- lymphoproliferative disorders part 2

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Background

Chroniclymphocyticleukaemia

Follicularlymphoma

Managing patientsreceivingchemotherapy

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PROFESSOR JOHN F SEYMOUR,consultant haematologist, head ofhaematology department, divisionof cancer medicine, PeterMacCallum Cancer Centre, EastMelbourne, Victoria.

The authors

DR SARAH KAMEL,advanced trainee in clinical andlaboratory haematology, divisionof cancer medicine, PeterMacCallum Cancer Centre, EastMelbourne, Victoria.

PROFESSOR H MILES PRINCE,consultant haematologist, divisionof cancer medicine, PeterMacCallum Cancer Centre, EastMelbourne, and Cabrini Hospital,Malvern, Victoria.

Part 2 — Chronic lymphocytic leukaemia andfollicular lymphoma

Lymphoproliferative disorders

Last week, Part 1 of this two-part series discussed the most common of the aggressive types of lymphoma. This week, Part 2 focuseson two of the indolent lymphoproliferative diseases — chronic lymphocytic leukaemia and follicular lymphoma. We discuss diagno-sis and management for these conditions, after patients have been referred to a haematologist. The outlook for these malignanciestoday is also reviewed.

THE lymphoproliferative diseasesare a heterogeneous group ofhaematological disorders charac-terised by malignant clonal prolifer-ation of cells derived from their‘normal’ lymphoid counterparts.They are classified according to dis-tinct clinicopathological features.This group of disorders is distinctfrom myeloid disorders, which are

malignancies that derive from cellsdestined to form neutrophils, mono-cytes, etc. (eg, chronic myeloidleukaemia, myeloproliferative dis-eases and myelodysplasia) (figure 1,page 30.).

The lymphoproliferative diseasescomprise the lymphomas and thechronic lymphoid leukaemias. Thelatest edition of the WHO Classifi-

cation of Tumours of Haematopoi-etic and Lymphoid Tissues listsmore than 40 different types of non-Hodgkin lymphoma (NHL). Thesecan broadly be divided into B- andT-cell disorders and further subdi-vided into clinically aggressive‘high-grade’ and clinically indolent‘low-grade’ malignancies.

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CLL is the most commontype of leukaemia in West-ern societies and is lesscommon in people of Asiandescent. It is characterisedby the protracted but pro-gressive accumulation ofsmall, relatively slow-grow-ing lymphocytes. Themedian age at diagnosis is70.

PrognosisMedian patient survival is10 years. However, thisnumber does not take intoaccount the heterogeneityseen in the CLL patient pop-ulation. Many patients willhave a very indolent courseand ultimately succumb toan illness other than theirCLL, while a small propor-tion of patients will haveaggressive disease and liveonly 1-2 years from diagno-sis. Apart from initial stagingof the disease, a variety ofprognostic markers has beenrecognised that aid in risk-stratifying patients and guid-ing clinicians as to who islikely to require treatmentand when.

PresentationMany laboratories with alarge referral base of GPswill often encounter routineFBCs as part of annualhealth checks that show amild lymphocytosis (5-10 ×109 cells/L), but are other-wise unremarkable. In mostcases, this lymphocytosis isreactive and thus transient(see box, right, for causes oflymphocytosis). Lymphocytecounts >15 × 109 cells/L aremore concerning. Many GPswill prudently repeat theFBC in a few weeks ormonths and in a minority ofcases the lymphocytosis willbe persistent.

It is essential to assess thepatient clinically for lym-phadenopathy and spleno-megaly. With regard to theirblood tests, the presence ofan anaemia or thromboycy-topenia is more suggestive ofunderlying malignancy. If

any of these clinical or labo-ratory features are present,further investigations shouldbe pursued.

Rarely, patients can pres-ent with a lymphocyte countof >50 × 109 cells/L. Thismagnitude of lymphocytosisis almost always malignant.A good laboratory willalways make an urgentblood film and review thelymphocyte morphology inaddition to performing fur-ther tests, if required, toexclude an acute leukaemia.

DiagnosisA peripheral blood filmshould be examined by alaboratory haematologist tolook for abnormal lympho-cytes. CLL cells classicallylook like small mature lym-phocytes. Due to their

fragility, the cell membranecan easily tear when a dropof blood is smeared across aglass slide. This results in thelaboratory artefact of a‘smear’ or ‘smudge’ cell(figure 2).

Morphology is generallynot sufficient to define themalignant nature of the cellsor that the lymphoprolifera-tive disease is CLL and notanother disorder (such asmantle-cell or marginal-zonelymphoma, T-cell or naturalkiller (NK) cell prolifera-tions).

If CLL is suspected basedeither on a persistent lym-phocytosis, abnormal lym-phoid morphology or pres-ence of lymphadenopathy orsplenomegaly, flow cytome-try of the peripheral bloodshould be performed to fur-

ther characterise the cellpopulation in question. Therequest slip should state asmuch clinical information aspossible and stipulate thatCLL/NHL is being consid-ered.

Flow cytometryFlow cytometry, also knownas ‘cell surface markers’, hasa rapid turnaround time andcan definitively establish thepresence of an abnormalpopulation of cells in theperipheral blood, bonemarrow, excised lymphnodes and even CSF or pleu-ral fluid.

The principle of flowcytometry is to measure thelight-scatter characteristicsof a stream of cells in singlefile, which run past a laser(figure 3, see page 32). Addi-tionally, the light emission offluorescent markers (fluo-rochromes) tagged to anti-bodies that attach to variouscluster-of-differentiation(CD) cell surface markers ischaracterised (figure 4, seepage 32).

All haematopoietic cellsexpress CD markers, whichperform different cellularfunctions. Different celltypes have their own typicalpattern of normal CDexpression — a ‘phenotype’.Malignant lymphocytesexpress an aberrant lympho-cyte phenotype. For exam-ple, all B cells are CD19 pos-itive (CD19+) and thisincludes CLL cells. Whatdefines the CLL cells asabnormal is they are alsoCD5+, whereas normal Bcells are CD5-.

