seyyed reza safaee md internist- hematologist&oncologist hematology&oncology&...

Seyyed Reza Seyyed Reza Safaee MDSafaee MD

Internist- Hematologist&Oncologist

Hematology&Oncology& Hematopoietic Stem Cell

Transplantation Ward

Imam Khomeini General Hospital

Tehran University Of

Medical Sciences (Tehran-Iran)

Aplastic anemiaAplastic anemia

Aplastic anemia is characterized by Aplastic anemia is characterized by diminished or absent hematopoietic diminished or absent hematopoietic precursors in the bone marrow, most often precursors in the bone marrow, most often due to injury to the pluripotent stem celldue to injury to the pluripotent stem cell..

The disease is estimated to occur in two to The disease is estimated to occur in two to fourfour subjects per million population per yearsubjects per million population per year..

CAUSES AND MECHANISMS OF STEM CELL CAUSES AND MECHANISMS OF STEM CELL

FAILUREFAILURE CongenitalCongenital::

Fanconi anemiaFanconi anemia

Dyskeratosis congenitaDyskeratosis congenita Shwachman-Diamond Shwachman-Diamond

syndromesyndrome

Amegakaryocytic Amegakaryocytic thrombocytopenia thrombocytopenia

AcquiredAcquired:: External radiationExternal radiation Drugs:Drugs: nonsteroidal nonsteroidal antiinflammatory drugs antiinflammatory drugs (particularly (particularly phenylbutazone)phenylbutazone) chloramphenicol, gold, chloramphenicol, gold, sulfonamides, sulfonamides, antiepileptic drugs (eg, antiepileptic drugs (eg, felbamate, felbamate, carbamazepine, valproic carbamazepine, valproic acid,phenytoin), acid,phenytoin), nifedipinenifedipinesolvents/degreasing agentssolvents/degreasing agents Industrial chemicals Industrial chemicals Aninsecticides(benzene)Aninsecticides(benzene)Viral infection:Viral infection: parvovirus parvovirus B19,Hepatitis viruses B19,Hepatitis viruses A,B,C,GA,B,C,GHIVHIVIdiopathic aplastic anemiaIdiopathic aplastic anemia

Fanconi anemiaFanconi anemiaUpper extremity deformities are presentUpper extremity deformities are present

in over half of Fanconi anemia patientsin over half of Fanconi anemia patients

Radial hypoplasiaRadial hypoplasia Absent thumbs ,radius, wristAbsent thumbs ,radius, wrist SyndactylySyndactyly

Short stature, microcephalyShort stature, microcephaly , ,microphthalmia, small chinmicrophthalmia, small chin

Dyskeratosis CongenitaDyskeratosis Congenita

Abnormal Fingernails and ToenailsAbnormal Fingernails and Toenails : :ridges, splitting, wrinkled, soft, poorridges, splitting, wrinkled, soft, poornail growthnail growth

Reticular Pigmentation of the NeckReticular Pigmentation of the Neck and Chestand Chest

Oral Leukoplakia: white patches in theOral Leukoplakia: white patches in theinside of the mouth and tongueinside of the mouth and tongue

Idiopathic aplastic anemiaIdiopathic aplastic anemia

Many of these patients respond to immunosuppressive Many of these patients respond to immunosuppressive therapytherapy . .

There is an association of aplastic anemia with the rare There is an association of aplastic anemia with the rare immunologic disease, eosinophilic fasciitisimmunologic disease, eosinophilic fasciitis..

Aplasia can occur in the context of graft-versus-host Aplasia can occur in the context of graft-versus-host disease following allogeneic hematopoietic cell disease following allogeneic hematopoietic cell transplantationtransplantation..

Bone marrow lymphocytes of patients with aplastic Bone marrow lymphocytes of patients with aplastic anemia can inhibit hematopoiesis when cocultured anemia can inhibit hematopoiesis when cocultured with patient or normal marrowwith patient or normal marrow . .

Clonal disorderClonal disorder::There is a close relationship between aplastic anemia There is a close relationship between aplastic anemia and the clonal multilineage hematopoietic disorders: and the clonal multilineage hematopoietic disorders: paroxysmal nocturnal hemoglobinuria, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome with a hypoplastic bone myelodysplastic syndrome with a hypoplastic bone marrowmarrow..

