Heme-Onc Subspeciality RoundsHeme-Onc Subspeciality Rounds

Dr.ChaudhryDr.Chaudhry

Dr.VysettiDr.Vysetti

CaseCase

HPI:HPI:57 Yr old male from Philippines gets admitted for evaluation of progressively 57 Yr old male from Philippines gets admitted for evaluation of progressively worsening fatigue and shortness of breath -2 wks.worsening fatigue and shortness of breath -2 wks.

- Had a mild sore throat and headache about a week ago which resolved on its own.Had a mild sore throat and headache about a week ago which resolved on its own.- Low grade feversLow grade fevers- ROS otherwise negativeROS otherwise negative

PMH:PMH:- Gout- Gout

PSH:PSH:-Hand surgery involving the joints.-Hand surgery involving the joints.

CaseCase

Meds:Meds:1.Allopurinol 100mg po qdaily1.Allopurinol 100mg po qdaily2.Tylenol Prn.2.Tylenol Prn.

Family History:Family History:Non contributoryNon contributory

Social History :Social History :Moved to US about a year ago.Moved to US about a year ago.Currently unemployed.Currently unemployed.lives with his wife who is a nurselives with his wife who is a nurse..

CaseCase

Vitals Vitals : Afeb P:102 B.p 80/50 98% on RA: Afeb P:102 B.p 80/50 98% on RA

Exam : Exam : Gen: Positive for Icterus and pallor.No enlarged LymphnodesGen: Positive for Icterus and pallor.No enlarged Lymphnodes

RS:CTARS:CTA

CVS:S1S2 no murmersCVS:S1S2 no murmers

GI :Soft, Spleen palpable 4 cm below the left subcostal margin.liver not palpable.Otherwise GI :Soft, Spleen palpable 4 cm below the left subcostal margin.liver not palpable.Otherwise Nontender ,BS +Nontender ,BS +

CNS : No focal deficits.CNS : No focal deficits.

Ext :No pedal odema.Ext :No pedal odema.

Labs on admission :Labs on admission :

CBC :CBC : Hgb 3.3 and Hematocrit of 13.5 (MCV – 98.2,MCH-41.9,MCHC-42.7,Bands 7%,Monocytes of Hgb 3.3 and Hematocrit of 13.5 (MCV – 98.2,MCH-41.9,MCHC-42.7,Bands 7%,Monocytes of 31%,Neutrophils -52%)31%,Neutrophils -52%)

CMP :CMP : Na :123,K:4.2 ,HCO3 17, Cl 93,BUN 18 and Creat 1.1,Total Bili 3.3,Alkphos 99,AST and ALT wnl. Na :123,K:4.2 ,HCO3 17, Cl 93,BUN 18 and Creat 1.1,Total Bili 3.3,Alkphos 99,AST and ALT wnl.

PT 18.7 & INR – 1.6 PT 18.7 & INR – 1.6

Hospital CourseHospital Course

Diagnostic Work up :Diagnostic Work up :-LDH -1145,-LDH -1145,

-Haptoglobin <6 ,-Haptoglobin <6 ,

-Retic count : 13.6-Retic count : 13.6

- PBS:clumping of RBC’s at room temp which resolved upon warming the slides.No Schistocytes.- PBS:clumping of RBC’s at room temp which resolved upon warming the slides.No Schistocytes.

Hospital CourseHospital Course

Follow up :Follow up :-Daily CBC’s,Total Bilirubin,Serum haptoglobulin and LDH.-Daily CBC’s,Total Bilirubin,Serum haptoglobulin and LDH.-RBC count and platelets remain low but stable.-RBC count and platelets remain low but stable.-H&H – 6.0 -9.8 Most recent -6.4-H&H – 6.0 -9.8 Most recent -6.4-Haptoglobulin <6 until recently reported as 27 (ref 36-195)-Haptoglobulin <6 until recently reported as 27 (ref 36-195)-LDH down to 464 from 1145.Recent uptrending 634.(132-268)-LDH down to 464 from 1145.Recent uptrending 634.(132-268)-Total Bilirubin 6.8-3.5.(0.0-1.0)-Total Bilirubin 6.8-3.5.(0.0-1.0)

Autoimmune hemolytic AnemiaAutoimmune hemolytic Anemia

--Autoimmune hemolytic anemia (AIHA) refers to a collection of disorders characterized by the Autoimmune hemolytic anemia (AIHA) refers to a collection of disorders characterized by the presence of autoantibodies that bind to antigens on patient's own erythrocytes, leading to presence of autoantibodies that bind to antigens on patient's own erythrocytes, leading to premature red cell destructionpremature red cell destruction

- Immune Disorder caused by antibodies directed against unmodified autologous red cells.- Immune Disorder caused by antibodies directed against unmodified autologous red cells.

