Leukemia John H. Ward, MD Professor of Medicine Chief, Oncology Division Department of Internal...

LeukemiaLeukemia

John H. Ward, MDJohn H. Ward, MDProfessor of MedicineProfessor of Medicine

Chief, Oncology DivisionChief, Oncology Division

Department of Internal MedicineDepartment of Internal Medicine

University of Utah School of MedicineUniversity of Utah School of Medicine

Huntsman Cancer InstituteHuntsman Cancer Institute

Fall, 2005

LeukemiaLeukemia

Hallmark: proliferation of malignant cells in Hallmark: proliferation of malignant cells in the bone marrowthe bone marrow

Divided into:Divided into: acuteacute v. v. chronic chronic lymphoblastic lymphoblastic v.v. myeloid (non-lymphoblastic) myeloid (non-lymphoblastic)

Each type of leukemia has a different Each type of leukemia has a different presentation, natural history, prognosis, presentation, natural history, prognosis, and treatment.and treatment.

LeukemiaLeukemia

Acute leukemias: rapid onset, rapid death Acute leukemias: rapid onset, rapid death if treatment is not successful if treatment is not successful

Chronic leukemias: natural history Chronic leukemias: natural history measured in years, even without initial measured in years, even without initial treatmenttreatment

Acute LeukemiaAcute Leukemia Presenting features:Presenting features:

AnemiaAnemia• Fatigue, dyspnea, angina pectorisFatigue, dyspnea, angina pectoris

Neutropenia - the leukocyte count may be Neutropenia - the leukocyte count may be high or low, but high or low, but neutropenianeutropenia is characteristic is characteristic• Unexplained fever, serious infectionsUnexplained fever, serious infections

ThrombocytopeniaThrombocytopenia• Bruising, petechiaeBruising, petechiae

Less common: lymphadenopathy, Less common: lymphadenopathy, splenomegaly, skin infiltration, chloromas splenomegaly, skin infiltration, chloromas (tumors composed of malignant marrow cells)(tumors composed of malignant marrow cells)

Acute LeukemiaAcute Leukemia

Diagnosis: >20% blasts in the bone Diagnosis: >20% blasts in the bone marrowmarrow

Categorized byCategorized by H&E stainingH&E staining Cytochemical stains (myeloperoxidase, NSE)Cytochemical stains (myeloperoxidase, NSE) Flow cytometryFlow cytometry CytogeneticsCytogenetics

Acute LeukemiaAcute Leukemia

No evidence of maturation within No evidence of maturation within blood or marrow blood or marrow

Acute Non-Lymphoblastic Acute Non-Lymphoblastic Leukemia (ANLL, AML)Leukemia (ANLL, AML)

Age: Adults - incidence increases with ageAge: Adults - incidence increases with age Median age = 60 yearsMedian age = 60 years Incidence = 10/100,000 per year in those Incidence = 10/100,000 per year in those

> 60 years of age> 60 years of age ~9700 cases per year in USA~9700 cases per year in USA

PrognosisPrognosis Untreated - ~ six weeksUntreated - ~ six weeks With treatment - median survival = 18 monthsWith treatment - median survival = 18 months Some long term survivorsSome long term survivors

Acute Non-Lymphoblastic Acute Non-Lymphoblastic Leukemia (ANLL, AML)Leukemia (ANLL, AML)

TreatmentTreatment Anthracyclines + cytarabineAnthracyclines + cytarabine Upfront aggressive therapy with induction & Upfront aggressive therapy with induction &

consolidationconsolidation Stem cell transplantation for those in Stem cell transplantation for those in

remission with appropriate physiology, age remission with appropriate physiology, age and match.and match.