The classic phenotype ofCLL cells is CD19+ CD5+CD10-, with either lambdaor kappa light chain restric-tion. The term light chainrestriction implies that allcells in a given populationexpress the same light chaintype (ie, kappa or lambda)because they are clonal.

Flow cytometry is invalu-able not only for the diag-

30 | Australian Doctor | 8 April 2011 www.australiandoctor.com.au

Lymphoproliferative disorders — Part 2HOW TO TREAT

The two most common indolentlymphoproliferative diseases arechronic lymphocytic leukaemia(CLL) and follicular lymphoma(FL), both of B-cell origin. Includedwith the term ‘CLL’ is small lym-phocytic lymphoma (SLL), whichis essentially a lymphomatous pres-entation of CLL.

First, to clarify a few terms,low-grade implies a slow-growingindolent tumour. Both CLL andFL are in this category. However,both may (albeit unusually) trans-form into a more aggressive lym-phoma. In the case of CLL this isreferred to as a Richter’s transfor-mation. Once this occurs, theprognosis for these patients ismuch bleaker than for de novoaggressive lymphomas such asthose discussed in Part 1, and cureis not attainable with currently

available therapies. Broadly speaking, indolent lym-

phoproliferative diseases can

grumble on for years, even formore than a decade in somepatients. In many cases they can

be observed for a period of timebefore therapy is required. Theflipside of their indolent nature isthat they are generally incurable,although in selected patients, anallogeneic bone marrow trans-plant may offer the hope of acure. Similarly, localised FL is cur-able with radiotherapy. When dis-cussing FL, we focus be on dis-seminated disease, as this is by farthe more common presentation.

EpidemiologyMany of you will have beeninvolved in the care of lymphomapatients in your practice. Accord-ing to Australian Institute ofHealth and Welfare data for 2005,lymphomas were the fifth mostcommonly diagnosed group ofcancers in both men and women.This translates to 4400 new casesof lymphoma, or an incidence of

21/100,000 Australians per year,which equates to just over 4% ofall cancer diagnoses.

Of these cases, CLL/SLL and FLwere each diagnosed in almost1000 Australians in 2005, withincidences of 4.5 and 4.3cases/100,000 people, respectively.For CLL the incidence climbssteeply in people over 65, with 22-30/100,000 people in this agegroup diagnosed each year withthe disease.

By comparison, prostate cancercomprised 16.3% of all cancers,with an annual incidence in menof 164/100,000. Breast cancermade up 12.2% of new cancersand was diagnosed in 111/100,000women. Other frequently diag-nosed malignancies such lungcancer and colorectal cancer com-prised 9.1% and 13% of all cancerdiagnoses, respectively.

from previous page

Chronic lymphocytic leukaemia

Differential diagnosis ofa lymphocytosis (otherthan a lympho-proliferative disease)

• Viral infection (eg, influenza,Epstein–Barr virus (EBV),cytomegalovirus (CMV),HIV, toxoplasmosis

• Stress-relatedlymphocytosis (during anMI, post-trauma)

• Some bacterial infections(eg, pertussis, brucellosis,tuberculosis)

• Post-splenectomy

• Allergic reaction to amedication

• Post-seizure

Figure 1: Ontogeny of haematopoietic cells.

Common lymphoidprogenitor cell

Common myeloidprogenitor cell

B cells

T cells

NK (natural killer) cells

Myeloblast

Neutrophilis

Monocytes

Eosinophils

Platelets Red cells Basophils

Pluripotentstem cell

LPDs originate fromB or T cells

Figure 2: A ‘smear’ or ‘smudge’ cell seen in patients with chronic lymphocytic lymphoma (CLL).These cells are fragile and are damaged in the process of blood slide preparation. The presence ofthese cells should alert the treating doctor that CLL is a possible diagnosis. They may be presenteven when the absolute lymphocyte count is normal.

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LPD = lymphoproliferative disease

Two intact CLL cells

A smear cell

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nosis of haematologicalmalignancies but also fordetecting minimal residualdisease (MRD) post-therapywith a sensitivity of up to1/10,000 abnormal cells insome laboratories. Addition-ally, markers of poor prog-nosis, such as CD38 andZAP-70 expression in CLLcan also be identified.

Monoclonal B lymphocytosisIt should be noted that thepresence of cells in theperipheral blood with a‘CLL phenotype’ is notenough to diagnose CLL. Ifthe total abnormal lympho-cyte population is <5 × 109

cells/L and there is no evi-dence of lymphadenopathyor organomegaly, the patientis considered to have a‘monoclonal B lymphocyto-sis’, which is essentially pre-CLL. This pattern occurs inat least 3% of people aged60-80 years.

The International Work-shop on Chronic Lympho-cytic Leukaemia (IWCLL)guidelines state that to diag-nose CLL there must be anabsolute peripheral bloodlymphocytosis (of phenotyp-ically abnormal cells) of >5 ×109 cells/L. This lymphocy-tosis must be present for atleast three months.

The progression of mono-clonal B lymphcytosis tofrank CLL is at the rate of 1-2% of patients per annum,and these patients typicallyhave very indolent disease,with only about 15% everrequiring therapy. In generalthey should be monitored onan annual basis.

Small lymphocytic lymphomaSLL is considered biologi-cally the same disease asCLL and is treated in thesame way. Patients diag-nosed with SLL have lym-phadenopathy and/orsplenomegaly but lack theperipheral blood lymphocy-tosis of >5 × 109 cells/L thatis required for a diagnosis ofCLL. The different presenta-tion of what is essentially thesame disease may be due todifferent expression of adhe-sion proteins that result inSLL manifesting in a morelymphomatous rather thanleukaemic form.

StagingWho should be investigated?After a patient has beendiagnosed with CLL, the firstthing to decide is how exten-sively they need to be investi-gated. It is our practice toaddress this issue by firstasking how will this altermanagement. In other words,if the patient is over 60 andasymptomatic, a ‘watch andwait’ approach is appropriate.In almost all cases, specialistreferral should be sought, aspatient investigation and man-agement needs to be individu-alised.

