leukemia john h. ward, md professor of medicine chief, oncology division department of internal...
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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
Myelodysplastic syndromesMyelodysplastic syndromesFAB WHO ClassificationFAB WHO Classification
RARA RARSRARS RAEBRAEB RAEBIT now AMLRAEBIT now AML CMMLCMML now in myelodysplastic/myeloproliferative now in myelodysplastic/myeloproliferative
diseasedisease
Myelodysplastic syndromesMyelodysplastic syndromesFAB WHO ClassificationFAB WHO Classification
RARA RARSRARS RAEBRAEB
RAEB-1: 5-9% blastsRAEB-1: 5-9% blasts RAEB-2: 10-19% blastsRAEB-2: 10-19% blasts
Myelodysplastic syndromesMyelodysplastic syndromesFAB WHO ClassificationFAB WHO Classification
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 syndromesFAB WHO ClassificationFAB WHO Classification
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
Chronic Lymphocytic LeukemiaChronic 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
Chronic Lymphocytic LeukemiaChronic Lymphocytic Leukemia
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
Chronic Lymphocytic LeukemiaChronic Lymphocytic Leukemia
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
Hairy Cell LeukemiaHairy Cell Leukemia
Hairy Cell LeukemiaHairy Cell Leukemia
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
Lymphoma ClassificationLymphoma Classification
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
Lymphoma ClassificationLymphoma Classification
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
Lymphoma ClassificationLymphoma Classification
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