CLINICAL CLINICAL MANIFESTATIONSMANIFESTATIONS

AnemiaAnemia::PallorPallorFatigueFatigue

Cardiopulmonary Cardiopulmonary compromisecompromise

ThrombocytopeniaThrombocytopenia:: Mucosal hemorrhageMucosal hemorrhageIncreased menstrual flowIncreased menstrual flowPetechiae, Purpura, Petechiae, Purpura, EchymosisEchymosis

NeutropeniaNeutropenia::Bacterial sepsisBacterial sepsisPneumoniaPneumoniaUrinary tract Urinary tract infectioninfectionInvasive fungal Invasive fungal infectioninfection

Viral infectionViral infection

The liver, spleen, and lymph nodes are The liver, spleen, and lymph nodes are notnot enlargedenlarged..

DIAGNOSISDIAGNOSIS

Complete blood Complete blood countcount::

PancytopeniaPancytopenia

Reduced reticulocytesReduced reticulocytes

Peripheral Blood Peripheral Blood SmearSmear::

The red blood cells are The red blood cells are normocytic but normocytic but occasionally may be occasionally may be macrocyticmacrocytic . .

The remaining cellular elements are The remaining cellular elements are morphologically normalmorphologically normal..

PBSPBS

Bone marrow examinationBone marrow examination Aspiration an adequate BIOPSY of the Aspiration an adequate BIOPSY of the

bone marrowbone marrow

Bone marrow examinationBone marrow examination Aspiration and adequate BIOPSY of the Aspiration and adequate BIOPSY of the

bone marrowbone marrow

The marrow space is composed mostly of fat cells and marrow The marrow space is composed mostly of fat cells and marrow stromastroma

The bone marrow is profoundly hypocellular with a decrease in all The bone marrow is profoundly hypocellular with a decrease in all elementselements

Infiltration of the bone marrow with malignant cells or fibrosis is not Infiltration of the bone marrow with malignant cells or fibrosis is not present present

Residual hematopoietic cells are morphologically normal and Residual hematopoietic cells are morphologically normal and

hematopoiesishematopoiesis is not megaloblasticis not megaloblastic

Bone Marrow Bone Marrow CellularityCellularity

Normal Hypercellular Hypocellular

Normal BMNormal BM

Hypocellular BMHypocellular BM

Other tests or findings can confirm other Other tests or findings can confirm other potential diagnosespotential diagnoses::

Measurement of red cell membrane CD59 ,CD55 by Measurement of red cell membrane CD59 ,CD55 by flow cytometry: flow cytometry: PNHPNH ( coincident hemolysis or venous ( coincident hemolysis or venous thromboembolism with Aplastic anemia)thromboembolism with Aplastic anemia)

Cytogenetic analysis: Cytogenetic analysis: Hypoplastic myelodysplastic Hypoplastic myelodysplastic syndromesyndrome

Increased chromosomal breakage in lymphocytes Increased chromosomal breakage in lymphocytes cultured in presence of DNAcross-linking agents: cultured in presence of DNAcross-linking agents: Fanconi anemiaFanconi anemia

The The viral hemophagocytic syndromeviral hemophagocytic syndrome, , which may also which may also present with pancytopenia, is characterized by the present with pancytopenia, is characterized by the presence of bone marrow macrophages engorged presence of bone marrow macrophages engorged with hematopoietic cellswith hematopoietic cells

Diagnostic criteriaDiagnostic criteriaModerate aplastic Moderate aplastic anemiaanemia::

Bone marrow cellularity <30%Bone marrow cellularity <30%

Absence of severe pancytopeniaAbsence of severe pancytopenia Depression of at least two of Depression of at least two of

threethreeblood elements below normal blood elements below normal

Very severe aplastic Very severe aplastic anemiaanemia::

Severe aplastic anemiaSevere aplastic anemia::

A bone marrow biopsy showing A bone marrow biopsy showing <25% of normal cellularity<25% of normal cellularity

oror : :A bone marrow biopsy showing A bone marrow biopsy showing <50 percent normal <50 percent normal cellularity in which fewer than cellularity in which fewer than 30 percent of the cells are 30 percent of the cells are hematopoietic and at least hematopoietic and at least two of the following are two of the following are presentpresent : :

absolute reticulocyte count absolute reticulocyte count <40,000/microliter<40,000/microliter;;absolute neutrophil count (ANC) absolute neutrophil count (ANC) <500/microliter<500/microliterplatelet count platelet count <20,000/microliter<20,000/microliter

Severe aplastic anemia &the Severe aplastic anemia &the ANC is <200/microliterANC is <200/microliter

Prognosis FactorsPrognosis Factors

Disease severityDisease severity

Unless patients with Unless patients with SAA or vSAA are SAA or vSAA are successfully successfully treated, over 70 treated, over 70 percent will be dead percent will be dead within one yearwithin one year . .

