Acute LeukemiaRakesh Biswas

MD, Professor, Department of Medicine, People's College of Medical Sciences,

Bhanpur, Bhopal, India

A 16 year old girlA 16 year old girl

Extreme pallorExtreme pallorgum bleeds, Purpura,With gum bleeds, Purpura,With

Lymphadenopathy and Lymphadenopathy and HepatosplenomegalyHepatosplenomegaly

Possible causes: Possible causes:

Investigations and treatmentInvestigations and treatment

Only a week later, D was ill Only a week later, D was ill again, with a fever, severe again, with a fever, severe headache, and extreme headache, and extreme lethargy. lethargy.

During a sunny spring weekend, During a sunny spring weekend, D would go outside to play, only D would go outside to play, only to return minutes later to return minutes later exhausted, flopping herself onto exhausted, flopping herself onto the sofa to restthe sofa to rest

LeukemiaLeukemia

Group of malignant disorders of the Group of malignant disorders of the hematopoietic tissues characteristically hematopoietic tissues characteristically associated with increased numbers of associated with increased numbers of white cells in the bone marrow and / or white cells in the bone marrow and / or peripheral bloodperipheral blood

Once inside the van and on our Once inside the van and on our way out of the clinic parking lot, way out of the clinic parking lot, she asked, she asked,

"Dad, what is leukemia?" "Dad, what is leukemia?"

"Can I die from this?""Can I die from this?"

ClassificationClassified based on cell type involved Classified based on cell type involved

and the clinical courseand the clinical course1. 1. Acute Acute : : ALLALLAMLAML

2. 2. ChronicChronic : :CLLCLLCMLCML

Subclassification

ALL ALL Common type( pre-B)Common type( pre-B)B-cellB-cellT-cellT-cellUndifferentiatedUndifferentiated

After the oncologist performed a bone marrow aspiration to confirm the diagnosis of leukemia, we learned specifically what type it was and the count. "D had acute lymphoblastic leukemia, early pre-B cell.

Myelomono

AMLAMLFrench-American-British (FAB) ClassificationFrench-American-British (FAB) Classification

M0: Minimally differentiated leukemiaM0: Minimally differentiated leukemiaM1: Myeloblastic leukemia without maturationM1: Myeloblastic leukemia without maturationM2: Myeloblastic leukemia with maturationM2: Myeloblastic leukemia with maturationM3M3: Hypergranular promyelocytic leukemia: Hypergranular promyelocytic leukemiaM4Eo: Variant: Increase in abnormal marrow M4Eo: Variant: Increase in abnormal marrow eosinophils eosinophilsM4:M4: Myelomonocytic leukemia Myelomonocytic leukemiaM5M5: Monocytic leukemia: Monocytic leukemiaM6: Erythroleukemia (DiGuglielmo's disease)M6: Erythroleukemia (DiGuglielmo's disease)M7: Megakaryoblastic leukemiaM7: Megakaryoblastic leukemia

Ref-Harrison’s Principle of Internal Medicine

CLLCLLB-cell: commonB-cell: commonT-cell: rareT-cell: rare

CMLCML Ph +vePh +vePh –ve, BCR-abl +vePh –ve, BCR-abl +vePh –ve, BCR-abl -vePh –ve, BCR-abl -veEosinophilic LeukemiaEosinophilic Leukemia

Ph: Philadelphia chromosomePh: Philadelphia chromosome BCR: Breakpoint cluster region; abl : Abelson oncogeneBCR: Breakpoint cluster region; abl : Abelson oncogene

Acute Myeloid Leukemia

( AML)Malignant transformation of a Malignant transformation of a

myeloid precursor cell ; myeloid precursor cell ; usually occurs at a very early stage usually occurs at a very early stage of myeloid developmentof myeloid development

Rare in childhood & incidence Rare in childhood & incidence increases with ageincreases with age

EtiologyUnknown / De-novo !! In majority Unknown / De-novo !! In majority

Predisposing factorsPredisposing factors:: Ionizing radiation exposureIonizing radiation exposurePrevious chemotherapy : alkylating agentsPrevious chemotherapy : alkylating agentsOccupational chemical exposure : benzeneOccupational chemical exposure : benzeneGenetic factors: Down’s Syndrome, Bloom’s, Genetic factors: Down’s Syndrome, Bloom’s,

Fanconi’s AnemiaFanconi’s AnemiaViral infection ( HTLV-1)Viral infection ( HTLV-1) Immunological : hypogammaglobulinemiaImmunological : hypogammaglobulinemiaAcquired hematological condition -SecondaryAcquired hematological condition -Secondary

Epidemiology

M > FM > F

ALL which predominantly affects ALL which predominantly affects younger individualsyounger individuals

