Acute myeloid leukaemia

Treatment with curative intent is undertaken in the majorityof adults below the age of 60 years, provided there is nosignificant co-morbidity. Risk of failure is based on the cytogeneticPattern. Those at ‘low risk’ are treated withmoderately intensive combination chemotherapy. This alwaysincludes an anthracycline such as daunorubicin and cytosinearabinoside (cytarabine) and consolidation with a minimumof four cycles of treatment given at 3- to 4-week intervals.Those at ‘high risk’ may only be treated with curative intentif an HLA-identified sibling is available for stem celltransplantation.

Those at ‘intermediate risk’ are a heterogeneous group.When possible they should be given consolidating chemotherapyto induce remission followed by sibling-matchedallogeneic transplantation, despite its attendant risks.For those with a favourable risk profile, allogeneic transplantationis not recommended to consolidate first remission.In this group the potential morbidity from the procedureoutweighs the potential risk of relapse

The initial treatment of the older patient is much morecontentious. Intuitively, biological age should determine themanagement of the individual patient. Unfortunately ‘highriskAML’ is commoner with increasing age, but is onlycurable with allogeneic transplantation, and the toxicity ofthis treatment increases dramatically with age

Complete remission will be achieved in about three-quartersof patients under the age of 60, failure being due to eitherresistant leukaemia or death due to infection or (rarely) bleeding.Approximately 50% of those entering complete remissionwill be cured. (i.e. approximately 30% overall).The management of recurrence is undertaken on an individualbasis, since the overall prognosis is very poor despite the fact that second remissions may be achieved. Longsurvival following recurrence is rarely achieved withoutallogeneic transplantation. Experimental therapy shouldbe considered.

Acute promyelocytic leukaemia(APML)

This is an uncommon variant of AML characterized by thetranslocation t(15;17) and with particular morphological features

.There is an almost invariable coagulopathy,which was a major cause of death. The empiricaldiscovery that all-trans-retinoic acid (ATRA) causes differentiationof promyelocytes and rapid reversal of the bleedingtendency was a major breakthrough. APML is treated withATRA combined with chemotherapy and, following successfulremission induction, with maintenance ATRA. Allogeneictransplantation may be necessary either if the leukaemia isnot eliminated at the molecular level, or following a secondremission after recurrence. Arsenic trioxide, which induces

apoptosis via activation of the caspase cascade,(is used with resistant or relapsed disease

Complete remission and molecular remission occur in atleast 80% of younger adults with APML (it is uncommon inthe elderly). At least 60% will expect to be cured. In contrastto the other subtypes of AML, the prognosis after recurrenceis quite favourable with prolonged second remissions beingpossible with further blocks of ATRA and chemotherapy evenif allogeneic transplant is not able to be performed, althoughit is the treatment of choice.

• Acute lymphoblastic leukaemia (ALL)

The overall strategy for the treatment of ALL differs in detailfrom that for AML. Remission induction is undertaken withcombination chemotherapy including vincristine, a glucocorticoid,an anthracycline and asparaginase (crisantaspase).Daunorubicin is perhaps the most frequently used anthracycline,and dexamethasone is replacing prednisolone as theglucocorticoid of choice. Once remission is achieved, thedetails of consolidation will be determined by the anticipatedrisk of failure. Intensive consolidation of remission with variablenumbers of chemotherapy cycles comprising cytotoxicswith different mechanisms of action has been standard practice

including the administration of high-dose methotrexate.Consolidation high-dose chemotherapy and autologousstem cell rescue is probably equivalent to standard consolidationbut is rarely used. In those patients with high-riskfeatures), allogeneic transplantation is recommendedupon achieving first complete remission.

The other major difference between therapy for ALL andAML is the need for central nervous system directed therapy.Prophylaxis should be given with intrathecal chemotherapyunder platelet cover if necessary, as soon as blasts arecleared from the blood. Depending upon risk this may becontinued for up to 2 years, and complemented by highdoses of systemic cytosine arabinoside (cytarabine) or methotrexate.Cranial irradiation was previously given to allpatients to reduce the risk of relapse within the centralnervous system; some risk adapted strategies now reservethis only for those patients at very high risk

After intensive induction and consolidation, maintenancetherapy for 2 years is required to reduce the risk of diseaserecurrence in certain subtypes. This typically comprises 2years of treatment with methotrexate and mercaptopurine,although more intensive regimens are used by some groups.During this period of time chemotherapy dosing/schedulingis adjusted to maintain a target white cell count of 3

×109/L.