Patient agePatient age

The increase in The increase in mortality in the mortality in the older patients was older patients was mainly due to mainly due to infection or infection or

bleedingbleeding . .

OCCURRENCE OF CLONAL DISORDERSOCCURRENCE OF CLONAL DISORDERS

following treatment for AAfollowing treatment for AA

Myelodysplastic syndrome (MDS)Myelodysplastic syndrome (MDS)

Acute myeloid leukemia (AML)Acute myeloid leukemia (AML)

Paroxysmal nocturnal hemoglobinuria (PNH)Paroxysmal nocturnal hemoglobinuria (PNH) ) )

Solid tumorsSolid tumors

Myelodysplastic syndrome Myelodysplastic syndrome

(MDS)(MDS) A heterogeneous group of malignant stem cell A heterogeneous group of malignant stem cell disorders characterized by disorders characterized by dysplasticdysplastic and and ineffective blood cell productionineffective blood cell production (ie, apoptotic (ie, apoptotic death) and a variable death) and a variable risk ofrisk of transformation to transformation to

acute leukemiaacute leukemia ..

These disorders may occur de novo or arise These disorders may occur de novo or arise years after exposure to potentially mutagenic years after exposure to potentially mutagenic therapy (radiation exposure, chemotherapy)therapy (radiation exposure, chemotherapy)..

The risk of developing MDS increases with The risk of developing MDS increases with ageage..

The median age in most series is ≥65 years, The median age in most series is ≥65 years, with a male predominancewith a male predominance..

Onset of the disease earlier than age 50 is Onset of the disease earlier than age 50 is unusual ,with the exception of treatment- unusual ,with the exception of treatment-

induced MDSinduced MDS..

CLINICAL PRESENTATIONCLINICAL PRESENTATION Many patients are Many patients are asymptomaticasymptomatic, with the , with the diagnosis established upon routine diagnosis established upon routine

laboratory screeninglaboratory screening . .

SymptomsSymptoms resulting from resulting from::AnemiaAnemia( fatigue, weakness, exercise ( fatigue, weakness, exercise intolerance, angina, dizziness, cognitive intolerance, angina, dizziness, cognitive impairment, or an altered sense of well impairment, or an altered sense of well being)being)

InfectionInfection (De to neutropenia& granulocyte (De to neutropenia& granulocyte dysfunction)dysfunction)::

Bacterial,fungal,viral,mycobacterialBacterial,fungal,viral,mycobacterial

Easy bruising or BleedingEasy bruising or Bleeding

Fever and Weight lossFever and Weight loss (uncommon) (uncommon)

Autoimmune manifestationsAutoimmune manifestations

Autoimmune manifestationsAutoimmune manifestations

Connective tissue Connective tissue disordersdisorders : :

Relapsing polychondritisRelapsing polychondritis

Polymyalgia rheumaticaPolymyalgia rheumatica

Raynaud phenomenon Raynaud phenomenon SjSjöögren's syndrome gren's syndrome Inflammatory bowel Inflammatory bowel diseasedisease

Pyoderma gangrenosum Pyoderma gangrenosum GlomerulonephritisGlomerulonephritis

Cutaneous vasculitisCutaneous vasculitisMonoarticular arthritisMonoarticular arthritisPericarditisPericarditisPleural effusionsPleural effusionsSkin ulcerationsSkin ulcerationsIritisIritisMyositisMyositis Peripheral neuropathyPeripheral neuropathy Pure red cell aplasiaPure red cell aplasia

Physical findingsPhysical findings Chronic myelomonocytic Chronic myelomonocytic leukemia (CMML) is leukemia (CMML) is exceptionexception::

Splenomegaly is massive Splenomegaly is massive in up to 25 percent of in up to 25 percent of patients and is often patients and is often accompanied by accompanied by hepatomegaly,lymphadehepatomegaly,lymphadenopathyand nodular nopathyand nodular cutaneous leukemic cutaneous leukemic

infiltratesinfiltrates . .

