Trans OS216 Hema 15

Bone Marrow Failure States

Dr. Beatrice J. Tiangco

OS 2 16

Trans 15 | Exam 1

Block B

HEMATOLOGY OUTLINE I. Clinical Case II. Bone Marrow Failure III. Aplastic Anemia IV. Severe Aplastic Anemia

V. Transfusion Principles for Managing Aplastic Anemia

VI. Pure Red Cell Aplasia (PRCA) VII. Acquired Pure Amegakaryocytic

Thrombocytopenic Purpura (APATP) VIII. Pure White Cell Aplasia

IX. Myelodysplastic Syndrome (MDS) X. Anemia of Chronic Disease (ACD)

A 14 year old boy presents with sore throat, rash, gum bleeding. He was well until three weeks ago. The throat was red. His legs have petechiae. No lymphadenopathy, no organomegaly, with temperature of 38 C. Labs: Hb: 8.9g/dl Hct: .30 MCV: 103 fL WBC: 2,200/L Neutrophil: 10-20 Lymphocytes: 80 Platelet: 18,000 Reticulocyte count: 1%

[picture was shown]

Normal Bone Marrow: 50% is occupied by marrow,

non-uniform population of cells due to varying degrees of maturation and presence of three cell lineages

Abnormal Bone Marrow: marrow is limited to

<10%, mostly occupied by fat; hypocellular

A. CAUSESOF BONE MARROW FAILURE

* Primary reduction in hematopoietic cells, e.g. aplastic anemia

* Replacement of marrow by malignant cells, e.g. leukemia, lymphoma, carcinoma

* Ineffective hematopoiesis, e.g. MDS, MA * Infiltration by abnormal tissue, e.g.

myelofibrosis, amyloidosis

B. CLINICAL FEATURES

* S/Sx: anemia, infection, bleeding as result of the underlying cause

* Laboratory features

~ Leucopenia, thrombocytopenia of varying severity

~ Blood film may show circulating red cell and white cell precursors (leukoerythroblastic), caused by bone marrow infiltration or may show evidence of primary hematological malignancy (e.g. blasts)

~ Bone marrow aspirate and biopsy are required to define the cause

*

Clinical disorder defined by pancytopenia and

bone marrow hypocellularity

* Must be differentiated from other disease conditions presenting with pancytopenia and hypocellular marrow

A. DIFFERENTIAL DIAGNOSISOF PANCYTOPENIAAND BONE

MARROW HYPOCELLULARITY

* Idiopathic Aplastic Anemia * Inherited Aplastic Anemia * Hypocellular Myelodysplasia * Aleukemic Leukemia

* Paroxysmal Nocturnal Hemoglobinuria * Myelofibrosis

* Hairy Cell Leukemia * Tuberculosis * Anorexia Nervosa

B. KEY POINTSINTHE DIAGNOSTIC APPROACHFOR PATIENTS WITH PANCYTOPENIA

* History including medications, previous chemotherapy and radiotherapy, occupational toxic exposure and family history

* Physical Examination paying attention to presence of organomegaly, lymphadenopathy, musculoskeletal abnormalities

* CBC including absolute reticulocyte count and peripheral smear

* LFT, hepatitis serologies, Vit B12, Folate * Bone Marrow Aspirate and Biopsy * Cytogenetic studies for congenital forms * Chromosomal fragility if <40yo

C. GRADING AND SEVERITYOF AA

A.

SEVERE

Peripheral blood: 2 of three values ANC/Granulocytes <0.5 x 10 /L Platelets < 20 x 10 /L

Corrected Reticulocytes < 1% Bone marrow trephine

Markedly hypocellular marrow <25% cellular Moderately hypocellular, 25-50%

Normal cellularity with <30% of remaining cells hematopoietic B. VERY SEVERE

As above but granulocytes < 0.2 x 10 /L Infection present

Bone Marrow Failure

II

Aplastic Anemia (AA)

III

Clinical Case

Bone Marrow Failure States

Dr. Beatrice J. Tiangco

OS 2 16

Trans 15 | Exam 1

Block B

HEMATOLOGY D. EPIDEMIOLOGY

* May present at any age, predominantly a disease of young people (median 20-25 years) * Annual European/North American incidence: 2

per million

* Asian countries: 11 per million

* Poor prognosis, 1 year survival of <20% with supportive treatment only

E. PATHOGENESIS

* Stem cell defects

* Stromal cell defect and overproduction of negative hematopoietic regulatory growth factors, e.g. interferon, TNF

* Lymphocyte-mediated suppression of hematopoiesis

F. ETIOLOGY OF ACQUIRED APLASTIC ANEMIA

* Idiopathic: 70% in NA, 50% in the Philippines * Toxins: benzene, petroleum products,

insecticides

* Drugs: NSAIDs, anticonvulsants, antithyroid, gold, quinacrine, sulfonamides, phenothiazines, etc.

