medicine.Acute leukemias.(dr.sabir)

Acute leukemiasAcute leukemias

Dr. Sabir M. AminDr. Sabir M. Amin

DefinitionDefinition

Acute leukaemia is a clonal ( derived from a single Acute leukaemia is a clonal ( derived from a single cell) malignant disorder characterised by the cell) malignant disorder characterised by the accumulation of immature blast cells in the BM, accumulation of immature blast cells in the BM, which replace normal marrow tissue, including which replace normal marrow tissue, including haemopoietic precursor cellshaemopoietic precursor cells..

This results in BM failure, reflected by peripheral This results in BM failure, reflected by peripheral blood cytopenias and circulating blast cells. blood cytopenias and circulating blast cells. Infiltration of various organs is also aInfiltration of various organs is also a

feature of some forms of leukaemiafeature of some forms of leukaemia..

EtiologyEtiology

• •UnknownUnknown (usually) (usually)•• HereditaryHereditary

Down’s syndromeDown’s syndromeAtaxia telangiectasiaAtaxia telangiectasiaKleinfelter’s syndromeKleinfelter’s syndromeOsteogenesis imperfectaOsteogenesis imperfectaWiskott-Aldrich syndromeWiskott-Aldrich syndrome

• •ChemicalsChemicalsChronic benzene exposureChronic benzene exposureAlkylating agents (chlorambucil, melphalan)Alkylating agents (chlorambucil, melphalan)

•• RadiationRadiation • •Predisposing Predisposing haematological diseaseshaematological diseases (myeloproliferative (myeloproliferative

disorders, myelodysplasia, and aplastic anaemiadisorders, myelodysplasia, and aplastic anaemia(( • •VirusesViruses (HTLV-I causing adult T cell leukaemia/lymphoma (HTLV-I causing adult T cell leukaemia/lymphoma

ClassificationClassification

) ) aa ( (acute lymphoblastic leukaemia (ALLacute lymphoblastic leukaemia (ALL), in which the ), in which the abnormal proliferation is in the lymphoid progenitor cells abnormal proliferation is in the lymphoid progenitor cells ( immature lymphocytes)( immature lymphocytes)

))bb ( (acute myeloid leukaemia (AMLacute myeloid leukaemia (AML), which involves the), which involves themyeloid lineages ( cells from which neutrophilsmyeloid lineages ( cells from which neutrophils,,

eosinophils, monocytes, basophils, megakaryocytes, etc. eosinophils, monocytes, basophils, megakaryocytes, etc. are derived). The distinction between the two leukaemias are derived). The distinction between the two leukaemias is based on morphological, cytochemical, immunological is based on morphological, cytochemical, immunological and cytogenetic differences and is of paramount and cytogenetic differences and is of paramount importance as the treatment and prognosis are usually importance as the treatment and prognosis are usually differentdifferent

SubclassificationSubclassification

further subdivided on the basis offurther subdivided on the basis of

morphological criteria: ALL into FABmorphological criteria: ALL into FAB

))French-American-BritishFrench-American-British ( (subtypes L1, L2, subtypes L1, L2, and L3, and AML into FAB subtypes M0 to and L3, and AML into FAB subtypes M0 to M7M7..

FAB for AMLFAB for AML

M0 AML with minimal differentiationM0 AML with minimal differentiationM1 AML without maturationM1 AML without maturationM2 AML with maturationM2 AML with maturationM3 Acute promyelocytic leukaemiaM3 Acute promyelocytic leukaemiaM4 Acute myelomonocytic leukaemiaM4 Acute myelomonocytic leukaemiaM5 Acute monocytic/monoblastic leukaemiaM5 Acute monocytic/monoblastic leukaemiaM6 Acute erythroleukaemiaM6 Acute erythroleukaemiaM7 Acute megakaryoblastic leukaemiaM7 Acute megakaryoblastic leukaemia

IncidenceIncidence

ALL is most common in the age 2-10 years, ALL is most common in the age 2-10 years, ( peak at 3-4)( peak at 3-4) . .