Before referring a patient itis helpful to order a Coombs

test (to assess for autoim-mune haemolysis). Baselineimmunoglobulin levels arehelpful to assess the degreeof underlying immunosup-pression.

In early-stage CLL we rec-ommend three-monthlyreviews in the first year pri-marily to assess the tempoof disease. The peripheralblood lymphocyte doublingtime (the time for the base-line lymphocyte count todouble) is one of the mostuseful prognostic measures,as doubling in less than sixmonths confers a poor prog-nosis.

Conversely, if the patientclearly needs treatment in theforeseeable future (eg, cytope-nias, lymphadenopathy,organomegaly or constitu-tional symptoms are present),immediate staging will help‘prognosticate’ for thatpatient. The staging approachdescribed below applies tosuch patients.

Staging investigationsGenerally, if therapy isbeing considered in patientswith cytopenias, a bone

marrow biopsy is per-formed. This will distin-guish between cytopeniascaused by marrow infiltra-tion by CLL and autoim-mune cytopenias, which areseen in about 7% ofpatients with CLL. In thepresence of an autoimmunecytopenia there will berobust marrow productionof the affected cell lineage,indicating that there isperipheral destruction ofcells. An autoimmunecytopenia does not ‘up-stage’ the disease and thepresence of autoimmunecytopenias does not confera worse overall survival. Abone marrow biopsy willalso help with prognostica-tion, as the extent ofmarrow infiltrate and cyto-genetic abnormalities influ-ence prognosis.

Most patients will alsohave CT to assess for thepresence of lymphadenopa-thy, splenomegaly andhepatomegaly. About one-quarter of patients with noclinically detectable lym-phadenopathy have occultabdominal lymphadenopa-

thy on CT, which has beenshown to confer a worseprognosis.

Both the Rai and Binetstaging systems for CLL areused by clinicians. The Raiclassification is comprisedof five stages, whichdescribe the progressiveincrease in disease burdenover time. In the earlieststage (stage 0), CLL ispurely ‘leukaemic’; thereare only circulating malig-nant lymphocytes in theperipheral blood.

The stage after thisinvolves the lymph nodes(stage I). An involvedlymph node will contain aninfiltrate of malignant lym-phocytes that are morpho-logically the same as thecells circulating in theperipheral blood.

As the disease progresses,the spleen and liver becomeengorged with malignantlymphocytes, leading toorganomegaly (stage II).

At all stages in CLL, thebone marrow will containmalignant cells. However,in the most advanced stages(III and IV), the burden of

marrow involvement is soextensive that normalhaematopoiesis is compro-mised and the patient devel-ops cytopenias — anaemia(stage III) and thrombocy-topenia (stage IV).

Table 1, adapted fromthe original 1975 article byRai, describes each stage ofdisease. With the increasingutilisation of blood tests inthe community, up to 60%of patients may presentwith isolated lymphocyto-sis.

Prognostic markersThe Rai staging system haslimitations with regard toits ability to risk-stratifypatients, as there arepatients within Rai 0 or Idisease, who only live 1-2years from the time of diag-nosis. In addition to lym-phocyte doubling time andstaging, several new prog-nostic markers have beenidentified (table 2), ofwhich the most importantis the presence of a chro-mosome 17p deletion, iden-tified by standard cytoge-netics.

In addition, CD38 andZAP-70 (by flow cytome-try) are thought to haveprognostic utility becauseof their correlation withunmutated immunoglobu-lin variable heavy chain(IgVH) status, which is anindicator of more aggres-sive disease. These lattertests are variably used andtheir place in CLL manage-ment is still being investi-gated.

TreatmentAs with most incurable dis-eases, the treatment para-digm for CLL is not uni-form; there is no single‘one-size-fits-all’ treatment.In patients with early-stagedisease, treatment may notbe indicated. Indeed, even inyoung patients a period ofobservation is recommendedto gauge the tempo of dis-ease. Moreover, early inter-vention does not improve

Figure 4: CD19+ cell tagged by a fluorochrome.from page 30

After a patienthas beendiagnosed withCLL, the firstthing to decide ishow extensivelythey need to beinvestigated.

Fluorochromeconjugated to anti-

CD19 antibody

CD19

Figure 3: Schematic of a flow cytometer.

Single file of cells in sheath fluid

Detector

DetectorFluorescent emission

Laser strikes cell

Light scattercomprised of forward

and side scatter

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survival, and indeed prema-ture and prolonged exposureto unnecessary therapy maylead to drug resistance.

ChemotherapyFor patients who ultimatelyrequire chemotherapy, thepredominant indicationsare:• Progressive ‘marrow fail-

ure’ (ie, symptoms ofanaemia, progressivethrombocytopenia orinfections).

• Constitutional symptomssuch as weight loss orfatigue.

• Progressive symptomaticlymphadenopathy.Symptoms such as fever

or sweats are quite rare.When deciding on the

treatment plan, the patient’sage and fitness for therapyare paramount (table 3).Consideration should alwaysbe given to enrolling eligiblepatients in a clinical trial.

In older patients, lessintensive oral therapy withalkylating agents such aschlorambucil or cyclophos-phamide is often used forsymptom control.

In younger patients andselected older patients wegenerally aim to get a deepresponse, as this generallytranslates into more pro-longed remissions. As such,more intensive therapy withfludarabine-based regimensis frequently used. Recently,the addition of the anti-CD20 antibody rituximabhas improved patient sur-vival when used in combi-nation with chemotherapy.This progressive improve-ment has led to drug combi-nations such as FCR (flu-darabine, cyclophosphamideand rituximab) being usedrelatively early in the diseasecourse.

Allogeneic stem celltransplantAn allogeneic stem cell trans-plant (SCT), or allograft, isconsidered in patients under55 (keeping in mind that themedian age for CLL is 70).

Allogeneic SCT is differentfrom autologous SCT(described in Part 1 of thisarticle) in several importantways. Firstly, the stem cellsare not the patient’s owncells; they are obtained froma donor who is HLA (humanleukocyte antigen) matchedas closely as possible to thepatient.