* Viruses: hepatitis, infectious mononucleosis * Radiation

* Chemotherapy * Pregnancy

G. ETIOLOGY OF GENETIC APLASTIC ANEMIA

* Fanconi’s anemia with or without physical abnormalities ~ Microcephaly ~ hypogonadism * Dyskeratosis congenita ~ Hyperpigmentation ~ Dystrophic nails ~ Mucosal leukoplakia ~ Pancytopenia

* Shwachman Diamond Syndrome ~ Pancreatic exocrine insufficiency ~ Neutropenia, pancytopenia

Table: Salient and clinical features of inherited bone marrow failure states

Features Fanconi

Anemia Dyskeratosis Congenit a Shwachm an-Diamond Syndrom e Cases reported 1000 225 200 Genetics Autosomal

recessive X-linked Autosomal recessive Physical abnormalit ies Microceph aly, hypogonad ism, malformati on of thumb and kidney Reticulate d pigmentati on, dystrophic nails, leukoplaki a Failure to thrive, diarrhea (pancreatic insufficien cy), metaphyse al chondropla sia Median age at diagnosis

7.5 yrs 16 yrs 4 months

First hematolog ic manifestat ion pancytope

nia pancytopenia Pancytopenia

Bone

marrow aplastic aplastic Hypocellular, maturation

arrest Features Fanconi

Anemia Dyskeratosis Congenit a Shwachm an-Diamond Syndrom e Leukemia 12% 0.4% 5% Solid Tumors 5% 10% 0% Chromoso

mes Increased breaks with clastogens (DEB, mitomyoci n C) Bleomycin sensitive Normal

* Marrow biopsy <25% cellularity * Any two of the following

~ ANC < 500 ~ Platelets < 20,000

~ Absolute reticulocyte count < 60,000

A. TREATMENT CONSIDERATIONS

* Severity of aplasia * Age

* Availability of HLA-id donor

B. TREATMENT MODALITIESIN SAA

* Bone Marrow Transplantation (BMT)

~ Hematopoietic recovery is faster, complete, stable

~ High TRM

~ Long-term complications

Severe Aplastic Anemia (SAA)

Bone Marrow Failure States

Dr. Beatrice J. Tiangco

OS 2 16

Trans 15 | Exam 1

Block B

HEMATOLOGY

Cyclophosphamide: Used in the preparation of Bone Marrow ATG

Methylprednisone: immunosuppressant and is afterwards

useful in countering the effects of ATG (eg. fever, chills) – Only done in PGH, not in other hospitals

* Immunosuppressive Therapy

~ Hematopoietic response is slow, often incomplete

~ Transfusion independent rather than normalization of blood counts ~ Relapse is common

~ Evolution to clonal disease

Cyclosporine may have effect on the BM of the patient

Bone marrow transplantation has a higher survival rate (60-70%) compared to Immunosuppressive Therapy (<50%)

Patients >40yo are better candidates for

Immunosuppressive Therapy than BMT (because of side effects)

C. KEY POINTS: TREATMENTOF APLASTIC ANEMIA

* SCT from a mismatched sibling donor is the treatment of choice for patients < 30 -years with ANC < 500 and adults 20-40 years with ANC <200

* For older patients, those without sibling donors, and those who refuse SCT, immunosuppression with ATG and cyclosporine should be initiated within 14 days of diagnosis

D. MAJOR FACTORS WHICH INCREASE RISK OF

GRAFT REJECTION IN BMT IN SAA

Not Discussed * Any degree of HLA mismatching

* Sensitization of recipient through multiple blood/platelet transfusions prior to BMT

* Infusion of low numbers of donor cells

* Reduction in strength of IS conditioning regimen employed * Reduction in post-transplant immunosuppression

Bone Marrow Failure States

Dr. Beatrice J. Tiangco

OS 2 16

Trans 15 | Exam 1

Block B

HEMATOLOGY

* Use of T-cell depletion to prevent GVHD

* Transfuse RBCs for symptomatics only, for Hb < 8 g/dL

* Transfuse platelets for bleeding only or if platelets < 10,000

*

Employ prophylactic EACA (E-Amino Caproic Acid) to reduce mucosal bleeding

* Use leukocyte-poor filtered and irradiated blood products to minimize allosensitization

*

Avoid use of family members as blood donors (because of transfusion-associated GVHD)

***OUTCOMEOF CLINICAL CASE***

* Accordingly, the recommended treatment for the 14 year old boy would be bone marrow

transplant.