Secondary rise after 40 yearsSecondary rise after 40 years . .

In children it is the most common malignant In children it is the most common malignant disease and accounts for 85% of disease and accounts for 85% of childhood leukaemiachildhood leukaemia

IncidenceIncidence

AML accounts for 10-15% of childhoodAML accounts for 10-15% of childhood

leukaemia, but it is the commonest leukaemia, but it is the commonest leukaemia of adulthood. The incidence leukaemia of adulthood. The incidence increases with age, and the median age at increases with age, and the median age at presentation is 60 yearspresentation is 60 years..

PresentationPresentation

Symptoms and signs result from Symptoms and signs result from BM failureBM failure or, less or, less commonly, commonly, organ infiltrationorgan infiltration

AnaemiaAnaemia result in pallor, lethargy, and dyspnoea result in pallor, lethargy, and dyspnoea..

NeutropeniaNeutropenia results in bacterial infections of results in bacterial infections of

the mouth, throat, skin, chest or perianal regionthe mouth, throat, skin, chest or perianal region..

ThrombocytopeniaThrombocytopenia may present as spontaneous may present as spontaneous bruising, menorrhagia, bleeding from bruising, menorrhagia, bleeding from venepuncture sites, gingival bleeding, or venepuncture sites, gingival bleeding, or prolonged nose bleedsprolonged nose bleeds

PresentationPresentation

Organ infiltrationOrgan infiltration: in ALL is bone pain, superficial : in ALL is bone pain, superficial lymphadenopathy, abdominal distension due tolymphadenopathy, abdominal distension due to

abdominal lymphadenopathy and abdominal lymphadenopathy and hepatosplenomegaly, respiratory hepatosplenomegaly, respiratory embarrassment due to a large mediastinal mass, embarrassment due to a large mediastinal mass, testicular enlargement, or a meningeal testicular enlargement, or a meningeal syndromesyndrome..

Gum hypertrophy and skin infiltration are more Gum hypertrophy and skin infiltration are more commonly seen in AML than in ALLcommonly seen in AML than in ALL

Severe gum swelling at presentation in Severe gum swelling at presentation in AML M5AML M5

InvestigationInvestigation

Full blood count Full blood count ( CBC)( CBC)

usually but not invariably shows reduced Hb conc. usually but not invariably shows reduced Hb conc. and platelet count. The WBC can vary from 1000 and platelet count. The WBC can vary from 1000 to 200000, and the differential WBC is often to 200000, and the differential WBC is often abnormal, with neutropenia and the presence of abnormal, with neutropenia and the presence of blast cellsblast cells. The anaemia is a normochromic, . The anaemia is a normochromic, normocytic anaemia, and thenormocytic anaemia, and the

thrombocytopenia may be severe (PLT 10000)thrombocytopenia may be severe (PLT 10000)..

Blood film of patient with ALLBlood film of patient with ALL

Blood film of patient with AMLBlood film of patient with AML


Coagulation screeningCoagulation screening::in promyelocytic leukaemia (AML M3) in promyelocytic leukaemia (AML M3) granules from the leukaemic blasts can granules from the leukaemic blasts can have procoagulant activity and trigger a have procoagulant activity and trigger a consumptive coagulopathy( DIC)consumptive coagulopathy( DIC)Biochemical screeningBiochemical screening

when the leucocyte count is very high, there when the leucocyte count is very high, there may be evidence of renal impairment and may be evidence of renal impairment and hyperuricaemiahyperuricaemia


Chest radiographyChest radiography: : is mandatory to exclude the is mandatory to exclude the presence of a mediastinal mass, which is presence of a mediastinal mass, which is present in up to 70% of pts with T cell ALL. In present in up to 70% of pts with T cell ALL. In childhood ALL lytic bone lesions may be seenchildhood ALL lytic bone lesions may be seen..