AML – adults and the elderlyAML – adults and the elderlyMedian age gp-65yrsMedian age gp-65yrs

Geographical variation-noneGeographical variation-none

Clinical features

GeneralGeneral : : Onset is abrupt & stormy Onset is abrupt & stormy

(usually present within 3 months)(usually present within 3 months)

Bone marrow failure Bone marrow failure (anemia, infection ,bleeding)(anemia, infection ,bleeding)

Bone pain & tendernessBone pain & tenderness

Specific:Specific:M2M2 : Chloroma:-presents as a mass lesion : Chloroma:-presents as a mass lesion

‘tumor of leukemic cells’ ‘tumor of leukemic cells’ M3M3 : DIC : DICM4/M5M4/M5 : Infiltration of soft tissues, : Infiltration of soft tissues,

gum infiltrationgum infiltration, skin , skin deposits ,Meningeal involvement-headache, deposits ,Meningeal involvement-headache, vomiting, eye symptomsvomiting, eye symptoms

Skin Infiltration with AML (Leukemia Cutis)

Diagnosis

Blood countBlood count : : WBC usually elevated (50,000- WBC usually elevated (50,000- 1,00,000 / cmm ); may be normal or 1,00,000 / cmm ); may be normal or low; often low; often anemia & thrombocytopeniaanemia & thrombocytopenia

Blood filmBlood film : (as above) : (as above) Blast cells Blast cells

P. Smear AML

Bone marrow aspirate & trephineBone marrow aspirate & trephine: : Hypercellular, Hypercellular, blast cells blast cells ( > 20%),( > 20%), presence of presence of Auer rods - Auer rods - AML type AML type

Cytochemistry Cytochemistry : : Special stains to Special stains to differentiate AML from ALL ;differentiate AML from ALL ; Positivity Positivity with Sudan black & with Sudan black & Myeloperoxidase (MPO) in AMLMyeloperoxidase (MPO) in AML

Jemshidi trephine & Salah aspiration needle

Auer Rods in Leukemia cells

MPO (right) & Sudan black (left) showing intense localised positivity in blasts

Confirmation:Confirmation:ImmunophenotypingImmunophenotypingMolecular geneticsMolecular geneticsCytogenetics: Chromosomal Cytogenetics: Chromosomal

abnormalitiesabnormalities

Other InvOther Inv::

Coagulation screen, Coagulation screen, fibrinogen, fibrinogen, D- D- dimerdimer

RFT, LFTRFT, LFT LDH, Uric acidLDH, Uric acid Urine Urine CXRCXR ECG, ECHOECG, ECHO

Management

I. I. Supportive careSupportive care : : Anemia – red cell transfusionAnemia – red cell transfusion Thrombocytopenia – platelet concentratesThrombocytopenia – platelet concentrates Infection – broad spectrum IV antibioticsInfection – broad spectrum IV antibiotics Hematopoietic growth factors : Hematopoietic growth factors :

GM-CSF, G-CSF GM-CSF, G-CSF

Barrier nursingBarrier nursing Indwelling central venous catheterIndwelling central venous catheter

Metabolic problemsMetabolic problems : : Monitoring hepatic / renal Monitoring hepatic / renal / hematologic function; / hematologic function; Fluid & Fluid & electrolyte balance, nutrition electrolyte balance, nutrition Hyperuricemia- hydration, AllopurinolHyperuricemia- hydration, Allopurinol

Psychological supportPsychological support

The white blood cell count in her peripheral blood was about

550,000.

Her bone marrow was packed with leukemia blasts."

The next thing that occurred was a procedure called leukopheresis.

This procedure lasted 4 hours and cut D’s white blood cell (WBC) count in half--to about 250,000.

She was administered chemotherapy immediately following the leukopheresis procedure.

The next day we learned that the chemo had produced an effect as well: The WBC had halved again--125,000.

SPECIFIC THERAPHY:SPECIFIC THERAPHY:

ChemotherapyChemotherapy : :

InductionInduction: (4-6 wks): (4-6 wks)

vincristine, prednisone,vincristine, prednisone,

anthracycline, anthracycline, (idarubicin or (idarubicin or daunorubicin)daunorubicin)

cyclophosphamide, and L-asparaginasecyclophosphamide, and L-asparaginase

ConsolidationConsolidation: : (multiple cycles of (multiple cycles of intensive chemotherapy given over a 6 to 9 intensive chemotherapy given over a 6 to 9

month period).month period).

Cytosine arabinoside, high-dose Cytosine arabinoside, high-dose methotrexate, etoposide methotrexate, etoposide anthracycline, anthracycline, (idarubicin or daunorubicin)(idarubicin or daunorubicin)

Maintenance phase:(18 to 24 months).

LPs with intrathecal MTX every 3 months,

Monthly vincristine,

Daily 6-MP, and weekly MTX.