Paleness(60%)Paleness(60%)

Petechiae and/or Purpura(26%)Petechiae and/or Purpura(26%)

Hepatomegaly (uncommon)Hepatomegaly (uncommon)

Splenomegaly (uncommon)Splenomegaly (uncommon)

Lymphadenopathy(uncommon)Lymphadenopathy(uncommon)

Cutaneous manifestationsCutaneous manifestations

((uncommonuncommon))::Sweet's syndromeSweet's syndrome

((acute febrile neutrophilic dermatosisacute febrile neutrophilic dermatosis))

Myeloid sarcomaMyeloid sarcoma

((granulocytic sarcoma or chloromagranulocytic sarcoma or chloroma))

LABORATORY FINDINGSLABORATORY FINDINGS CBCCBC::

Anemia Anemia (almost uniformly (almost uniformly present)present)

Pancytopenia(50%)Pancytopenia(50%)Isolated neutropenia (<5%)Isolated neutropenia (<5%)

Isolated thrombocytopenia (<5%)Isolated thrombocytopenia (<5%)

Monocytosis (<5%)Monocytosis (<5%)

PBSPBS::

Normocytic,Macrocytic,MiNormocytic,Macrocytic,Microcytic Hypochromic crocytic Hypochromic red cellsred cells

OvalomacrocytosisOvalomacrocytosis,,Elliptocytes ,Teardrops, Elliptocytes ,Teardrops, Stomatocytes, Stomatocytes, AcanthocytesAcanthocytes

Basophilic stipplingBasophilic stipplingHowell-Jolly bodiesHowell-Jolly bodies

Megaloblastoid nucleated Megaloblastoid nucleated red cellsred cells

Peripheral Smear Peripheral Smear AnisopoikilocytosisAnisopoikilocytosis

Peripheral Blood Smear Peripheral Blood Smear Macrocytic Anemia

Ovalocytes&Macrocytosis Teardrop cells

Dimorphic Red Cell PopulationDimorphic Red Cell Population

Pelgeroid (pseudo Pelger-Huet) Pelgeroid (pseudo Pelger-Huet) NeutrophilNeutrophil

BONE MARROW EXAMINATIONBONE MARROW EXAMINATION

Bone Marrow aplasia or hypoplasia or hyperplasia Bone Marrow aplasia or hypoplasia or hyperplasia or normalor normal

Ringed sideroblastsRinged sideroblasts

Erythroid hyperplasia (ineffective erythropoiesis)Erythroid hyperplasia (ineffective erythropoiesis)

Red cell aplasia or hypoplasiaRed cell aplasia or hypoplasia

Internuclear bridging characterized by chromatin Internuclear bridging characterized by chromatin threads tethering dissociated nuclei, reflects threads tethering dissociated nuclei, reflects impaired mitosisimpaired mitosis

Bone Marrow Biopsy Bone Marrow Biopsy Hypocellular

Dyserythropoeisis on Bone Marrow Dyserythropoeisis on Bone Marrow AspirateAspirate

Bone MarrowBone Marrow DysplasticDysplastic Erythroid Precursors Erythroid Precursors

Dyserythropoiesis on Bone Marrow Dyserythropoiesis on Bone Marrow AspirateAspirate

Megaloblastoid Change on Bone Megaloblastoid Change on Bone Marrow AspirateMarrow Aspirate

Megaloblastoid ChangeMegaloblastoid Change

Hypersegmented NeutrophilHypersegmented Neutrophil

MicromegakaryocyteMicromegakaryocyte

Bone MarrowBone Marrow

Dysplastic Megakaryocytes

Hypolobated megakaryocytesHypolobated megakaryocytes

MDS/MPDMDS/MPD

Ringed SideroblastsRinged Sideroblasts

CLASSIFICATIONCLASSIFICATION Refractory anemiaRefractory anemia

Refractory anemia with ringed sideroblastsRefractory anemia with ringed sideroblasts

Refractory cytopenia with multilineage dysplasiaRefractory cytopenia with multilineage dysplasia

Refractory anemia with excess blastsRefractory anemia with excess blasts

Refractory anemia with excess blasts in Refractory anemia with excess blasts in transformationtransformation

Chronic myelomonocytic leukemiaChronic myelomonocytic leukemia

5q- syndrome5q- syndrome

Refractory anemiaRefractory anemia

is characterized by less than 5 percent bone is characterized by less than 5 percent bone marrow (BM) blasts, ≤1 percent blasts in marrow (BM) blasts, ≤1 percent blasts in the peripheral bloodthe peripheral blood..

