A patient was treated withan allogeneic graft from a matched sibling. Thepatient relapsed 39 days post-transplant and died8 days later. The autopsy revealed eradication ofHIV infection but not lymphoma.

The treatment outcome for patients with AIDSassociated lymphoma is less promising. Completeremission rates are lower than the correspondingrates seen in non-HIV (human immunodeficiencyvirus) infected patient groups. HIV complicated byNHL presents difficult management problems sincethe efficacy of current therapies remain unsatis-factory.27

Conclusion

It has not been possible to discuss the countlessnumber of papers and reports relating to thistopic, but prominent issues have been highlighted.

Stem cell transplantation in NHL 207

Allogeneic transplants are not much favoured inNHL management, due in part to the significantresults being achieved with ABMT. These encour-aging results have led to the use of ABMT for highrisk patients in first remission and for selectedpatients with poor prognosis. The effectiveness ofthis method has been further enhanced by theaddition of haematological growth factors, whichhave not only minimised the incidence of post-transplant infections, but as a consequence, alsoincreased the patients overall well being, reducingthe period of hospitalisation.

The overall response to treatment differs,however, depending upon clinical status. Patientswhose disease is responsive to chemotherapy tendto do best. Long term disease-free survival ratesare currently quoted at 40e50%. Improved survivalrates are, however, overshadowed by the latecomplications induced by therapeutic interven-tion. The incidence of MDS and AML appear to besignificant, with little evidence to indicate anyeffective management therapies for MDS, which isalways fatal. One of the few documented studieson this subject proved to be very disappointing.Further continuing research aims to improve theoutcomes of patients with poor-risk intermediateand high grade lymphoma.

The role of PBSCs as an alternative to ABMT isincreasing in popularity. Where sufficient PBSCscan be collected, it has become the treatment ofchoice. The advantages of not requiring generalanaesthesia and the unpleasant side effects ofmarrow harvesting, weigh heavily in its favour.Current methods of purging and priming of PBSCsand ABMT is implicated in the acceleration of theonset of MDS and second malignancy and thuscontinues to be an area of active research.

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