ANLL - FAB ClassificationANLL - FAB Classification

M0M0 Undifferentiated leukemiaUndifferentiated leukemia

MIMI AML without maturationAML without maturation

M2M2 AML with maturationAML with maturation

M3 M3 Acute promyelocytic leukemiaAcute promyelocytic leukemia

M4M4 Acute myleomonoblastic leukemiaAcute myleomonoblastic leukemia

M5M5 Acute monoblastic leukemiaAcute monoblastic leukemia

M6M6 ErythroleukemiaErythroleukemia

M7M7 Megakaryoblastic leukemiaMegakaryoblastic leukemia

Myeloblasts

Acute Myelogenous Leukemia

Acute Myelogenous Leukemia:Acute Myelogenous Leukemia:Auer RodAuer Rod

Blasts

Acute Myelogenous Leukemia with differentiation

Promyelocyes

Acute Promyelocytic Leukemia

Acute Monoblastic LeukemiaAcute Monoblastic Leukemia

Acute Myelomoncytic LeukemiaAcute Myelomoncytic Leukemia

ANLL - Clinical CorrelatesANLL - Clinical Correlates

M3: disseminated intravascular M3: disseminated intravascular coagulationcoagulation

M4, M5: skin & gum infiltrationM4, M5: skin & gum infiltration hypokalemia hypokalemia

M7: acute myelofibrosisM7: acute myelofibrosis

ANLLANLL Initial evaluation and managementInitial evaluation and management Define the phenotype of the leukemiaDefine the phenotype of the leukemia Correct metabolic abnormalitiesCorrect metabolic abnormalities Correct symptomatic anemiaCorrect symptomatic anemia Treat infectionTreat infection Control bleedingControl bleeding Begin tissue typing of potential transplant Begin tissue typing of potential transplant

candidatescandidates

ANLL - ANLL - TreatmentTreatment

Induction therapyInduction therapy Anthracycline + cytarabineAnthracycline + cytarabine goal: to ablate abnormal clone and achieve a goal: to ablate abnormal clone and achieve a

complete remission (CR)complete remission (CR) CR: normal blood counts with no increase in CR: normal blood counts with no increase in

marrow blasts.marrow blasts. Chance of CR: 60-85%Chance of CR: 60-85%

Acute Promyelocytic LeukemiaAcute Promyelocytic Leukemia

Associated with a 15;17 translocationAssociated with a 15;17 translocation Associated with severe DICAssociated with severe DIC May go into remission using all-May go into remission using all-trans trans

retinoic acidretinoic acid The only cause of DIC for which heparin is The only cause of DIC for which heparin is

occasionally usedoccasionally used

ANLL - TreatmentANLL - Treatment

After a CR is obtained, After a CR is obtained, consolidation consolidation therapy is needed.therapy is needed. In its absence, CRs are shortIn its absence, CRs are short With consolidation, 20-40% may be long-term With consolidation, 20-40% may be long-term

survivorssurvivors One form of consolidation therapy is marrow One form of consolidation therapy is marrow

transplanttransplant

ANLLANLLRole of Marrow TransplantRole of Marrow Transplant

Used as consolidation therapy of ANLL in Used as consolidation therapy of ANLL in 1st remission1st remission

Need HLA-matched donor, preferably a Need HLA-matched donor, preferably a siblingsibling

Typically requires a recipient aged 55 or Typically requires a recipient aged 55 or lessless

May have cure rates of 50-60%, but upfront May have cure rates of 50-60%, but upfront morbidity and mortality is problematicmorbidity and mortality is problematic

ANLL ANLL Features conferring a poor prognosisFeatures conferring a poor prognosis

ANLL arising from myelodysplastic ANLL arising from myelodysplastic syndromes (AML with multilineage syndromes (AML with multilineage dysplasia)dysplasia)

ANLL after chemotherapyANLL after chemotherapy Leukocyte count > 100 x 10Leukocyte count > 100 x 1099/L/L Complex karyotypeComplex karyotype Age > 60Age > 60 Need for mechanical ventilationNeed for mechanical ventilation

Some Important Translocations Some Important Translocations in Leukemiain Leukemia

15;17 translocation seen in acute 15;17 translocation seen in acute promyelocytic leukemia.promyelocytic leukemia.

