CHAPTER 13

Bone MarrowTransplantation

The idea of rescuing patients by infusing bonemarrow after myeloablative chemotherapy orradiotherapy is not a new concept. Animalexperiments carried out in the 1950s demon-strated that intravenous infusion of marrowcells could protect against lethal irradiation.Subsequently, successful engraftment wasdemonstrated in humans. The understandingof the human leucocyte antigen system (HLA)meant that tissue matching between donor andpatient was possible and successful bone marrow transplants (BMTs) using matcheddonors (allogeneic BMT) followed in increasing numbers (Fig. 13.1). Overall mortality from the procedure remains high (30%) and thisincreases with age. Patients over 45 years areoften considered too old for this procedure.Patients with certain disorders may benefitfrom high-dose chemotherapy (myeloablative)and be rescued by infusing their own stored marrow stem cells (autologous BMT).Indications for BMT include both malignant andnon-malignant disorders (Table 13.1).

Allogeneic bone marrowtransplantation

The necessary elements for a successful bonemarrow transplant include:1 An HLA-matched donor (Fig. 13.2).2 Immunosuppression (chemotherapy andradiotherapy) prior to marrow infusion toallow engraftment.3 Continuing immunosuppression after infusionto prevent graft-versus-host disease (GVHD).

Donors can be matched siblings or volun-teer donors. The chance of any sibling being a

152

match is one in four whereas the chance of a volunteer being a match is closer to one in100 000. Most developed countries have regis-ters of donors against which a patient’s HLAtype can be matched.

The process of allogeneic bone marrowtransplantation involves:1 High-dose chemotherapy either with or withouttotal body radiotherapy. This is used to eradicatethe neoplastic cells and to allow engraftment ofthe donor marrow.2 Infusion of bone marrow or peripheral bloodstem cells. These are collected directly from thebone marrow of the donor, or by leukaphere-sis of a donor who has been primed by growthfactors such as granulocyte or granulocyte–macrophage colony-stimulating factor (G-CSF,GM-CSF).3 Supportive care. Following high-dose therapythere is inevitably a period of profound mar-row suppression which typically lasts 2–3weeks until the newly infused marrow engrafts.Red cells, platelets and antibiotics are themainstay of supportive care. Severe mucositisand gastroenteritis often develops and, con-sequently, many patients require parenteralnutrition during this time.4 Prevention of GVHD. A number of immuno-suppressive drugs are used to control theimmune component of the donor-derivedengrafted marrow. Cyclosporin is the mainstayof this treatment, but other drugs such asmethotrexate and prednisolone are frequentlyused.

Complications of allogeneic BMTThe principal complication of allogeneic BMT isinfection. The severe neutropenia that follows

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Allogeneic bone marrow transplantation 153

(a)

(b)

1970 1975 1985 1990 1995 2000

Non-Hodgkin'slymphoma

1980

Year

INDICATIONS FOR BLOOD AND MARROWTRANSPLANTATION

Autologous

AllogeneicNu

mbe

r of

tra

nsp

lan

ts

40000

35000

30000

25000

20000

15000

10000

5000

0

4000

4500

35003000

2500200015001000

500

0

Multiplemyeloma

AML

Breastcancer

Hodgkin'sdisease

Othercancers

CML

ALL

MDS otherleukemia

Non-malignantdisease

Tra

nsp

lan

ts

CLL

Ovariancancer

BLOOD AND MARROW TRANSPLANTSWORLDWIDE

Allogeneic (total n = 6700)

Autologous (total n = 11000)

Table 13.1 Diseases for which allogeneic and autologous BMT may be considered.

INDICATIONS FOR BMT

Diseases for which allogeneic and autologous BMT may be considered Allogeneic BMT Autologous BMT

MalignantAcute leukaemia + +Chronic myeloid leukaemia + (+)Lymphoma (relapsed) (+) +Myeloma + +

Non-malignantAplastic anaemia + −Thalassaemia + −Sickle-cell anaemia + −

Fig. 13.1 (a) Annual numbers ofblood and marrow transplantsworldwide 1970–2000. (b)Indications for blood andmarrow transplantation inNorth America in 2000.Courtesy of the IBMT Registry.