Prognostic factorsA number of clinical and laboratory features are determinantsof treatment response and survival in ALL. Increasingly therapeuticstrategies, based upon prognostic risk, are being usedin the management of the disease.

■Age. Overall survival decreases with increasing age inadult ALL.

■White cell count. High white cell counts at the time ofdiagnosis (> 30 000 × 109/L); associated with high risk ofCNS relapse.

■Immunophenotype. The immunophenotype ischaracterized at presentation and can be used to divideALL patients into risk groups. B cell ALL represents

75% of ALL, with the remainder of T cell lineage. In theformer, Pro-B ALL is considered a poor prognosticgroup compared to the more common Pre B-ALL form.

T-ALLs are associated with the presence of amediastinal mass although they may have superioroutcomes to those of B-cell lineage.

■Cytogenetic aberrations. Chromosomal abnormalitiesare detected in 60% of adult ALL patients. Thepresence of t(9;22)or t(4;11) is associated with a poorprognosis, the former being particularly unfavourable. Itis unclear yet what the role of imatinib will be in thissetting.

■Time to response. Early clearance of blasts isfavourable, with failure to achieve a CR within 3–4weeks being adverse

Minimal residual disease. Highly sensitive techniqueshave been employed to detect low level leukaemicpopulations in the morphologically normal bone marrow.These include flow cytometry, PCR quantitativeassessment of immunoglobulin gene rearrangement andof chromosomal translocation. This identifies patientswith high levels of minimal residual disease who may beat high risk of relapse and thus suitable for therapeuticintensification.

PrognosisThe prognosis of ALL in childhood is now excellent: completeremission is achieved in almost all, with up to 80% beingalive without recurrence at 5 years. Failure occurs mostfrequently in those with high blast count and t(9;22)translocation.

The situation is far less satisfactory for adults, the prognosisgetting worse with advancing years. Co-morbidity andt(9;22) translocation increases in frequency with age. Overallthe complete remission rate is 70–80%, failure being duepartly to resistant leukaemia and partly to failure of supportivecare. Failure to achieve complete remission with first-linetherapy carries a very poor prognosis. If CR can be achievedwith new therapies, it should be consolidated with siblingor possibly even unrelated donor transplantation despite thehigh risk of graft-versus-host disease. Between 30% and

40% of patients continue in durable first remissions, resultingin approximately 25–30% overall patient cure.

As with AML, most recurrences occur within the first 3years and the outcome is extremely poor. Second remissions,though usually achieved, are rarely durable exceptfollowing allogeneic transplantation. Isolated extramedullaryrecurrences, however, may be cured.

CHRONIC LEUKAEMIASChronic myeloid leukaemia (CML)Chronic myeloid leukaemia (CML), which accounts forabout 14% of all leukaemias, is almost exclusively a diseaseof adults with the peak of presentation being between

40 and 60 years and is characterized by the presence of thePhiladelphia chromosome. Unlike the acute leukaemiaswhich are either rapidly reversed or rapidly fatal

CML has a more slowly progressive course which if notinitially cured will be followed eventually by blast crisis (90%myeloid, 20% lymphoid) or myelofibrosis and death after 3–4years

Clinical featuresCML usually presents in the chronic phase and some patientshave no symptoms. Symptoms include:

■symptomatic anaemia (e.g. shortness of breath) ■abdominal discomfort due to splenomegaly

■ weight loss ■fever, sweats, in the absence of infection

■headache (occasionally) due to hyperleucocytosis ■bruising, bleeding (uncommon), priapism.

Signs include: ■pallor

■splenomegaly, often massive ■lymphadenopathy (uncommon, when found suggests

blast crisis( ■retinal haemorrhage due to leucostasis

Investigations ■Blood count. Hb low (normochromic and normocytic) or

normal, WBC raised (usually > 100 × 109/L), plateletslow, normal or raised.

■Blood film. Neutrophilia with the whole spectrum ofmyeloid precursors including occasional blasts. Elevatedbasophils and eosinophils.

■Bone marrow aspirate. Increased cellularity,increased myeloid precursors. Cytogenetics revealst(9;22) translocation (the Philadelphia chromosome).