Secondly, the aim of infus-ing donor stem cells is notonly to ‘rescue’ the patientfrom lethal bone marrowfailure resulting from high-dose chemotherapy, as is thecase in autologous trans-plant. In allogeneic SCT, theinfused stem cells are them-selves an important elementof treatment. Once theyrepopulate the patient’sbone marrow (engraftment),the patient effectively has anew immune system, whichideally will recognise as for-eign and kill the patient’smalignant cells. This is atherapeutic form of graft

versus host disease. Thirdly, the chemotherapy

(with or without radiother-apy) used in allogeneic SCT(termed ‘conditioning’) notonly directly treats the dis-ease (as in autologous SCT)but also prepares the bonemarrow to receive the donorstem cells, and suppresses thepatient’s immune system toprevent graft rejection.

A recent study of patientswith CLL undergoingreduced-intensity, condition-ing allogeneic stem cell trans-

plants showed that for asubset of patients, no evi-dence of relapse wasdetectable for up to 96months (the period offollow-up of this study). Forappropriately selectedpatients, allografting canoffer long-term disease-freesurvival and possibly cure.

IV immunoglobulinIt is well recognised thatpatients with CLL are oftenhypogammaglobulinaemic,that is, they have low levels

of IgG, IgA and IgM. Inpatients with severe recurrentinfections, monthly infusionsof IV immunoglobulin (IVIg)are administered to increasebaseline immunoglobulinlevels. There are small studiesthat show reduced numbersof infections in thesepatients.1,2 In Australia, CLLwith recurrent bacterialinfection due tohypogammaglobulinaemia isan approved indication forperiodic IVIg infusions.

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Wouldn’t you treat the whole thing?Depression may manifest as a variety of emotional, somatic and other associated symptoms.1

Reference: 1. AmericanPsychiatric Association,Diagnostic and StatisticalManual of MentalDisorders, 4th ed. Textrevision, Washington DC:American PsychiatricAssociation; 2000.Eli Lilly Australia Pty Ltd,ABN 39 000 233 992,112 Wharf Road, WestRyde NSW 2114. 01/11AUCYM00348 ELB0071/AD

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Table 2: ‘New’ prognostic markers in CLL

Prognostic marker Detection Example

Cytogenetics/fluorescentin situ hybridisation(FISH)

The malignant cellkaryotype is analysed.Several cytogeneticabnormalities are recognised in CLL thathelp determine prognosis

A deletion of the short arm of chromosome 17 (del17p) confers a poor prognosis andresistance to chemotherapy (mediansurvival 32 months). Trisomy 12 anddeletion of chromosome 13 confer a betterprognosis

CD38 (surrogate markerfor unmutated IgVHstatus)

The presence of CD38 onCLL cells is detected by flow cytometry

CD38 positivity indicates a worse prognosis

ZAP-70, a tyrosinekinase not normallyfound in B cells

Expression of ZAP-70 can be readily detected usingflow cytometry

The presence of ZAP-70 suggests a worseprognosis but the assay is notoriouslyunreliable in inexperienced hands

When decidingon the treatmentplan, the patient’sage and fitnessfor therapy areparamount.

Table 3: Treatment options in patients with CLL

Patient ‘type’ Goal of treatment First-line treatment options

The elderly patientwith comorbidities

Symptom control/quality of life. Anytherapy must be balanced againstcomorbidities

Observe, or ‘gentle’ oral chemotherapywith chlorambucil orcyclophosphamide

The robust olderpatient

Quality of life always paramount.Aim for tumour bulk-reduction with‘deepest’ response achievable, ie,reduced lymphadenopathy andreduced marrow infiltrate

Observe if asymptomatic. However, iftreatment is required, use up-frontmultidrug chemotherapy + rituximab(eg, fludarabine-based combinationtherapy) to achieve prolongedremission

The younger patient As above. However, consider forallogeneic bone marrow transplantas part of therapy

As above

Table 1: Rai staging system for CLL

Stage (at timeof diagnosis)

Description Comments

0 Peripheral bloodlymphocytosis

In the modern eraabout 60% ofpatients present inthis way

I Lymphadenopathy

II Organomegaly

III and IV Cytopenias due to the burden of marrowinvolvement. Hb<110g/L or platelets<100 × 109 cells/L

Autoimmunecytopenias are notincluded as stage IIIor IV disease

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NeutropeniaMANY of the chemotherapeuticregimens used in patients with lym-phoproliferative disorders will resultin a period of neutropenia. The nadirof this neutropenia is generally 7-12days after the first day of chemother-apy administration.

Haematology staff provide educa-tion on the expected effects ofchemotherapy and tell patients that ifthey feel unwell or have a fever theymust call their haematologist oroncologist immediately and presentto an ED for prompt assessment.

Neutropenic patients can deterioraterapidly, so the time to the first doseof antibiotics must be minimised.

As part of supportive carethroughout chemotherapy, patientsare given additional medications forsome regimens. Granulocyte colonystimulating factor (G-CSF) is givento minimise the period of neutrope-nia. This is a cytokine that stimulatesthe marrow production of neu-trophils. Pegfilgrastim is a pegylatedlong-acting form of G-CSF, which isgiven as a one-off injection eachcycle. Regardless of whether they

have received such cytokine support,any patient with fever post-treatmentmust be assessed without delay.

ImmunosuppressionReactivation of herpes simplex virus Iand II as well as varicella zoster isnot uncommon during this time,and many patients are prescribedprophylactic antiviral therapy.Additionally, oral candidiasis iscommon in immunosuppressedpatients, and some patients are alsoprescribed prophylactic antifungalagents. Antibiotics to prevent Pneu-

mocystis jirovecii (previously P.carinii [PCP]) infection are used inselected patients, especially ifsteroids are used.