* The patient has an HLA-compatible sister and he received a bone marrow transplant within 6 months of his diagnosis. His transplant was uncomplicated and he is now finishing his high school.

* Selective aplasia of the erythroid cell line * Anemia and reticulocytopenia

* Normal WBC and platelet counts

A. CLASSIFICATIONOF PRCA

* Congenital – Diamond Blackfan Syndrome * Acquired

~

Primary – autoimmune, idiopathic, preleukemia

~ Secondary – associated with thymoma, infections, nonthymic solid tumors,

hematologic malignancies, collagen vascular diseases, drugs, pregnancy, severe renal failure, ABO incompatible BMT

B. PATHOGENESISOF PRCA

* Antibody-mediated

* Lymphocyte-mediated erythroid aplasia

*

Human Parvovirus-induced (attach to

erythroblast)

* Stem cell disorder – PRCA as a preleukemic manifestation

C. PROGNOSISOF PRCA

* Acute and self-limited disease in children * Chronic and relapsing course in adults * Spontaneous remissions in 10-12% * Evolution to AA

* Transformation to ANLL

D. THERAPYOF PRCA

* Discontinuation of suspected offending drugs * Immunologic surgery (thymectomy,

splenectomy)

* Immunosuppressive therapy, cytotoxic * Immunosuppressive therapy, biological * Plasmapheresis, lymphocytopheresis * Immunomodulating-IV Ig

* Severe thrombocytopenia associated with total absence or marked reduction in BM

megakaryocytes

* Minimal changes in other hematopoietic cellular elements

* Pathogenesis of APATP

~ Viral: hepatitis, parvo, HIV, measles ~ Immune-mediated: systemic lupus

erythematosus (SLE)

~ Stem-cell disorder: evolution to AA

* Complete disappearance of granulocytopoietic tissue from the BM

* Normal erythroid/megakaryocytopoiesis * Associated with thymoma, infections, drugs * Recurrent infections with fever, chills, sepsis

*

Heterogenous group of clonal hematologic

disorders characterized by ineffective hematopoiesis (unable to mature and differentiate  pancytopenia) and usually, hypercellular bone marrow

*

Dysplastic features of the erythroid, myeloid,

megakaryocytic cell lines (at least two cell

lines)

* Preleukemic disease

A. CLASSIFICATIONOF MDS

FAB Classification of

MDS: WHO classification of MDS: Transfusion Principles for

Managing AA

V

Pure Red Cell Aplasia (PRCA)

VI

Acquired Pure Amegakaryocytic

Thrombocytopenic Purpura (APATP)

VI I

Pure White Cell Aplasia

VIII

MyeloDysplastic Syndrome (MDS)

Bone Marrow Failure States

Dr. Beatrice J. Tiangco

OS 2 16

Trans 15 | Exam 1

Block B

HEMATOLOGY

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

Refractory anemia with excess blasts (RAEB) Refractory anemia with excess blasts in transformation (RAEB-T) Chronic myelomonocytic leukemia (CMML) Refractory Anemia With ringed sideroblasts (FAB RARS) Without ringed sideroblasts (FAB RA) Refractory Cytopenia with multilineage dysplasia (new) 5q- Syndrome (New) Unclassified (New) B. CLINICAL FEATURESOF MDS

* Most prevalent in older adults (median age – 64 years)

* Natural history ranges from rapid progression to AML or chronic course that can last for years * Death due to complications of cytopenias,

progression to AML, or other co-morbidities not related to MDS

C. PATHOGENESISOF MDS

* Ineffective hematopoiesis rather than lack of hematopoietic activity – increased levels of apoptotic mediators like TNF-a

* Chromosomal abnormalities – deletions or gains in all or parts of chromosomes 5, 7, 8, 20

* Therapy-related MDS

Table: FAB Classification of MDS

Disease Periphera

l Blood MarrowBone SurvivalMedian

RA Blasts < 1% Blasts < 5% 50 months RARS Blasts < 1% RS > 15% 50 months RAEB Blasts < 5% Blasts 5-20% 11 months RAEB-1 Blasts > 5% Blasts 20-30% 5 months CMML > 1x10/L

monocytes Any of the above 11 months

Table: International Prognostic Scoring System (IPSS) for MDS

Parameter Criteria Score

BM Blast Count < 5% 5-10% 11-20% 21-30% 0 0.5 1.5 2.0 Karyotype Normal/5q-Other 3 abnormalities 0 0.5 1.0 Cytopenias None or 1 2 or 3 00.5 D. TREATMENTOF MDS * Conventional chemotherapy