Bone marrow aspiration:Bone marrow aspiration: with or without trephine with or without trephine bx is essential to confirm acute leukaemia. The bx is essential to confirm acute leukaemia. The marrow is usually hypercellular, with a marrow is usually hypercellular, with a predominance of immature (blast) cellspredominance of immature (blast) cells..


ImmunophenotypingImmunophenotyping of the antigens of the antigens present on blasts isolated from the BM or present on blasts isolated from the BM or peripheral blood is the most reliableperipheral blood is the most reliable

method of determining whether the method of determining whether the leukaemia is lymphoid or myeloid, and leukaemia is lymphoid or myeloid, and cytochemistry helps to confirm myeloid orcytochemistry helps to confirm myeloid or

monocytic originmonocytic origin..


CytogeneticsCytogenetics and molecular studies and molecular studies often often detect abnormalities within the leukaemic detect abnormalities within the leukaemic clone that can have diagnostic orclone that can have diagnostic or

prognostic value—e.g, Philadelphia chrprognostic value—e.g, Philadelphia chr

which is the product of a translocation which is the product of a translocation between chromosomes 9 and 22, the between chromosomes 9 and 22, the presence of which confers a very poor presence of which confers a very poor prognosis in cases of ALLprognosis in cases of ALL


Lumbar puncture:Lumbar puncture: with CSF cytospin is an with CSF cytospin is an important initial staging investigation in important initial staging investigation in ALL or AML with neurological symptoms to ALL or AML with neurological symptoms to detect leukaemic cells in the CSF, detect leukaemic cells in the CSF, indicating involvement of the CNSindicating involvement of the CNS..

DDxDDx

• •IfIf lymphadenopathy lymphadenopathy: infectious mononucleosis or : infectious mononucleosis or lymphomalymphoma

• •If If hepatosplenomegalyhepatosplenomegaly: myeloproliferative or: myeloproliferative orlymphoproliferative disorder, myelodysplasia, metaboliclymphoproliferative disorder, myelodysplasia, metabolic,,

storage or autoimmune disorders (rarely, visceral storage or autoimmune disorders (rarely, visceral leishmaniasis)leishmaniasis)

• •If no peripheral leukaemic blasts but If no peripheral leukaemic blasts but pancytopeniapancytopenia: : aplastic anaemia or infiltrated BM involvement from aplastic anaemia or infiltrated BM involvement from nonhaemopoietic small round cell tumournonhaemopoietic small round cell tumour

• •MyelodysplasiaMyelodysplasia

TreatmentTreatment

• •Immediate (same day) referral to specialistImmediate (same day) referral to specialist

• •Prompt diagnosisPrompt diagnosis

• •Intensive supportive careIntensive supportive care

• •Systemic chemotherapySystemic chemotherapy

• •Treatment directed at CNS (in children and in Treatment directed at CNS (in children and in adult ALL)adult ALL)

• •Minimising early and late toxicity of treatmentMinimising early and late toxicity of treatment

Supportive treatmentSupportive treatment

Prophylactic PLT transfusions are given if PLT Prophylactic PLT transfusions are given if PLT count is 10000count is 10000..

Clotting abnormalities may result from a DIC Clotting abnormalities may result from a DIC where infusions of FFP and cryoprecipitate may where infusions of FFP and cryoprecipitate may be beneficialbe beneficial..

Packed red cell transfusions are given for Packed red cell transfusions are given for symptomatic anaemia, though these are symptomatic anaemia, though these are contraindicated if the WBC is extremely high. In contraindicated if the WBC is extremely high. In most patients a central venous catheter is most patients a central venous catheter is inserted to facilitate blood product support, inserted to facilitate blood product support, administration of chemotherapy and antibiotics, administration of chemotherapy and antibiotics, and frequent blood samplingand frequent blood sampling..