All patients with a new diagnosisof lymphoma should be tested forhepatitis B, hepatitis C and HIV.This is because the latter two infec-tions may be aetiologically linkedto the development of the patient’slymphoma. Hepatitis B is particu-larly important to diagnose becausechemotherapy with high-dosesteroids can lead to a fulminantflare of the disease. Patients with

Managing patients receiving chemotherapy

Follicular lymphomaEpidemiologyWITH an annual incidence inAustralia of at least four per100,000 people, FL is the nextmost common NHL after dif-fuse large B-cell lymphoma(discussed in Part 1). Themedian age of diagnosis is inthe sixth decade and the dis-ease is generally more preva-lent in women, with afemale:male ratio of 1.7:1.

Eighty per cent of patientspresent with Ann Arbor stageIII or IV disease (ie, dissemi-nated disease) and half havebone marrow involvement(for a description of AnnArbor staging, please refer toPart 1). Despite being gener-ally considered incurable,there has been an improve-ment in overall survival inthese patients in recent years,which has been attributed tothe introduction of the mono-clonal antibody against CD20,rituximab.

PathologyThe malignant lymphocytes inFL are derived from germinalcentre (follicle centre) B cells. Bcells in germinal centres oflymph nodes normallyundergo immunoglobulin classswitching, switching from IgMto IgG or IgA. In FL theimmunoglobulin heavy chaingene (IgH) on chromosome 14is translocated and abuts theanti-apoptotic gene, bcl-2, onchromosome 18. This translo-cation is designated ast(14;18). The bcl-2 gene isalready switched on in germi-nal centre cells, as its anti-apoptotic function (preventingprogrammed cell death) isimportant in the developmentof normal memory B cells.Eighty-five per cent of FL caseshave a detectable t(14;18) andthe translocation is also foundin 30% of diffuse large B-celllymphomas.

DiagnosisUnfortunately, laboratories arefrequently sent tissue samplesfrom patients with suspectedlymphoma who have hadonly fine-needle aspirates ofan accessible node. This is nota practice we generally sup-port, for two reasons. Thefirst is that the limited volumeof diagnostic tissue obtainedby aspiration risks not captur-

ing malignant tissue in thesample. The second is thatnodal architecture cannot beassessed and thus the histolog-ical grade of FL cannot bedetermined.

FL is graded 1-3, withgrades 1-2 indicating a moreindolent lymphoma and grade3 being a more aggressive dis-ease, which in some cases willlead the treating haemato-oncologist to pursue moreintensive chemotherapy regi-mens.

The practice of most clini-cians would be to obtain anexcisional node biopsy (or atleast a core biopsy if accessi-bility is an issue, such as withretroperitoneal lymphad-enopathy).

Staging and prognosticmarkersAs previously described,anatomical staging is per-formed according to the AnnArbor staging system. Stages Iand II are considered early-stage disease and such a pres-entation is uncommon in FL.It is critical to accurately stageall patients, as distinguishingstage I, II (and some stage III)will identify a potentially cur-able group who can achievelong-term disease-free survivalwith radiotherapy.

Thus, most patients willhave staging CT in additionto a bone marrow biopsy.

Regardless of the CT findings,if the bone marrow is involvedthe patient is deemed to havestage IV disease (figure 5). 18F-fluorodeoxyglucose positronemission tomography (18F-FDG-PET) is being usedincreasingly to help separate

early- versus late-stage disease.A prognostic score, the Fol-

licular Lymphoma specificInternational Prognostic Index(FLIPI), was devised a fewyears ago using data collectedon almost 5000 patients withFL. This scoring system has

recently been updated (FLIPI-2). The five adverse prognosticmarkers that comprise thisscore are: • Age >60.• Hb <120g/L.• Beta2 microglobulin level

higher than the upper limitof normal.

• Largest involved node >6cmdiameter.

• Bone marrow involvement. Patients can then be risk-

stratified into one of threegroups (low, intermediate orhigh risk) based on whetherthey have none/one, two, orthree or more risk factors,respectively (table 4).

Several trials have nowshown improved responserates, time to progression andoverall survival when patientswith newly diagnosed FL aretreated with upfront ritux-imab plus chemotherapyversus chemotherapy alone.3,4

This new index showed a five-year overall survival rate of98%, 88% and 77% in eachrespective risk group and ismore reflective of survivalrates in the current rituximabera (table 4).

TreatmentIn the 20% of patients withstage I-II FL, local radiother-apy can achieve long-termremissions and potentiallycure in 50% or more of stageI patients. A retrospectivestudy of patients with stages Iand II FL treated with radio-therapy showed that at 10years 40% of patients wererelapse-free.5

However, for most patientswith stage III or IV disease,FL remains an incurable dis-ease. The frequently indolentnature of FL in some patientsmeans it can be viewed inmany cases as a chronic dis-ease. However, some patientswith FL undergo large celltransformation, which carriesa dismal prognosis.

In patients with asympto-matic disease, the watch-and-wait approach is usuallyappropriate, as there is no evi-dence that treating thesepatients early improves sur-vival. Studies assessing theearly use of rituximab areunderway.

The indications for treat-ment are similar to those of

CLL and include painful orcosmetically unappealingnodal disease or constitutionalsymptoms of fatigue andmalaise. Fever and sweats arerare presenting features oflow-grade NHL.

Generally, multi-agentchemotherapy in combinationwith rituximab is the standardapproach to front-line ther-apy. The two most commonlyused regimens are R-CVP (rit-uximab combined withcyclophosphamide and vin-cristine) or R-CHOP(cyclophosphamide, hydroxy-daunorubicin, vincristine[Oncovin] and prednisolonewith rituximab) — which isR-CVP with hydroxy-daunorubicin (doxorubicin)added. R-CHOP is generallyused in younger patients.These agents are given sequen-tially on the same day in anambulatory setting. Five daysof oral prednisolone 100mg isalso administered.

Dosing is spaced at three-weekly intervals to allow timefor the bone marrow torecover. The goal is to admin-ister six cycles of therapy, pro-viding the lymphoma ischemotherapy sensitive andthe patient is able to toleratethe treatment without signifi-cant toxicity. Again, as forCLL, less intensive regimensusing alkylating agents can beused for frailer patients.