8;21 translocation seen in 10% of ANLL, 8;21 translocation seen in 10% of ANLL, associated with better response to therapyassociated with better response to therapy

Inv16, associated with bone marrow Inv16, associated with bone marrow eosinophils and a good prognosiseosinophils and a good prognosis

11q23, associated with monocytic features 11q23, associated with monocytic features – intermediate survival– intermediate survival

Myelodysplastic SyndromesMyelodysplastic Syndromes

Hypercellular marrow with peripheral Hypercellular marrow with peripheral cytopeniascytopenias

Evidence of abnormal cellular Evidence of abnormal cellular maturation (ex. Dyserythropoiesis)maturation (ex. Dyserythropoiesis)

FAB classification subdivides disorders FAB classification subdivides disorders into clinically important groupsinto clinically important groups

May evolve into acute leukemiaMay evolve into acute leukemia

Myelodysplastic syndromesMyelodysplastic syndromesFAB classificationFAB classification

Refractory anemia (RA)Refractory anemia (RA) Refractory anemia with ringed sideroblasts Refractory anemia with ringed sideroblasts

(RARS)(RARS) Refractory anemia with excess blasts (RAEB)Refractory anemia with excess blasts (RAEB) Refractory anemia with excess blasts in Refractory anemia with excess blasts in

transformation (RAEBIT)transformation (RAEBIT) Chronic myelomoncytic leukemia (CMML)Chronic myelomoncytic leukemia (CMML)

Myelodysplastic syndromesMyelodysplastic syndromesFAB WHO ClassificationFAB WHO Classification

RARA RARSRARS RAEBRAEB RAEBITRAEBIT CMMLCMML


RARA RARSRARS RAEBRAEB RAEBIT now AMLRAEBIT now AML CMMLCMML now in myelodysplastic/myeloproliferative now in myelodysplastic/myeloproliferative

diseasedisease


RARA RARSRARS RAEBRAEB

RAEB-1: 5-9% blastsRAEB-1: 5-9% blasts RAEB-2: 10-19% blastsRAEB-2: 10-19% blasts


Refractory anemia (<5% blasts)Refractory anemia (<5% blasts) Refractory anemia with ringed sideroblasts (RARS)Refractory anemia with ringed sideroblasts (RARS)

RCMD with ringed sideroblasts (RSCMD)RCMD with ringed sideroblasts (RSCMD)

Refractory anemia with excess blasts (RAEB)Refractory anemia with excess blasts (RAEB) RAEB-1: 5-9% blastsRAEB-1: 5-9% blasts RAEB-2: 10-19% blastsRAEB-2: 10-19% blasts

Myelodysplastic syndromesMyelodysplastic syndromesWHO classificationWHO classification

Refractory anemia <5% blastsRefractory anemia <5% blasts Refractory anemiaRefractory anemia Refractory cytopenias with multilineage dysplasia (RCMD)Refractory cytopenias with multilineage dysplasia (RCMD) MDS with isolated del (5q-)MDS with isolated del (5q-) MDS-unclassified (MDS-U)MDS-unclassified (MDS-U)

Refractory anemia with ringed sideroblasts (RARS)Refractory anemia with ringed sideroblasts (RARS) RCMD with ringed sideroblasts (RSCMD)RCMD with ringed sideroblasts (RSCMD)

Refractory anemia with excess blasts (RAEB)Refractory anemia with excess blasts (RAEB) RAEB-1: 5-9% blastsRAEB-1: 5-9% blasts RAEB-2: 10-19% blastsRAEB-2: 10-19% blasts

MDS: IPSS scoreMDS: IPSS score

Score predicts prognosisScore predicts prognosis Features to be scoredFeatures to be scored

• Marrow blastsMarrow blasts• KaryotypeKaryotype• Number of CytopeniaNumber of Cytopenia

Scores split this group of diseases into Scores split this group of diseases into four prognostic groupsfour prognostic groups

Myelodysplastic SyndromesMyelodysplastic Syndromes

Survival depends on FAB subtype, or with Survival depends on FAB subtype, or with new classification, IPSS scorenew classification, IPSS score