Supportive RxSupportive Rx

Adequate hydration and allopurinol are Adequate hydration and allopurinol are essential at the start of treatment to essential at the start of treatment to reduce the risk of hyperkalaemiareduce the risk of hyperkalaemia,,

hyperuricaemia, and renal damagehyperuricaemia, and renal damage

Supportive RxSupportive Rx

Serious infection is a common cause of death in Serious infection is a common cause of death in patients with acute leukaemia, as BM failure due patients with acute leukaemia, as BM failure due to the leukaemia and to chemotherapy often to the leukaemia and to chemotherapy often results in profound neutropenia for 2 weeks or results in profound neutropenia for 2 weeks or more. Reverse-barrier nursing techniques more. Reverse-barrier nursing techniques should therefore be used for such patients, andshould therefore be used for such patients, and

iv antimicrobial agents should be started as soon iv antimicrobial agents should be started as soon as there is a fever or other sign of infectionas there is a fever or other sign of infection..

Pseudomonas infection of skin and nail bed in patient Pseudomonas infection of skin and nail bed in patient having treatment for AMLhaving treatment for AML

ChemotherapyChemotherapy

The aim is initially to The aim is initially to induce ainduce a remissionremission (5% blasts (5% blasts in the BM) and then to eradicate the residual in the BM) and then to eradicate the residual leukaemic cell population by further courses of leukaemic cell population by further courses of consolidationconsolidation therapy. The drugs damage the therapy. The drugs damage the capacity of the leukaemic cells to divide and capacity of the leukaemic cells to divide and replicate, and using cyclical combinations of replicate, and using cyclical combinations of three or more drugs increases the cytotoxic three or more drugs increases the cytotoxic effect, improves the chance of remission after effect, improves the chance of remission after the initial “induction” period, and reduces the the initial “induction” period, and reduces the emergence of drug resistanceemergence of drug resistance..


In ALL the induction course is followed by In ALL the induction course is followed by two or more consolidation periods and by two or more consolidation periods and by treatment directed at the CNS, followed by treatment directed at the CNS, followed by long term maintenance or continuation long term maintenance or continuation treatment for up to two years. This has treatment for up to two years. This has been shown to improve long term cure been shown to improve long term cure rates in ALL, though not in AMLrates in ALL, though not in AML..


In AMLIn AML: : treated with 4 or 5 courses of intensive treated with 4 or 5 courses of intensive chemotherapy when there is intent to cure. Each chemotherapy when there is intent to cure. Each course consists of 10 days of chemotherapy. course consists of 10 days of chemotherapy. Subsequent courses are started after cell counts Subsequent courses are started after cell counts have recovered and response to treatment is have recovered and response to treatment is established. In AML M3 the drug ATRA (all-established. In AML M3 the drug ATRA (all-trans-retinoic acid) is used as an adjunct totrans-retinoic acid) is used as an adjunct tochemotherapy as it causes differentiation of the chemotherapy as it causes differentiation of the malignant clonemalignant clone..

Treatment of CNSTreatment of CNS

The treatment or prevention of leukaemic The treatment or prevention of leukaemic cells in CNS is part of all treatment cells in CNS is part of all treatment protocols in childhood leukaemia and adult protocols in childhood leukaemia and adult ALL, but not in adults with AML unless ALL, but not in adults with AML unless they have symptoms or blasts in the CSF. they have symptoms or blasts in the CSF. TreatmentTreatment::

regular intrathecal chemotherapy (usually regular intrathecal chemotherapy (usually methotrexate), high dose intravenous methotrexate), high dose intravenous methotrexate, or cranial irradiationmethotrexate, or cranial irradiation..