Recently, results from alarge international trialshowed that initial chemother-apy with ongoing single-agentrituximab ‘maintenance’ ther-apy every three months fortwo years led to improvedprogression-free survival at amedium follow-up of 36months of 75% in the mainte-nance arm versus 58% inpatients not receiving three-monthly rituximab.6

When relapse occurs, a vari-ety of treatment options areavailable, including:• Repeating the above ther-

apy.• Rituximab alone.• Fludarabine-based therapy

(as for CLL).• Radioimmunotherapy

(radioisotope linked to amonoclonal antibody).

• Autologous or allogeneicstem transplantation foryounger patients.

Figure 5: Bone marrow involvement with follicular lymphoma (note the lymphomatous infiltratealong bony trabeculae).

Table 4: Overall survival of patients with follicularlymphoma based on FLIPI-2 prognostic scoring

systemRisk group Number of

risk factorsPercentage ofpatients

Five-yearoverallsurvival

Low 0 20 98%

Intermediate 1-2 53 88%

High ≥3 27 77%

Follicular lymphomainfiltrate

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THE patient diagnosedtoday with CLL or FL has abetter prognosis thanpatients diagnosed 10 yearsago. This is largely due tothe introduction of ritux-imab into modern treatmentregimens. For most patients,these malignancies can beviewed as chronic illnesseswith the goal of therapy toachieve the best possiblequality of life. In youngerpatients, more aggressivetreatment modalities may beappropriate.

Conclusion

THINK BROAD. TREAT BROAD.1†

†Targeting many of the symptoms of depression – DSM-IV.2References: 1. HirschfeldRMA, et al. DepressAnxiety 2005;21:170–7.2. American Psychiatric Association, Diagnosticand Statistical Manual ofMental Disorders, 4th ed.Text revision, WashingtonDC: American PsychiatricAssociation; 2000.Eli Lilly Australia Pty Ltd,ABN 39 000 233 992, 112 Wharf Road, WestRyde NSW 2114. 01/11 AUCYM00349 ELB0072/AD

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GP’s contribution

Case studyMR RW is a longstandingpatient of the practice. He is aresident of a local boardinghouse and suffers both fromchronic schizophrenia, forwhich he receives risperdone,and also from type 2 diabetes,for which he requires Mixtardinsulin. He is looked after pri-marily by the boarding-houseteam and community-supportliaison psychiatry.

He presented to us in 2006with new-onset enlargementof the lymph glands in his leftaxilla. This was associatedwith only mild local discom-fort but he had many constitu-tional symptoms, with drench-

ing night sweats, hot flushesat night and a 10kg weightloss. He was not able to tellus over what period his glandshad become swollen but hedid mention that he had alsonoticed lesser swellings in hisneck and groin. Although hissleep and appetite were good,he had noticed weight loss,having to tighten his belt sev-eral notches.

On examination he hadbilateral cervical, axillary andinguinal lymphadenopathy.The largest lymph node wasin the left axilla and measured3 × 3cm. It was mobile andnon-tender. He did not haveany organomegaly.

His initial white cell countwas 42 × 109 cells/L, which fellto 28.7 × 109 cells/L. Haemo-globin and platelets werenormal. He was initiallytreated with chlorambucil. Allsymptoms settled and lymphnodes regressed. However,with further deterioration hischemotherapy has beenchanged on several occasions

over the last five years.The most recent CT scan in

February 2011 showed wide-spread lymphadenopathy, withthe largest node being a 4cmleft axillary node. The spleen isenlarged at 16.9cm, but theliver is clear.

Questions for the authorMr RW was initially pre-scribed chlorambucil andprednisone (‘gentle chemother-apy’). This seemed to work fora period although he contin-ued to have palpable lymphnodes. After some time hisWCC became considerablyelevated and he was started onfludarabine, first as single-agent therapy and then com-bined with rituximab. Onwhat criteria was Mr RW’slymphoma deemed suitable forgentle chemotherapy?

We presume Mr RW hasCLL with lymphocytosis andorganomegaly. Importantlythe initial red cell and plateletcounts are preserved. In gen-eral, treatment is indicated for

symptomatic relief, marrowsuppression or constitutionalsymptoms, particularlyfatigue. A rapid lymphocytedoubling time or poor-riskcytogenetics may also influ-ence the decision towardschemotherapy. This patienthad notable weight loss andconstitutional symptoms andtherefore required treatment.Indeed, such a presentationcan sometimes indicate anunderlying transformation toa more aggressive lymphoma(Richter’s transformation).

There has been a shift awayfrom the use of gentle, lessintensive chemotherapy in anattempt to achieve deeper andlonger responses. However,such an approach is not forfrail elderly patients andpatients with multiple co-mor-bidities, such as Mr RW.While the disease tends toimprove in the majority ofpatients receiving chlorambu-cil monotherapy, less than 5%achieve a deep prolongedresponse. The average dura-

tion of response is typicallyless than two years. A moreusual approach in a patientable to tolerate more aggres-sive treatment is the use ofFCR (fludarabine, cyclophos-phamide and rituximab),which results in a completeremission rate of almost 90%and a superior overall sur-vival. In patients not suitablefor FCR, a combination ofchlorambucil and rituximabwould be the favouredapproach.

Are their any new treatmentregimens in the pipeline forRW?

Newer “next generation”CD20 antibodies haverecently been developed. Onesuch drug is ofatumumab,which appears to have greaterpotency than rituximab inpatients with relapsed/refrac-tory CLL. Bendamustine iseffective in CLL and follicu-lar lymphoma and has a par-ticularly good toxicity profile

cont’d next page

DR DIANNE CHAMBERSLeichhardt, NSW

quiescent hepatitis B are prescribedsuppressive antiviral therapythroughout their treatment.

VaccinationsPatients with indolent haematologi-cal malignancies, particularly CLL,are well recognised to be chronicallyimmunosuppressed, primarily due toimpaired humoral immunity.Chemotherapy agents, especiallypurine analogues such as fludarabine(which can impair T-cell immunity)and monoclonal antibodies can exac-erbate any underlying immune sup-pression.