Only curative treatment is BMTOnly curative treatment is BMT Supportive care is best option for those in Supportive care is best option for those in

whom marrow transplant is not feasiblewhom marrow transplant is not feasible New option for 5q- syndrome: New option for 5q- syndrome: lenalidomidelenalidomide

ANLLANLLSupportive CareSupportive Care

Erythrocyte transfusions - keep hematocrit Erythrocyte transfusions - keep hematocrit >30%>30%

Platelet transfusions - give when platelets Platelet transfusions - give when platelets <10 x 10<10 x 1099/L, or when at high bleeding risk/L, or when at high bleeding risk

Antibiotics - empiric antibiotics with feverAntibiotics - empiric antibiotics with fever Growth factorsGrowth factors

Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia (ALL)(ALL)

Age: Children (75% < 6 years of age)Age: Children (75% < 6 years of age) less common in adultsless common in adults

3200 cases/year3200 cases/year PrognosisPrognosis

Potential for cure is high in childrenPotential for cure is high in children long term remissions possible in adultslong term remissions possible in adults

TreatmentTreatment Induction therapy: vincristine + prednisone + other Induction therapy: vincristine + prednisone + other

agentsagents Consolidation and maintenance therapyConsolidation and maintenance therapy CNS prophylaxis mandantoryCNS prophylaxis mandantory

Acute Lymphoblastic Leukemia

ALLALL

Most cases are Tdt positiveMost cases are Tdt positive Most express CD10 (common ALL Most express CD10 (common ALL

antigen)antigen) Most are “pre-B cell” phenotypeMost are “pre-B cell” phenotype 15-20% T-cell lineage15-20% T-cell lineage 5% B-cell phenotype5% B-cell phenotype

ALLALL

With induction therapy, CR is attained in With induction therapy, CR is attained in 90% of patients.90% of patients.

Therapy usually lasts about 3 yearsTherapy usually lasts about 3 years Without CNS prophylaxis, CNS relapse is Without CNS prophylaxis, CNS relapse is

common and devastatingcommon and devastating

Acute Lymphoblastic LeukemiaAcute Lymphoblastic Leukemia

Bone marrow transplant reserved for Bone marrow transplant reserved for second remission or very high-risk up front second remission or very high-risk up front diseasedisease

High risk featuresHigh risk features Philadelphia chromosome +Philadelphia chromosome + B cell phenotypeB cell phenotype Leukocyte count > 100 x 10Leukocyte count > 100 x 1099/L/L Time to remission > 28 daysTime to remission > 28 days

Chronic LeukemiaChronic Leukemia

Often discovered because of an abnormal Often discovered because of an abnormal lab or an abnormal physical examinationlab or an abnormal physical examination

Severe cytopenias characteristic of acute Severe cytopenias characteristic of acute leukemia are seldom present at time of leukemia are seldom present at time of diagnosisdiagnosis

Chronic Myelogenous LeukemiaChronic Myelogenous Leukemia

Age: adultsAge: adults Prognosis: 3-4 years without BMT, cures Prognosis: 3-4 years without BMT, cures

possible with BMTpossible with BMT Treatment: Treatment:

Imatinib (Gleevec)Imatinib (Gleevec) Bone marrow transplantBone marrow transplant Hydroxyurea +/- interferon; Hydroxyurea +/- interferon;

Chronic Myelogenous LeukemiaChronic Myelogenous Leukemia

Leukocytosis Leukocytosis with all degrees of myeloid with all degrees of myeloid differentiationdifferentiation in blood and marrow in blood and marrow

Often associated with eosinophilia, Often associated with eosinophilia, basophilia, thrombocytosisbasophilia, thrombocytosis

Splenomegaly is characteristicSplenomegaly is characteristic LAP score is low (normal or high in other LAP score is low (normal or high in other

causes of leukocytosis)causes of leukocytosis)

Chronic Myelogenous Leukemia:Chronic Myelogenous Leukemia:Philadelphia ChromosomePhiladelphia Chromosome