PathophysiologyPathophysiology

IgG antibodies are relatively poor activators of complement and recognised more readily by the IgG antibodies are relatively poor activators of complement and recognised more readily by the Fc Receptors on the phagocytic cells.So in turn destroyed by Phagocytes of the RES.Fc Receptors on the phagocytic cells.So in turn destroyed by Phagocytes of the RES.

IgM-sensitised RBC’s generally are associated with both intravascular and extravascular IgM-sensitised RBC’s generally are associated with both intravascular and extravascular hemolysis.Intravascular because IgM unlike IgG more readily activate the complement pathway hemolysis.Intravascular because IgM unlike IgG more readily activate the complement pathway and produce intravascular hemolysis.Extravascular hemolysis occurs from RES being activated and produce intravascular hemolysis.Extravascular hemolysis occurs from RES being activated by the complement bound on the surface of the RBC.by the complement bound on the surface of the RBC.

Spleen is the principal site of IgG associated extravascular hemolysis and Kupffer cells in the liver Spleen is the principal site of IgG associated extravascular hemolysis and Kupffer cells in the liver are the principal effectors of IgM associated extravascular hemolysis.are the principal effectors of IgM associated extravascular hemolysis.

Classification of Immune hemolytic AnemiaClassification of Immune hemolytic Anemia

Warm Warm AIHA AIHA Idiopathic Vs SecondaryIdiopathic Vs SecondaryColdCold AIHA AIHA CAS :Idiopathic Vs Secondary CAS :Idiopathic Vs Secondary PCH : Idiopathic Vs Secondary PCH : Idiopathic Vs Secondary MixedMixed AIHA AIHA Drug InducedDrug Induced immune hemolytic anemia immune hemolytic anemiaAlloantibody-inducedAlloantibody-induced immune hemolytic anemia immune hemolytic anemia

Secondary causes: Infections, Autoimmune , Lymphoproliferative disordersSecondary causes: Infections, Autoimmune , Lymphoproliferative disorders..

DiagnosisDiagnosis

► Clinical Presentation and lab evidence of hemolysisClinical Presentation and lab evidence of hemolysis

► Serologic evidence of an AutoantibodySerologic evidence of an Autoantibody

Clinical PresentationClinical Presentation

--History : Recent Meds and Infections & Systemic illness.History : Recent Meds and Infections & Systemic illness.-Physical findings : Anemia,Jaundice, Organomegaly.-Physical findings : Anemia,Jaundice, Organomegaly.-Lab evaluation-Lab evaluation. Retic count-Increased. Retic count-Increased. PBS –Spherocytes,Schistocytes,Cold Agglutinins.. PBS –Spherocytes,Schistocytes,Cold Agglutinins.. Bone Marrow – r/o Malignancy.Erythroid Hyperplasia.. Bone Marrow – r/o Malignancy.Erythroid Hyperplasia.. UA – If Intravascular hemolysis -Hemoglobinuria. UA – If Intravascular hemolysis -Hemoglobinuria. Direct Globulin Test(Coomb’s) – identifies the presence of antibodies and/or complement . Direct Globulin Test(Coomb’s) – identifies the presence of antibodies and/or complement

on the surface of the erythrocyte.on the surface of the erythrocyte.. Other – elevated total bilirubin,AST and decreased Haptoglobin. Other – elevated total bilirubin,AST and decreased Haptoglobin. Immunohematologic studies. Immunohematologic studies

--

AutoantibodiesAutoantibodies

- - Two major types, each with specific characteristics, are produced in AIHA:Two major types, each with specific characteristics, are produced in AIHA:

- IgG antibodies : Generally react with protein antigens on the RBC surface at 37 c and so - IgG antibodies : Generally react with protein antigens on the RBC surface at 37 c and so called "warm agglutinins“. called "warm agglutinins“.

- IgM antibodies: Generally react with polysaccharide antigens on the RBC surface only at - IgM antibodies: Generally react with polysaccharide antigens on the RBC surface only at temperature 0-4 c and so called "cold agglutinins.” temperature 0-4 c and so called "cold agglutinins.”