At day 29 of the induction At day 29 of the induction protocol D was declared to be in protocol D was declared to be in complete remission. complete remission.

We were all relieved with this We were all relieved with this news. news.

Step two was the next phase of Step two was the next phase of treatment called consolidation treatment called consolidation therapy. therapy.

This entailed multiple This entailed multiple combinations of drugs combinations of drugs administered on a rotational administered on a rotational basis (on various weeks) for the basis (on various weeks) for the next six months. next six months.

For instance, she would receive For instance, she would receive an infusion of methotrexate for a an infusion of methotrexate for a couple of days and then take 6-couple of days and then take 6-MP by mouth for a week. MP by mouth for a week.

Another cycle included VM-26 Another cycle included VM-26 (Teniposide) and Ara-C. (Teniposide) and Ara-C.

Complete remissionComplete remission ( CR): ( CR): < 5% blast cells in normocellular bone < 5% blast cells in normocellular bone marrowmarrow

AutologousAutologous BMT BMT : : Can be curative in younger patient (< Can be curative in younger patient (< 40-50 yrs)40-50 yrs)

Exactly 5 months since her Exactly 5 months since her diagnosis, and 16 weeks of diagnosis, and 16 weeks of remission…remission…

"We're at the clinic. D has "We're at the clinic. D has relapsed. Her white count is relapsed. Her white count is 27,000." 27,000."

The Consolidation protocol had The Consolidation protocol had been dropped and replaced with been dropped and replaced with a new induction protocol. a new induction protocol.

After the bone marrow aspiration to After the bone marrow aspiration to determine the extent of the leukemia determine the extent of the leukemia relapse, she was given doxirubicin, relapse, she was given doxirubicin, vincristine and L-asparaginase. vincristine and L-asparaginase.

For several days following D‘s For several days following D‘s discharge from the bone discharge from the bone marrow transplant unit, all of us marrow transplant unit, all of us loaf around the house and loaf around the house and recuperate from our 90 day recuperate from our 90 day marathon… marathon…

……the first 30 days representing the first 30 days representing Ds' relapse and the induction Ds' relapse and the induction therapy to obtain a second therapy to obtain a second

remissionremission

Back in fighting form, D Back in fighting form, D proceeds directly to the final 30 proceeds directly to the final 30 days of the marathon--the days of the marathon--the actual bone marrow transplant.actual bone marrow transplant.

BMT patients are in a delicate BMT patients are in a delicate condition following dischargecondition following discharge

Looking back, the nine weeks or Looking back, the nine weeks or so--the post BMT discharge so--the post BMT discharge period--was a sublime time for period--was a sublime time for us. us.

D was home and was feeling D was home and was feeling pretty good. pretty good.

As D’s hair began to grow As D’s hair began to grow again, we rubbed her head again, we rubbed her head every night at the dinner table, every night at the dinner table, wondering what color it was wondering what color it was going to be or if it was going to going to be or if it was going to be curly or straight. be curly or straight.

We never found out.We never found out.

On Monday, March 1, 1999 we On Monday, March 1, 1999 we went to clinic and waited for the went to clinic and waited for the lab results. lab results.

The results came back as we The results came back as we feared.feared.

D had relapsed. Her white D had relapsed. Her white count was 47,000. We were count was 47,000. We were devastated. devastated.

III. PALLIATIVE THERAPHYIII. PALLIATIVE THERAPHYChemo, RT, Blood product support Chemo, RT, Blood product support

Prognosis

Median survival without treatment is 5 Median survival without treatment is 5 weeksweeks

30% 5-yr survival in younger patients with 30% 5-yr survival in younger patients with chemotherapy chemotherapy

Disease which relapses during treatment Disease which relapses during treatment or soon after the end of treatment has a or soon after the end of treatment has a poor prognosispoor prognosis

Poor prognostic factors

Increasing ageIncreasing ageMale sexMale sexHigh WBC count at diagnosisHigh WBC count at diagnosisCNS involvement at diagnosisCNS involvement at diagnosisCytogenetic abnormalitiesCytogenetic abnormalitiesAntecedent hematological Antecedent hematological

abnormalities (eg. MDS) abnormalities (eg. MDS) No complete remissionNo complete remission

Two things that I will always Two things that I will always remember about D: She was a remember about D: She was a collector of many things, trinket collector of many things, trinket boxes, key rings. boxes, key rings.

But she was first and foremost a But she was first and foremost a collector of "FRIENDS." collector of "FRIENDS."

Among other things, she wrote:Among other things, she wrote:

"Hair loss is a side effect of "Hair loss is a side effect of chemotherapy, and cancer is a chemotherapy, and cancer is a

side effect of life."side effect of life."

Summary;

Learning Points

THANK YOUTHANK YOU