9;22 translocation yields a chimeric gene 9;22 translocation yields a chimeric gene termed bcr-abltermed bcr-abl bcr derived from chromosome 22bcr derived from chromosome 22 abl derived from c-abl oncogene on chrom. 9abl derived from c-abl oncogene on chrom. 9

Encodes a 210,000 MW protein - a Encodes a 210,000 MW protein - a tyrosine protein kinasetyrosine protein kinase

Ability to detect transcript by PCR may Ability to detect transcript by PCR may enable us to detect molecular remissionsenable us to detect molecular remissions

Chronic Myelogenous Leukemia

PMN

Band

Eosinophil

Basophil

Early MyeloidCells

BCR-ABL translocation

Chronic Myelogenous Leukemia

Chronic Myelogenous LeukemiaChronic Myelogenous Leukemia Disease terminates in “blast crisis” in 3-4 Disease terminates in “blast crisis” in 3-4

years; this responds to treatment poorly, and years; this responds to treatment poorly, and is rapidly fatalis rapidly fatal Blast crisis may have the phenotype of non-Blast crisis may have the phenotype of non-

myeloid cellsmyeloid cells Leukocyte count > 200 x 10Leukocyte count > 200 x 1099/L may be /L may be

associated with leukostasisassociated with leukostasis Allogeneic BMT has been the treatment of Allogeneic BMT has been the treatment of

choice if the patient is a candidatechoice if the patient is a candidate Imatinib is a new optionImatinib is a new option

Chronic Myelogenous Leukemia:Chronic Myelogenous Leukemia:Results of BMTResults of BMT

Five year survival > 60% with allogeneic Five year survival > 60% with allogeneic BMTBMT

< 25% of patients have an HLA-matched < 25% of patients have an HLA-matched siblingsibling

Matched unrelated donors (MUD) may be Matched unrelated donors (MUD) may be usedused

Chronic Myelogenous LeukemiaChronic Myelogenous LeukemiaOther approachesOther approaches

Imatinib (Gleevec): Abl tyrosine kinase inhibitor: Imatinib (Gleevec): Abl tyrosine kinase inhibitor: dramatic responsesdramatic responses A classic example of targeted therapyA classic example of targeted therapy Probably not a cure, but a remarkable advanceProbably not a cure, but a remarkable advance 87% major genetic response in chronic phase87% major genetic response in chronic phase 55% response in blast crisis55% response in blast crisis

Alpha-interferonAlpha-interferon 34.7 % major genetic response34.7 % major genetic response

Hydroxyurea or alkylators can control Hydroxyurea or alkylators can control leukocytosisleukocytosis

Chronic Lymphocytic LeukemiaChronic Lymphocytic Leukemia

Age: the elderlyAge: the elderly Prognosis: may live for many years even Prognosis: may live for many years even

without treatmentwithout treatment Treatment: Watchful waiting, purine Treatment: Watchful waiting, purine

nucleoside analogues (fludarabine), nucleoside analogues (fludarabine), alkylatorsalkylators

Lymphocytosis

Chronic Lymphocytic Leukemia


Clonal proliferation of lymphocytesClonal proliferation of lymphocytes -95 % with B-cell phenotype-95 % with B-cell phenotype

Usually detected as an Usually detected as an asymptomatic asymptomatic lymphocytosislymphocytosis


Hypogammaglobulinemia is commonHypogammaglobulinemia is common Infection is the most common cause of Infection is the most common cause of

deathdeath Complications can include AIHA & ITPComplications can include AIHA & ITP May transform into an aggressive lymphomaMay transform into an aggressive lymphoma

Two staging systems exist: Rai & BinetEarly stage disease has a survival equivalent to age-

and sex-matched controls


Most patients do not require specific Most patients do not require specific treatmenttreatment

Indications for treatmentIndications for treatment anemiaanemia thrombocytopeniathrombocytopenia unsightly adenopathyunsightly adenopathy other complicationsother complications