These patients should receive theannual influenza virus vaccine, whichis comprised of inactivated virus.GPs should also ensure these patients

are up-to-date with their five-yearlypneumococcal vaccine. As towhether these two vaccines shouldbe administered before startingchemotherapy or after completion,no studies have been conducted thatanswer this question. Ideally we liketo have vaccines administeredmonths before chemotherapy. How-ever, this is not feasible in patientsrequiring more immediate treatment.

It should also be appreciated thatthe immune response an individualmounts to vaccination may be sub-optimal. There is no evidence to sug-gest that in significantly immuno-compromised patients a secondvaccination will result in a more suc-cessful response. Live attenuated vac-cines such as MMR and varicella

vaccines should be avoided inpatients receiving chemotherapy orthose with advanced disease.

For patients receiving autologousor allogeneic SCTs, revaccinationwith the diphtheria–tetanus–pertussisvaccine, in addition to inactivatedpolio, haemophilus influenzae typeb, hepatitis B, pneumococcal andinfluenza vaccines, is required.Administration of the MMR andvaricella vaccines is deferred until 24months post-transplant, the decisionas to whether a patient is appropri-ate for these vaccines being made bythe treating haematologist. At manytransplant centres both patients andtheir GPs are provided with a list ofwhich vaccinations are required atwhat time.

ReferencesAvailable on request [email protected]

Online resourcesA comprehensive list ofuseful websites can be foundat: www.petermac.org/haematologyinformation

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Lymphoproliferative disorders — Part 2 — 8 April 2011

INSTRUCTIONSComplete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzesby post or fax.The mark required to obtain points is 80%. Please note that some questions have more than one correct answer.

ONLINE ONLY

1. Which TWO statements are correct?a) If an indolent lymphoma transforms into a

more aggressive lymphoma, the prognosis ismuch better than for ‘de novo’ aggressivelymphomas

b) Indolent lymphomas are generally regardedas curable

c) On routine FBC, lymphocyte counts above 15 × 109 cells/L should be a cause for concern

d) Lymphocytosis with lymphadenopathy,splenomegaly, anaemia or thrombocytopeniais suggestive of underlying malignancy

2. Which TWO statements are correctregarding chronic lymphocytic leukaemia(CLL)?

a) Lymphocyte morphology on the blood film issufficient for the diagnosis of CLL

b) Flow cytometry identifies the cell surfacemarkers present on the cell population ofinterest

c) Flow cytometry is used only for the cells inperipheral blood

d) Flow cytometry can detect minimal residualdisease after treatment and can identifymarkers of poor prognosis

3. Which TWO statements are correct?a) The presence of <5 × 109 cells/L with the CLL

phenotype in peripheral blood withoutlymphadenopathy or organomegaly has noclinical significance

b) Patients with monoclonal B celllymphocytosis (pre-CLL) should be monitoredannually

c) Small cell lymphocytic lymphoma isessentially the same disease as CLL butwithout the leukaemic component

d) An asymptomatic patient over 60 with CLLalways requires full investigation andimmediate treatment

4. Which TWO statements are correctregarding CLL?

a) Before referring an anaemic patient with CLL,the GP should arrange a Coombs test toassess for autoimmune haemolysis

b) Baseline immunoglobulin levels do not usuallyreflect the degree of immunosuppression

c) A lymphocyte doubling time of 12 monthsconfers a poor prognosis

d) The need for treatment of CLL is determinedby the presence of cytopenias,lymphadenopathy, organomegaly orconstitutional symptoms


a) A bone marrow biopsy will make theimportant distinction between autoimmunecytopenias and cytopenias due to marrowinfiltration

b) The extent of bone marrow infiltrate andcytogenetic abnormalities does not influenceprognosis in CLL

c) Patients without clinically detectablelymphadenopathy are unlikely to have occultabdominal lymphadenopathy on CT

d) One of the most important prognosticmarkers for CLL is the presence of a

chromosome 17p deletion


a) Early treatment improves survivalb) Indications for chemotherapy include

symptomatic anaemia, infections, weight lossor fatigue

c) In older patients, less intensive oral therapy(chlorambucil or cyclophosphamide) is oftenused for symptom control

d) The combination of fludarabine,cyclophosphamide and rituximab improvessymptoms but does not improve survival inyounger patients

7. Which TWO statements are correct?a) In allogeneic stem cell transplant (SCT), the

patient’s own stem cells are transplantedb) In allogeneic SCT the transplanted stem cells

do not themselves have an anti-cancer effectc) For appropriately selected patients, allogeneic

SCT can offer long-term disease-free survivaland possibly cure

d) In patients with CLL, IV immunoglobulin maydecrease the number of infections associatedwith hypogammaglobulinaemia

8. Which TWO statements are correctregarding follicular lymphoma (FL)?

a) Most patients with FL present with early-stage disease

b) Fine-needle aspiration of lymph nodes is the preferred method of obtaining tissue for diagnosis

c) Excisional biopsy of a lymph node providesan adequate tissue sample and the nodalarchitecture is preserved for analysis

d) Adverse prognostic markers include age >60,involved lymph node >6cm, and bone marrowinvolvement

9. Which THREE statements are correct?a) Patients with early-stage FL can achieve long-

term remissions and possible cure with localradiotherapy

b) The indications for chemotherapy for FLinclude painful or cosmetically unappealingnodal disease, fatigue and malaise

c) After chemotherapy a patient with malaise orfever should be assessed urgently for febrileneutropenia

d) Patients who have received granulocytecolony stimulating factor (G-CSF) withchemotherapy are not at risk of febrileneutropenia

10. Which TWO statements are correct?a) Antiviral treatment for hepatitis B is

contraindicated in lymphoma patientsreceiving chemotherapy with high-dosesteroids

b) Patients with lymphoma should receiveannual influenza and five-yearlypneumococcal vaccines

c) Live attenuated vaccines (eg, MMR, varicella)should be avoided in patients with lymphomareceiving chemotherapy or those withadvanced disease

d) Re-vaccination is contraindicated after SCT

www.australiandoctor.com.au/cpd/ for immediate feedback

How to Treat Quiz

CPD QUIZ UPDATEThe RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2011-13 triennium. You cancomplete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post orfax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