■Fluorescein-in-situ hybridization (FISH) or reversetranscriptase polymerase chain reaction (RT-PCR) areused to demonstrate the cytogenetic/molecularabnormality. These are also used to quantitativelymonitor response to therapy.

■Leukocyte alkaline phosphatase is usually reduced

ManagementImatinib, a tyrosine kinase inhibitor that specifically blocksthe enzymatic action of the BCR-ABL fusion protein, is firstlinetreatment for the chronic phase. It has replaced alphainterferon.Imatinib produces a complete haematologicalresponse in over 95% of patients, and 70–80% of these haveno detectable BCR-ABL transcripts in the blood. Event-free,and overall, survival appear to be better than for other treatments.Imatinib can be continued indefinitely

In the acute phase (blast transformation) most patientshave only a short-lived response to imatinib, and other chemotherapyas for acute leukaemia is used in the hope ofachieving a second chronic phase.Side-effects of imatinib, which usually are well tolerated,include nausea, headaches, rashes and cytopenia. Resistanceto imatinib as a single agent may develop as a resultof secondary mutations beyond the t(9;22). The use ofsecond generation tyrosine kinase inhibitors, dasatinib andnilotinib, may restore haematological or molecular remissionsin those patients in the chronic phase that have primary oracquired resistance to imatinib

Stem cell transplantation (SCT)Allogeneic haemopoietic stem cell transplantation can cureapproximately 70% of chronic phase CML patients. SCT waschoice therapy for young patients with an HLA matcheddonor, but this has changed in the light of the success ofimatinib therapy. It is now only used in those with an inadequateresponse to imatinib or those that have disease progressionon therapy. There are many potential complicationswith an allogeneic transplantation approach; death mayoccur as a result of graft-versus-host disease (GVHD) oropportunistic infection, and the decision to proceed is basedupon a balance of risk.

Factors making complications more likely include:

■increasing age

■SCT in acute phase

■prolonged interval from diagnosis to transplantation

■degree of histocompatibility between donor and

recipient.

Graft-versus-leukaemia effect plays a role in the increased

survival following SCT so that reduced-intensity transplantation

is being more frequently used

Chronic lymphocytic leukaemia(CLL)

This is the commonest leukaemia, occurring predominantlyin later life and increasing in frequency with advancing years

)median age of presentation between 65 and 67 years .(Itresults from the clonal expansion of small lymphocytes andis almost invariably (95%) B cell in origin. The majority ofpatients are asymptomatic, identified as a chance findingon a blood count performed for another indication. Otherpatients, however, present with the features of marrow failureor immunosuppression.

The median survival is about 10years, and prognosis correlates with various clinical featuresat presentation. These clinical features simplyrepresent differences in the biology of the disease, and anumber of cytogenetic and molecular abnormalities arenow recognized as being of prognostic significance (seebelow). A pre-malignant condition, monoclonal B cell lymphocytosis

)MBL ,(occurs where there are less than the 5× 109/L B cells required for a diagnosis of CLL. Some of these

have CLL phenotype and may progress to CLL

Clinical featuresThe majority of patients are asymptomatic at presentation.Common symptoms are:

■recurrent infection because of (functional) leucopeniaand immune failure (reduced immunoglobulins)

■anaemia due to haemolysis or marrow infiltration ■painless lymphadenopathy

■left upper quadrant discomfort (from splenomegaly).The commonest findings on examination are:

■anaemia ■fever (due to infection)

■generalized lymphadenopathy (may involve single area) ■hepatosplenomegaly, sometimes massive.

However, none of these may be present

Investigations ■Blood count. Hb normal or low; WBC raised, and may

be very high; with lymphocytosis (criteria for diagnosis> 5 × 109/L), platelets normal or low.

■Blood film. Small or medium sized lymphocytes. Maysee smudge cells in vitro.

■Bone marrow. Reflects peripheral blood, often veryheavily infiltrated with lymphocytes.

■Immunophenotyping shows mainly CD19+, CD5,+CD23+ with a weak expression of CD20 and CD79b andsurface immunoglobulin (kappa and lambda light

chains.( ■Cytogenetics/FISH analysis are not essential

for diagnosis but may help in the assessment ofPrognosisCoombs’ test. May be positive if there is haemolysis.