When treatment is needed, alkylators or purine nucleoside analogues are used

Hairy Cell LeukemiaHairy Cell Leukemia

Age: adultsAge: adults Prognosis: many yearsPrognosis: many years Treatment: Adenosine deaminase Treatment: Adenosine deaminase

inhibitors (cladribine)inhibitors (cladribine)

Hairy cells: Cancerous leukocytes in the blood of a patient with hairy-cell leukaemia

Lancet Oncology Cover, February, 2003


Pancytopenia, splenomegalyPancytopenia, splenomegaly Marrow full of TRAP + lymphoid cellsMarrow full of TRAP + lymphoid cells Cells have projections when viewed with Cells have projections when viewed with

phase contrast or electron microscopyphase contrast or electron microscopy Very responsive to purine nucleoside Very responsive to purine nucleoside

analogues such as cladribineanalogues such as cladribine

Questions?Questions?Feel free to contact meFeel free to contact me

Office: 2141, Huntsman Cancer InstituteOffice: 2141, Huntsman Cancer Institute Office phone: 585-0255Office phone: 585-0255 Pager: 339-5214Pager: 339-5214 email: [email protected]: [email protected]

Lymphoma ClassificationLymphoma Classification

I. I. Good OnesGood Ones. (include nonconvoluted diffuse . (include nonconvoluted diffuse centrilobulated histioblastoma, immune binucleolar centrilobulated histioblastoma, immune binucleolar hyperbolic folliculated macrolymphosaracoma, Thyperbolic folliculated macrolymphosaracoma, T22--

terminal transferase-negative bimodal terminal transferase-negative bimodal prolymphoblastic leukosarcoma, Jergen-Kreuzart-prolymphoblastic leukosarcoma, Jergen-Kreuzart-Munier-Abdullah syndrome and reticulated Munier-Abdullah syndrome and reticulated histioblastic pseudo-Sezare IgM-secreting folliculoma).histioblastic pseudo-Sezare IgM-secreting folliculoma).

Characteristic: Characteristic: small tumor that does not recur after small tumor that does not recur after treatmenttreatment


II. II. Not-so-good OnesNot-so-good Ones. (formerly “hairy-cell” . (formerly “hairy-cell” pseudoincestuoblastoma, quasiconvoluted pseudoincestuoblastoma, quasiconvoluted binucleate germinoma, sarcoblastiocytoma, binucleate germinoma, sarcoblastiocytoma, Syrian variant of heavy chain disease, and Syrian variant of heavy chain disease, and German grossobeseioma).German grossobeseioma).

Characteristic: Characteristic: such tumors disappear with such tumors disappear with treatment but return and cause appreciable treatment but return and cause appreciable mortalitymortality


III. III. Really bad onesReally bad ones. (include farscial . (include farscial mononuclear diffuse convoluted mononuclear diffuse convoluted pseudoquasihistiolymphosarcomyleoblastoma, pseudoquasihistiolymphosarcomyleoblastoma, IgG variant of fragmented plasmatic IgG variant of fragmented plasmatic gammopathy, triconvoluted ipsilateral rhomboid gammopathy, triconvoluted ipsilateral rhomboid fever, Armour’s hyperthermic caninoma, and fever, Armour’s hyperthermic caninoma, and Hohner’s harmonica).Hohner’s harmonica).

Characteristic: Characteristic: regardless of treatment, these regardless of treatment, these tumors keep growingtumors keep growing


IV. IV. Ones that are not what they seemOnes that are not what they seem. (include . (include gall bladder disease, appendicitis, shotgun gall bladder disease, appendicitis, shotgun wounds, and ingrown toenails).wounds, and ingrown toenails).

Characteristic: Characteristic: these conditions are not actually these conditions are not actually lymphomas but are included for the sake of lymphomas but are included for the sake of completenesscompleteness

Leukemia John H. Ward, MD Professor of Medicine Chief, Oncology Division Department of Internal...

Documents

Transcript of Leukemia John H. Ward, MD Professor of Medicine Chief, Oncology Division Department of Internal...