BM transplantationBM transplantation

Up to 85% of patients who initially achieve a Up to 85% of patients who initially achieve a complete remission will subsequently complete remission will subsequently relapse. Transplantation reduces relapse relapse. Transplantation reduces relapse risk but has been associated with high risk but has been associated with high procedural mortality. The development of procedural mortality. The development of peripheral rather than BM stem cell peripheral rather than BM stem cell harvest has reduced proceduralharvest has reduced procedural

mortalitymortality..

BM transplantationBM transplantation

Autologous transplantation involves stem Autologous transplantation involves stem cell rescue (with patients’ own cells cell rescue (with patients’ own cells harvested in remission) after a potentially harvested in remission) after a potentially lethal dose of chemotherapylethal dose of chemotherapy..

Toxicity to therapyToxicity to therapy

Early side effectsEarly side effects Nausea and vomiting, mucositis, hair loss, Nausea and vomiting, mucositis, hair loss,

neuropathy, and renal and hepatic dysfunctionneuropathy, and renal and hepatic dysfunction . .Myelosuppression, resulting in profound Myelosuppression, resulting in profound neutropenia for two or more weeks with resultant neutropenia for two or more weeks with resultant opportunistic infection. Febrile neutropenic opportunistic infection. Febrile neutropenic episodes require prompt use of broad spectrum episodes require prompt use of broad spectrum antibiotics. Many patients also develop fungal antibiotics. Many patients also develop fungal infection requiring treatment with systemic infection requiring treatment with systemic antifungal drugs. Viral infection is predominantly antifungal drugs. Viral infection is predominantly seen in the post-transplant settingseen in the post-transplant setting..

Toxicity to therapyToxicity to therapy

Late effectsLate effects • •Cardiac: Cardiac: Arrhythmias, cardiomyopathyArrhythmias, cardiomyopathy

• •Pulmonary: Pulmonary: FibrosisFibrosis • •Endocrine: Endocrine: Growth delay, hypothyroidism, gonadalGrowth delay, hypothyroidism, gonadal

dysfunction or failure, infertilitydysfunction or failure, infertility • •Renal: Renal: Reduced glomerular filtration rateReduced glomerular filtration rate

• •Psychological: Psychological: Intellectual dysfunction, long term anxietyIntellectual dysfunction, long term anxietyabout relapseabout relapse

• •Second malignancy: Second malignancy: Secondary leukaemias or solid Secondary leukaemias or solid tumourstumours

.. CataractCataract

PrognosisPrognosis

Poor prognosis in ALLPoor prognosis in ALLAge < 1 year or > 10 yearsAge < 1 year or > 10 yearsSex MaleSex MalePresenting WBC 50000Presenting WBC 50000

CNS disease Presence of blasts in CSFCNS disease Presence of blasts in CSF at presentationat presentation

Remission problems Failure to remit after first induction treatmentRemission problems Failure to remit after first induction treatment

Cytogenetics Philadelphia positive—that is, t(9;22)or t(4;11) Cytogenetics Philadelphia positive—that is, t(9;22)or t(4;11) ALLALL

Poor prognosis in AMLPoor prognosis in AML

AgeAge > 60 years > 60 yearsSex Sex Male or female Male or femalePresenting WBCPresenting WBC >50000 >50000

CNS diseaseCNS disease Presence of blasts in CSF Presence of blasts in CSFat presentationat presentation

Remission problemsRemission problems 20% blasts in BM after 1st 20% blasts in BM after 1st coursecourse

Cytogenetics Cytogenetics Deletions or monosomy of Deletions or monosomy of chromosome 5 or 7 or complex chromosomal chromosome 5 or 7 or complex chromosomal abnormalitiesabnormalities

SurvivalSurvival

Type At 5 yearsType At 5 years

Childhood ALL 65-75%Childhood ALL 65-75%

Adult ALL 20-45%Adult ALL 20-45%

AML, aged < 60 yr 35-40%AML, aged < 60 yr 35-40%

AML, aged > 60 yr 10%AML, aged > 60 yr 10%

Health & Medicine

medicine.Acute leukemias.(dr.sabir)