■Immunoglobulins. Low or normal.

Prognostic factorsThe clinical course of CLL is variable. Several serum markers,e.g. β2 microglobulin, soluble CD23 and thymidine kinase,have been shown to predict progression and survival. Variationsin predictor cut-off levels have limited their widespreadapplication. Cytogenetic abnormalities are detected in > 90%of cases. Patients with an isolated deletion at 13q have anexcellent prognosis, in contrast to those with either 11q deletionsor 17p deletions (the sites of the tumour suppressorgenes ATM and TP53 respectively) who tend to have arapidly evolving clinical course

Trisomy of 12 is frequentlyobserved and similarly conveys risk of progression. In thosetumours that demonstrate a high level of mutation within thevariable region of the rearranged immunoglobulin heavychain (IgVH) the clinical course is more indolent than thosewhere the IgVH sequence more closely resembles that of thegerm line. Such assessments are technically demanding;

expression of ZAP70, a 70 kDa tyrosine kinase protein, correlateswell with mutational status. Patients with > 20%expression of ZAP70 have median 10-year survival of ≥ 50%;

in > 20% expression the median survival was > 5 years. Highexpression of CD38 on leukaemic cells may also indicateadverse prognosis.

ManagementIn CLL, the major consideration is when to treat, indeed 30%of patients will never require intervention. Treatment dependson the ‘stage’. of the disease and the prognosticbiomarkers. Choice of therapy will depend upon patient relatedfactors such as age and co-morbidity, adverse prognosticfeatures and anticipated response and toxicities

to therapy. Intervention, when indicated, usually causesimprovement in symptoms and in the blood count. The effecton survival is unclear. More aggressive treatments, particularlycombinations of cytotoxic chemotherapy with antibodytherapy, result in better quality remission of longer duration.These improvements may translate into a survival advantage,to accompany the improvement in quality of life afforded bygood supportive care.

Early-stage disease is usually managed expectantly,advanced-stage disease is always treated immediately andthe approach to the intermediate stage is variable. The absoluteindications for treatments are:

■marrow failure manifest by worsening anaemia and/orthrombocytopenia

■recurrent infection ■massive or progressive splenomegaly or

lymphadenopathy ■progressive disease manifest by doubling of the

lymphocyte count in 6 months ■systemic symptoms (fever, night sweats or weight loss)

■presence of haemolysis or other immune mediatedcytopenias.

General/supportive treatmentAnaemia due to haemolysis is treated with steroids. If it isrefractory or recurrent, or if splenic discomfort is a problem,a splenectomy is performed. Anaemia and thrombocytopeniadue to marrow infiltration is treated with chemotherapy and,when necessary, transfusion. Erythropoietin .mayavoid the need for transfusions, particularly in patients receivingchemotherapy.Infection is treated with antibiotics, with prophylactictherapy being given during periods of chemotherapy. Immunoglobulinreplacement may be helpful.Allopurinol is given to prevent hyperuricaemia.

Specific treatmentChlorambucil, given in modest doses, usually reducesthe blood count and decreases lymphadenopathy andsplenomegaly, and successfully palliates the disease.The bone marrow rarely returns to normal. Treatment isusually limited to a few months’ duration and thenwithheld until progression. In asymptomatic patientswithout an indication for therapy, early use ofchlorambucil does not provide a survival advantage overexpectant management.

■Purine analogues, fludarabine alone or in combinationwith cyclophosphamide or mitoxantrone (with or withoutsteroids), have had a much greater impact on the bonemarrow and can induce complete or molecular completeremission although they are not helpful in 17p-deletionor p53 mutations

■Combination therapy with rituximab (relatively ineffectivealone) shows a dramatic improvement in the responserate and has become standard choice first-line therapy.

Alemtuzumab, a humanized monoclonal antibodytargeting CD52 which is highly expressed on B-CLL,

may be used in those patients that progress afterfludarabine.

■Allogeneic stem cell transplantation with non myeloablativeconditioning regimens is undergoinginvestigation, particularly for the younger patient

Lymphomatous transformationCLL may undergo lymphomatous (Richter’s) transformationin 5–10% of cases, most typically to diffuse large B-celllymphoma, although Hodgkin’s like transformation is recognized.In the main, response to cytotoxic chemotherapy isunsatisfactory and survival short