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154 Chapter 13: Bone Marrow Transplantation

high-dose chemotherapy is frequently com-plicated by Gram-negative infection. Fungal(Aspergillus and Candida species) and viral (herpes viruses) infections are also found afterallogeneic BMT. The use of steroids to controlGVHD further increases the risk of fungalinfection.

CytomegalovirusCytomegalovirus (CMV) is a cause of morbid-ity and mortality in BMT patients. Patients mayacquire active CMV infection due to the use of seropositive marrow donors, seropositiveblood products or the reactivation of latentCMV infection in seropositive patients.

Infection and organ damage is related to viral load, which can be detected in theblood by the polymerase chain reaction (PCR).Interstitial pneumonitis is a serious complica-tion of CMV infection but other organs may beaffected, notably, the gastrointestinal tract.The use of CMV seronegative blood productsin patients who are not already infected helpsto reduce the chance of infection. Prophylacticaciclovir and the use of ganciclovir for treat-ment has reduced the morbidity and mortalityfrom CMV.

Graft-versus-host diseaseGVHD results from the reaction of donor T

Primary

disease

GVHD

Years

IPn Infection Organ

failure

Other

–

–

Dea

ths

%

(a)

(b)

100

80

60

40

20

0

100

80

60

40

20

0 1 2 3 4 5 6

HLA-identical sibling, < 1y (n = 2,876)HLA-identical sibling, > 1y (n = 1,391)

Unrelated, < 1y (n = 936)Unrelated, < 1y (n = 613)

Prob

abil

ity,

%

CAUSES OF DEATH AFTERHLA-IDENTICAL SIBLING TRANSPLANTS

SURVIVAL AFTER ALLOGENEICTRANSPLANTS FOR CML IN CHRONIC PHASE

Fig. 13.2 (a) The causes ofdeath after HLA-identicalsibling transplants (1994–99).(b) The probability of survivalafter allogeneic transplants forCML in the chronic phase bydonor type and diseaseduration (1994–99). IPn,interstitial pneumenitis.

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cells against the recipient’s tissues; the dis-order may be acute or chronic. Prophylacticcyclosporin, a T-cell poison, considerablyreduces the incidence and severity of GVHDand is given continuously throughout the post-transplant period. Other drugs such asmethotrexate and mycophenolate may be usedas alternatives, or in addition to cyclosporin, toprevent GVHD.

Acute GVHDThis may occur during the first 100 days after BMT and chiefly affects the skin, gastroin-testinal tract and liver. Skin involvement variesfrom a mild maculopapular rash to severedesquamation. Gastrointestinal involvementmay affect the upper or lower tract. Symptomsinclude nausea, vomiting or severe waterydiarrhoea. Biopsy is usually required to con-firm the diagnosis.

T-cell depletion of the donor marrowreduces the risk of GVHD, and some centresroutinely deplete donor marrow this way. T-cell depletion is, however, associated with a higher risk of relapse due to a reduction in the graft-versus-leukaemia effect (GVL; see below). Once established, acute GVHD is a serious disorder with a high mortality.Treatment with high-dose steroids can helpbut many patients with severe GVHD die ofinfection.

Chronic GVHDChronic GVHD is a serious complication ofBMT occurring after 100 days in approximately30–40% of patients. The syndrome is reminis-cent of the autoimmune disorder sclerodermaand the main manifestations are those of dryeyes, chronic liver disease, weight loss andincreased risk of infection. The prognosis is poor.