Factors affecting the rate and location of erythrocyte Factors affecting the rate and location of erythrocyte destruction:destruction:

Characteristics of the autoantibody Characteristics of the autoantibody - Antibody isotype (eg, IgG, IgM, IgA) - Antibody isotype (eg, IgG, IgM, IgA) - Antibody titer (high vs. low) - Antibody titer (high vs. low) - Thermal reactivity (optimal binding temperature) - Thermal reactivity (optimal binding temperature) - Ability to fix complement - Ability to fix complement

. . Characteristics of the erythrocyte antigen Characteristics of the erythrocyte antigen - Specificity of the antigen - Specificity of the antigen - Surface density of the antigen - Surface density of the antigen

. . Characteristics of the reticuloendothelial (RE) clearance Characteristics of the reticuloendothelial (RE) clearance - Preferential location of clearance (hepatic vs. splenic)- Preferential location of clearance (hepatic vs. splenic)

Direct Antiglobulin testDirect Antiglobulin test

- - The RBCs of the patient are washed free of adherent proteins and reacted with The RBCs of the patient are washed free of adherent proteins and reacted with antiserum or monoclonal antibodies prepared against the various immunoglobulins, antiserum or monoclonal antibodies prepared against the various immunoglobulins, particularly IgG and a fragment of the third component of complement, C3d. particularly IgG and a fragment of the third component of complement, C3d.

- Positive test –Presence of an autoantibody- Positive test –Presence of an autoantibody - Further the sample is tested seperately with reagents specific for anti IgG and Anti-- Further the sample is tested seperately with reagents specific for anti IgG and Anti-

C3d.C3d.

Anti-IgGAnti-IgG Anti-C3Anti-C3 AntigenAntigen OccurrenceOccurrence CommentComment

++ --Rh protein Rh protein complexcomplex

Drugs: penicillin, Drugs: penicillin, aldomet; not in aldomet; not in SLESLE

Warm AIHA. Warm AIHA. Antibody (Ab) is Antibody (Ab) is IgGIgG

++ ++ GlycoproteinGlycoprotein Less common Less common AIHAAIHA

Ab is IgG which Ab is IgG which fixes fixes complementcomplement

-- ++ PolysaccharidePolysaccharide Cold agglutinin Cold agglutinin diseasedisease

Cold agglutinins Cold agglutinins in serum. Ab is in serum. Ab is IgMIgM

-- ++P blood group P blood group polysaccharidepolysaccharide

Paroxysmal cold Paroxysmal cold hemoglobinuriahemoglobinuria

Donath Donath Landsteiner may Landsteiner may be pos. Ab is be pos. Ab is IgG*IgG*

±± ±± ProteinProteinDrug-related Drug-related immune immune hemolysishemolysis

Antibody found Antibody found with enzyme-with enzyme-treated RBCs Ab treated RBCs Ab is low affinity IgGis low affinity IgG

±± ±± Protein + drugProtein + drugDrug-related Drug-related immune immune hemolysishemolysis

Drug needed to Drug needed to detect antibody detect antibody in serum. Ab is in serum. Ab is IgG or IgMIgG or IgM

-- -- Any of aboveAny of above Multiple causesMultiple causes

May require May require more sensitive more sensitive test for presence test for presence of antibodiesof antibodies

Warm Agglutinin DiseaseWarm Agglutinin Disease

Incidence Incidence - - 50%-70% cases 50%-70% cases

Etiology Etiology : Idiopathic Vs Secondary( CLL,Hodgkins,NHL,Autoimmune ): Idiopathic Vs Secondary( CLL,Hodgkins,NHL,Autoimmune )

Clinical course Clinical course :Insidious onset with waxing and waning course Vrs Fulminant hemolysis.:Insidious onset with waxing and waning course Vrs Fulminant hemolysis.

DiagnosisDiagnosis : Positive DAT and lab evidence of hemolysis. : Positive DAT and lab evidence of hemolysis.

--Rx:Rx: - Steroids, If no response to steroids next line of Rx includes splenectomy and cytotoxic drugs.- Steroids, If no response to steroids next line of Rx includes splenectomy and cytotoxic drugs.- Splenectomy has a response rate of 60-75%(removal of site of hemolysis )- Splenectomy has a response rate of 60-75%(removal of site of hemolysis )- Cytotoxic drugs in people who failed steroids and/or splenectomy- response rateCytotoxic drugs in people who failed steroids and/or splenectomy- response rate- of 40-60%(Cyclophosphamide and Azathioprine)of 40-60%(Cyclophosphamide and Azathioprine)- Other therapies :Rituximab (Anti –CD20 monoclonal AB),Plasmapheresis,?IVIG,Danazol- Other therapies :Rituximab (Anti –CD20 monoclonal AB),Plasmapheresis,?IVIG,Danazol- PRBC transfusions limited to life threatening hemolytic anemia.- PRBC transfusions limited to life threatening hemolytic anemia.