HOW TO TREAT Editor: Dr Giovanna ZingarelliCo-ordinator: Julian McAllan Quiz: Dr Giovanna Zingarelli

NEXT WEEK More than one-quarter of the population have some hearing impairment, while in the 70+ age group, the prevalence rises to 87.5%, making this yet another condition that one is likely to see more of as the population ages. The next How to Treat tackles hearing loss in the ageing patient. The authors are Dr Phil Sale, cochlear implant research fellow, Kolling Deafness Research Centre, University of Sydney, NSW; and Clinical Associate Professor Nirmal Patel, clinical director, Northside Cochlear Implant Clinic, and Director, Kolling Deafness Research Centre, University of Sydney, NSW.

but is not yet approved inAustralia. Alemtuzumab, aCD52 antibody, which can beused in relapsed or refractoryCLL is useful in fit, youngerpatients. When all conven-tional options have beenexhausted, motivated andcompliant patients can be con-sidered for enrolment in clini-cal trials. One such agent cur-rently undergoing clinicaltrials in Australia is ABT-263,an inhibitor of bcl-2, which isdysregulated in CLL.

General questions for the authorPatients with febrile neutrope-nia may present to GPs. Canyou give more advice as towhat would be a critical leveland what is the appropriateantibiotic? Or do thesepatients all need G-CSF andhospitalisation?

It is hard to tell a patientwho is sitting in your clinicwith no apparent symptomsof impending sepsis, otherthan a temperature of 38degrees, that he or she needsto go to hospital. An absenceof neutrophils generally means

an absence of suppuration, sothere are often no localisingsigns. Many patients willdeclare that they feel “fine”.Unfortunately, febrile neu-tropenic patients can deterio-rate remarkably quickly,sometimes within the space ofa few hours. As a general rule,a febrile neutropenic patientshould come into hospital forintravenous antibiotic therapy+/- G-CSF. We use a broadspectrum antibiotic such aspiperacillin/tazobactam. If aninfected intravenous cannulasite or central venous catheteris suspected as the source ofinfection, vancomycin isadded to cover MRSA (methi-cillin resistant Staphylococcusaureus). Recent Australianguidelines have been pub-lished on the management offebrile neutropenia in cancerpatients.1

Part 1 of your article advisesthat both mantle cell andBurkitt’s lymphoma are asso-ciated with a characteristicchromosomal translocation. Isthe chromosome abnormalitythe primary cause for theselymphomas, or does it just

represent an increased suscep-tibility. If it is the primarycause, are we moving towardsgenetic screening and antici-patory care?

The chromosomal translo-cations that occur in haemato-logical malignancies such asthose associated with Burkitt’slymphoma (involving the c-myc gene) and mantle celllymphoma (involving thecyclin D1 locus) are mutationsthat occur within malignantcells only and are the mainpathogenic steps in the devel-opment of these lymphomas.

These translocations are notconstitutional abnormalities(present in the germ line of thepatient), rather they areacquired ‘random’ geneticevents in B-lymphocytes. Con-sequently, there is no role forscreening for these transloca-tions in the absence of clini-cal disease.

In Part 1, you advise there is a20% risk of subsequent breastcancer risk in those who havehad mantle radiotherapy. Thisis news to me. You also men-tion that this radiotherapywas the standard of care

about 15 or more years ago. Isuspect that these patientsmay no longer be under thecare of haematology units andwould be seeing their GPs.These patients warrant aggres-sive breast surveillance. Youstate that the method of inves-tigation is under discussion. Inthe meantime, would you sug-gest MRI (which has MBSfunding for breast cancerscreening in high-riskpatients), ultrasound, mam-mogram or a combination?

Due to the multitude oflate effects that can occur, werecommend that all patientstreated for HL (and indeedall long-term lymphoma sur-vivors) are followed up in thelong term by their haematol-ogist/oncologist or in spe-cialised multidisciplinaryclinics dedicated to the man-agement of the long-termeffects associated with cancertreatment. Depending onrisks, a review every 1-5years may be appropriate.

We suggest annual mam-mography and ultrasoundfor patients with exposure ofbreast tissue to radiation.However, the young age of

some patients makes mam-mography a less sensitivemodality due to density ofbreast tissue. Given the sensi-tivity of breast MRI fordetecting abnormalities, itmay be desirable to use thismodality for very selectpatients at high risk of subse-quent breast cancer (eg, sig-nificant radiation exposureand young age); however,currently patients wouldhave to self-fund for thisinvestigation. The originaltreating team should be con-sulted in order to establishtreatment details and to seekadvice on subsequent breastcancer risk.

Table 1 in Part 1 alerts us tothe need to manage Heli-cobacter pylori and Chlamy-dia psittaci infections as effec-tive treatment of extranodaldisease in MALToma. Whatis the risk for lymphomadevelopment in these illnesses?What is thought to be thepathophysiological effect ofthese organisms?

Given the high prevalenceof H. pylori infection (abouthalf of the world’s population)

and the relative rarity of gas-tric MALToma, the percent-age of patients infected withH. pylori who will go on todevelop gastric MALToma isextremely low. While theexact pathogenesis of extran-odal MALToma is still beingelucidated, the currenthypothesis is that H. pylori orC. psittaci induces abnormalaggregations of lymphoidtissue, which (through chronicantigen stimulation) eventu-ally develop a degree ofautonomous growth.

In the early stages of dis-ease, the lymphocyte prolifer-ation is still partially depend-ent on the presence ofbacterial antigen, so removingthe organism may result inresolution of the lymphoma.However, as the disease pro-gresses, the B-lymphocytesacquire further genetic abnor-malities that lead to furtherautonomy, independence frombacterial antigen stimulationand frank malignant behav-iour.

Reference1. Internal Medicine Journal2011; 41:75-81.

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- lymphoproliferative disorders part 2

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