Monocytosis, significant numbers of ringed Monocytosis, significant numbers of ringed sideroblasts, and Auer rods are absentsideroblasts, and Auer rods are absent . .

Refractory anemia with ringed Refractory anemia with ringed

sideroblastssideroblasts

fulfills all of the criteria for RA plus >15 fulfills all of the criteria for RA plus >15 percent ringed sideroblastspercent ringed sideroblasts..

Refractory cytopenia with multilineage Refractory cytopenia with multilineage

dysplasiadysplasia

is characterized by less than 5 percent BM is characterized by less than 5 percent BM blasts but severe dysplasia in two or more blasts but severe dysplasia in two or more

cell lineagescell lineages . .

Refractory anemia with excess Refractory anemia with excess

blastsblasts

is characterized by 5 to 19 percent BM blastsis characterized by 5 to 19 percent BM blasts . .

Refractory anemia with excess blasts in Refractory anemia with excess blasts in

transformationtransformation

Refractory anemia with excess blasts in Refractory anemia with excess blasts in transformation (RAEB-T) in the FAB transformation (RAEB-T) in the FAB classification system is characterized by 21 classification system is characterized by 21 to 30 percent BM blasts or ≥5 percent blasts to 30 percent BM blasts or ≥5 percent blasts

in the blood or the presence of Auer rodsin the blood or the presence of Auer rods . .

However, in the WHO classification system this However, in the WHO classification system this category is considered an evolving acute myeloid category is considered an evolving acute myeloid leukemia (AML) or AML with multilineage dysplasialeukemia (AML) or AML with multilineage dysplasia

Chronic myelomonocytic leukemiaChronic myelomonocytic leukemia Chronic myelomonocytic leukemia is considered Chronic myelomonocytic leukemia is considered by the WHO to be one of the by the WHO to be one of the myelodysplastic/myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, as it has features of both disordersas it has features of both disorders..

CMML is associated with up to 20 percent BM CMML is associated with up to 20 percent BM blasts, <5 percent blasts in the peripheral blasts, <5 percent blasts in the peripheral blood, and a peripheral blood monocyte count blood, and a peripheral blood monocyte count >1000/microL>1000/microL..

Auer rods are absent and ringed sideroblasts Auer rods are absent and ringed sideroblasts may or may not be presentmay or may not be present . .

In some classification systems, CMML has been divided into two In some classification systems, CMML has been divided into two subtypes: patients with a white blood cell count (WBC) subtypes: patients with a white blood cell count (WBC) ≤12,000/microL who are generally considered to have MDS, ≤12,000/microL who are generally considered to have MDS, and the proliferative-type of CMML with a WBC and the proliferative-type of CMML with a WBC >12,000/microL, who are often considered to have a >12,000/microL, who are often considered to have a myeloproliferative disordermyeloproliferative disorder

5q- syndrome5q- syndrome The finding of an interstitial deletion of the long The finding of an interstitial deletion of the long arm of chromosome 5 in some patients with MDS arm of chromosome 5 in some patients with MDS has led to an appreciation of this MDS subtypehas led to an appreciation of this MDS subtype..

Female predominance (7:3) with a median age at Female predominance (7:3) with a median age at diagnosis of 68 yearsdiagnosis of 68 years Transfusion-dependent anemia (80 %)Transfusion-dependent anemia (80 %) Low incidence of neutropenia( infection), Low incidence of neutropenia( infection),

thrombocytopenia (bleeding)thrombocytopenia (bleeding) Normal or increased platelet counts along with Normal or increased platelet counts along with

bone marrow hyperplasia of hypolobulated bone marrow hyperplasia of hypolobulated micromegakaryocytes micromegakaryocytes

Low incidence of transformation into acute Low incidence of transformation into acute leukemia (16%) leukemia (16%)

DIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS

Megaloblastic anemiaMegaloblastic anemia

Aplastic anemiaAplastic anemia

MyelofibrosisMyelofibrosis

Atypical CMLAtypical CML

HIV infectionHIV infection