Graft-versus-leukaemia/lymphomaeffectThe suggestion that the lymphocytes from thegraft can initiate an immune response againstthe abnormal cells of the recipient comes fromthe observation that patients who receivebone marrow stem cells from an identical

twin (and therefore receive a perfectly tissue-matched transplant) have a higher risk ofrelapse than patients receiving marrow from amatched sibling. Patients receiving a bone mar-row transplant for CML often have molecularevidence of persistent leukaemia (the presenceof the Philadelphia chromosome) in the imme-diate post-transplant period but this later dis-appears. T-cell depletion of the donor marrowis associated with a higher risk of relapse.Donor lymphocyte infusion (DLI) after BMThas been shown to have a powerful antitumoureffect and may induce remission after relapse.The understanding of the process of GVLshould provide a powerful tool to eradicatemalignant disease.

Mini-allograft or reduced-intensity conditioning transplantA technique has recently been introducedwhereby patients receive less ablative chemo-therapy. The conditioning regimen is designedto be immunosuppressive enough to allowmarrow engraftment but not to eradicate allmalignant cells. The lower dose of chemother-apy or radiotherapy reduces the toxicity andtherefore the mortality of the procedure. Themini-allogeneic transplant or reduced-intensity con-ditioning (RIC) transplant, in which a state of tolerance between patient and donor marrowis achieved, has application to an older agegroup since allogeneic transplantation is lim-ited to patients under 45–50 years. GVL can beaugmented by infusing into the patient lympho-cytes collected from the donor in the post-transplant period (DLI) to induce GVHD andthus a GVL. The mortality of this procedure is still in the order of between 10 and 20% inmost of the reported series.

Autologous bone marrowtransplantation (high-dosetherapy)

In autologous BMT, the patient’s own marrowstem cells are used to reconstitute the bonemarrow after intensive chemotherapy with or

Autologous bone marrow transplantation (high-dose therapy) 155

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156 Chapter 13: Bone Marrow Transplantation

without radiotherapy. There is therefore norequirement for tissue matching and the risk ofGVHD is eliminated.

Chemotherapy or radiotherapy acts bykilling a fraction of the tumour. Dose is, how-ever, limited by the myeloablative effects ofvery high-dose treatment. This can be over-

come by collecting stem cells before high-dosetherapy and infusing the stem cells into thepatient after intensive conditioning therapy.

There are four phases of high-dose therapy:1 Marrow harvest/peripheral blood stem cellharvest (Fig. 13.3).2 Conditioning therapy.3 Reinfusion of the stem cells.4 Supportive therapy.

Stem cells can either be collected directly bymarrow puncture under general anaesthesia orby apheresis. In both cases patients need to be

COLLECTION OF PBSC BY LEUKAPHERESIS

PBSC collected in bags

Collection Return

MNCsout

RBC+plasma

out

Wholeblood

in

Centrifugalseparation

Whole blood into machine

RBC+ plasma returns to patient

Fig. 13.3 Diagram showing the collection ofperipheral blood stem cells using a COBE spectraapheresis machine. MNC, mononuclear cells;PBSC, peripheral blood stem cells.

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primed with chemotherapy and granulocyte-stimulating factor (G-CSF).

A serious disadvantage of autologous BMT is the potential for reinfusing malignant cells. Various purging strategies have beentried in an effort to reduce this risk but nonehave so far been shown to positively affect outcome.

Supportive therapy is very similar to thecare given after any intensive chemotherapy.

Autologous bone marrow transplantation (high-dose therapy) 157

SURVIVAL AFTER AUTOTRANSPLANTSFOR HODGKIN'S LYMPHOMA

Years

100

80

60

40

20

0 1 2 3 4 5 6

Prob

abil

ity,

%

CR1, (n = 184)CR2+, (n = 734)Relapse, (n = 1,806)Never in remission, (n = 632)

p < 0.0001Fig. 13.4 The probability ofsurvival after autotransplantsfor Hodgkin’s disease(1994–99). CR, completeremission.

Blood products a red cells and platelet concentrates a together with antibiotics andnutritional support are the mainstay of therapyat this stage. Most patients will engraft after2–3 weeks, and some centres use G- or GM-CSF to aid engraftment.

The principal indications for this type of pro-cedure include relapsed Hodgkin’s (Fig. 13.4)and non-Hodgkin’s lymphoma and myeloma inyounger patients.

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