Cold AIHACold AIHA

CASCAS

- - More common More common - Middle-elderlyMiddle-elderly- Prim Vs Sec (MC)Prim Vs Sec (MC)- IgM IgM - Max reactivity in the cold but Max reactivity in the cold but

reactive up to 30 creactive up to 30 c

- Resistant to RxResistant to Rx

PCHPCH

- - Less commonLess common- ChildrenChildren- Often follows a URI Often follows a URI - IgG (DL)IgG (DL)- Biphasic hemolysin Biphasic hemolysin

demonstrated by incubation in demonstrated by incubation in cold followed by incubation at 37 cold followed by incubation at 37 c in presence of C.c in presence of C.

- Supportive Rx.Supportive Rx.

CAS CAS

IncidenceIncidence : : 16-32%16-32%

EtiologyEtiology : : Primary Vs Secondary Primary Vs Secondary -Infections: Mycoplasma,EBV,Influenza,HIV,E.coli,listeria-Infections: Mycoplasma,EBV,Influenza,HIV,E.coli,listeria -Lymphoproliferative : CLL,Lymphomas,Waldenstrom’s.-Lymphoproliferative : CLL,Lymphomas,Waldenstrom’s.

CF :CF : -Mild chronic hemolytic anemia exacerbated by cold environment-Mild chronic hemolytic anemia exacerbated by cold environmentepisodes of acute episodes of acute

hemolysis common in winter months.hemolysis common in winter months. -Clinical presentation corresponds with the immune response to an infectious agent.-Clinical presentation corresponds with the immune response to an infectious agent. -Symptoms appear 2-3 wks after the infections begins(corresponding to Cold Agglutinin titre) -Symptoms appear 2-3 wks after the infections begins(corresponding to Cold Agglutinin titre)

and resolve 2-3 wks later.and resolve 2-3 wks later.

CASCAS

DiagnosisDiagnosis

- - Typically Clumping of the RBC even before Typically Clumping of the RBC even before the antisera is added and dissolution of the the antisera is added and dissolution of the clumping upon warming indicates the clumping upon warming indicates the presence.presence.

- Positive DAT with Anti –C3 and often negative - Positive DAT with Anti –C3 and often negative for IgG.for IgG.

- IgM can be Monoclonal and Polyclonal.- IgM can be Monoclonal and Polyclonal.- Antigens usually “ I “ on adult RBC - Antigens usually “ I “ on adult RBC

TreatmentTreatment

--- Avoidance of cold exposure.

- Therapy directed against secondary causes.

- Immunosuppression with chlorambucil,cyclophosphamide.

-Steroids are rarely helpful.

-Splenectomy-? Since extravascular hemolysis (IgM mediated )occurs in Liver.

-Plasmapheresis

- Rituximab has shown success.

PCHPCH

IncidenceIncidence -Rare 2-10% -Rare 2-10%ChildrenChildren MC affected MC affected EtiologyEtiology:: - Idiopathic Vrs Secondary- Idiopathic Vrs Secondary - Infections Measles,Mumps,EBV,CMV,VZ,Adeno,Influenza,Mycoplasma,Hemophilus.- Infections Measles,Mumps,EBV,CMV,VZ,Adeno,Influenza,Mycoplasma,Hemophilus.Diagnosis :Diagnosis : - DAT: positive with Anti-C3 but is generally negative for anti-IgG unless performed at - DAT: positive with Anti-C3 but is generally negative for anti-IgG unless performed at

colder temperatures.colder temperatures. - Donath Landsteiner AB –Biphasic hemolysin- Donath Landsteiner AB –Biphasic hemolysin - Antigen is P present on most of RBC- Antigen is P present on most of RBC Rx :Rx : - Generally self limited.No need for aggressive measures.- Generally self limited.No need for aggressive measures.

Drug Induced IHADrug Induced IHA

- MC drugs : Alpha methyl dopa,PCN,2MC drugs : Alpha methyl dopa,PCN,2ndnd & 3 & 3rdrd Cephalosporins Cephalosporins- Rarely Levodopa,Diclofenac.Rarely Levodopa,Diclofenac.- CF:Variable MC subacute onset but rarely acute hemolysis.CF:Variable MC subacute onset but rarely acute hemolysis.- Prognosis –Excellent.Prognosis –Excellent.

- Therapy –Stop drug and rarely empiric course of steroidsTherapy –Stop drug and rarely empiric course of steroids..

Hospital CourseHospital Course

Diagnostic Work up:Diagnostic Work up:- CMV IgG > 5.0 (ref <0.9) IgM Pending.- CMV IgG > 5.0 (ref <0.9) IgM Pending.- EBV cap AB,IgG- 1: 10,240 & IgM- Neg- EBV cap AB,IgG- 1: 10,240 & IgM- Neg- Bone marrow Biopsy (Day 6)-Flow cyto:Small population of monoclonal B cell (1%).Final - Bone marrow Biopsy (Day 6)-Flow cyto:Small population of monoclonal B cell (1%).Final

reports – negative for Acute leukemia,MDS,LPD,plasma cell dyscrasia.reports – negative for Acute leukemia,MDS,LPD,plasma cell dyscrasia.- Cold agglutinin titres 1:512- Cold agglutinin titres 1:512-Preliminary results : ID antibody as Anti-S-Preliminary results : ID antibody as Anti-S-Mycoplasma IgG and IgM –ve.-Mycoplasma IgG and IgM –ve.-Hep A,B and C – Non reactive-Hep A,B and C – Non reactive- HIV – Non reactive- HIV – Non reactive- PNH :r/o by flow cytometry- PNH :r/o by flow cytometry- SPEP : unremarkable .Low IgM- SPEP : unremarkable .Low IgM- Donath Landsteiner Antibody negative r/o PCH.- Donath Landsteiner Antibody negative r/o PCH...- HIT panel negative (was ordered because of low platelet count).- HIT panel negative (was ordered because of low platelet count).

Hospital CourseHospital Course

- Admitted to ICUAdmitted to ICU- Inetially transfused 4U of PRBC which brought his H/H to 6/13Inetially transfused 4U of PRBC which brought his H/H to 6/13

- High dose IV steroids initiated on Day 3 x 3 d following by high dose - High dose IV steroids initiated on Day 3 x 3 d following by high dose oral prednisone (60mg po daily).oral prednisone (60mg po daily).

- On day 2 pt had to be intubated because of ?TRALI ,was weaned off On day 2 pt had to be intubated because of ?TRALI ,was weaned off the ventilator over couple of days.the ventilator over couple of days.

- The pt continued to require daily transfusions.(received 17 U Prbc’s The pt continued to require daily transfusions.(received 17 U Prbc’s so far since admission).so far since admission).

- Plasmapheresis initiated on Day 3 continued for total of 7 days.Plasmapheresis initiated on Day 3 continued for total of 7 days.- Relative stabilisation of H&H after Plasmapheresis was initiatedRelative stabilisation of H&H after Plasmapheresis was initiated- Held for a couple of days and reinitiated because of persisting Held for a couple of days and reinitiated because of persisting

Hemolysis.Hemolysis.- Danazol started on Day 3 (200mg po BID)Danazol started on Day 3 (200mg po BID)- Cyclophosphamide (100mg po q daily) started on Day 10.Cyclophosphamide (100mg po q daily) started on Day 10.- Rituximab (Received 3 doses so farRituximab (Received 3 doses so far

Hospital CourseHospital Course

Follow up :Follow up :

-Daily CBC’s,Total Bilirubin,Serum haptoglobulin and LDH.-Daily CBC’s,Total Bilirubin,Serum haptoglobulin and LDH.

-RBC count and platelets remain low but stable.-RBC count and platelets remain low but stable.

-H&H – 6.0 -9.8 Most recent -8.0 and is stable-H&H – 6.0 -9.8 Most recent -8.0 and is stable

-Haptoglobulin <6 until recently reported as 27 (ref 36-195)-Haptoglobulin <6 until recently reported as 27 (ref 36-195)

-LDH down to 464 from 1145.Recent uptrending 634.(132-268)-LDH down to 464 from 1145.Recent uptrending 634.(132-268)

-Total Bilirubin 6.8-3.5.(0.0-1.0)-Total Bilirubin 6.8-3.5.(0.0-1.0)

THANK YOU !THANK YOU !