* Growth factor support and supportive care * Transplantation

* Novel therapies: azacytidine, decitabine, thalidomide, arsenic trioxide

E. PROGNOSISOF MDS

Low risk 0 3.9 – 11.8 y

INT – 1 0.5-1.0 2.4 – 5.2 y INT – 2 1.0-2.0 1.2 – 1.8 y

HIGH >2.5 0.3 – 0.4 y

* Anemia associated with reduced erythropoietin response

* Inflammatory states: acute and chronic bacterial infections, collagen vascular disease, AIDS, malignancies

* Renal disease: nephritis, ESRD

* Hypometabolic states: protein deprivation, endocrine deficiency states (hypothyroidism, hypopituitarism, hyperparathyroidism) * Therapy of ACD

~ Treat underlying cause ~ Transfusion support ~ Erythropoietin

* in patients with chronic disease anemia has multiple etiologies: poor nutrition, blood loss, anemia of chronic disease (ACD)

* ACD is 2nd to iron deficiency anemia in incidence

* There is decreased serum iron and transferrin saturation

* There is normal to increased ferritin and increased iron in bone marrow macrophages

Jan: Hello 2010! Last trans for this module. Sana magamit niyo ito, dahil pinaghirapan namin ito. Last People, the fun never stops with you guys around! The End, ang galing talaga natin, same ang date ng lecture at ng trans deadline, pero ano, nagawa natin! Thanks for the effort! Hehe. Block B, good luck sa exam tomorrow! Punta kayo bukas sa diliman, bahay ng alumni, What’s up doc? Heroes on Call:The Step UP concert feat parokya ni edgar, kjwan, mojofly, sago, pedicab, hemp republic, typecast and many more.…P50 lang tickets for UP students, 100 for nonUP. Sulit talagang pangdetox after ng hema. Punta na! God bless!

Table: Comparison of IDA and Anemia due to Chronic Disease

Normal

range Iron defiency anemia

Chronic disease

Anemia of Chronic Disease (ACD)

Bone Marrow Failure States

Dr. Beatrice J. Tiangco

OS 2 16

Trans 15 | Exam 1

Block B

HEMATOLOGY Plasma iron, μg/dl 70-190 30 (↓) 30 (↓) TIBC, μg/dl 250-400 450 (↑) 200 (↓) % saturation 30 7 (↓↓) 15 (↓) Macrophag e iron in bone marrow 2+ 0 (↓)/none 3+ (↑) Serum ferritin, μg/L 20-200 10 (↓) 50 (↔) Serum ferritin receptor, nmol 8-28 Increased Normal

*

three separate pathophysiological defects exist and interact in ACD:

~ failure of erythropoiesis ~ lack of iron for Hb synthesis ~ decreased RBC survival

* the above defects result from increased TNF-α (due to inflammation), which causes sustained secretion of IL-1

* increased levels of TNF- α and IL-1 tend to: ~ decreased plasma iron

~ decreased transferring

~ shunting of iron to macrophages via

lactoferrin; once iron is bound to lactoferrin, it is delivered exclusively to macrophages and is no longer available for erythropoiesis

GREeTINGs!

TINA: Thank you Shiney for helping me type the additional notes! Tatang, are you ready for love? Lalalalala =D Mamai, brace yourself for my stories! bwahaha! Japs, it’s a privilege to be your ex. =b Fidesky, bata ka pa. Tarsky, Mel R., Leah, Jo T, Jobs, Vivi, Trina, Sheng, Odelle, Iaia, Glai, Mabelle, thank you! Last People Standing, sayang hindi ako nakasama.  Psychmates, and saya ng elective natin! Ang saya niyong kasama! Agape, I’m so excited for Overjoyed! Domdom, I’ll miss you a lot when you go to the community  hay, three months of med school left…God bless you all!  PeeWeeWee: Sabog na ako and stressed so baka di ko magreet ang lahat ng greetables. Gid (borrow ng Melancholy Whores ni Marquez ), Siena (sorry nahawa ka sa akin! Here’s to never assuming), Aldi and Kimmy ng 2011, was fun going to the island with you. Sama uli ako next time. The End: Jan (kilabot ka talaga ng mga pasyente) Iaia (salamat sa pagformat), Tina (salamat sa pagpicture and patypeng ppt!), to more transes til the year ends. Kris, samahan mo na ako sa Agent X44, ikaw lang gusto ko makasama dun. Sige na para di naman puro Taming of the Shrew ang maexpose tayo sa mga Dunkin Donato type films. Lastpeoplestanding (LPS), here’s to more outing extremes. Bakit puro We love you lahat? Nakakain lang kayo ng crispy pata, nasenti na kayo? Pero sige na nga (pee)We(e) love(s) you LPS na din. I cant’t speak for my group kasi. Anne Lim! Hi, gusto lang kita igreet. Ang ganda ng combination ng

RAW/Smackdown at Disney Songs? Hehe Download ka ng Hercules, yung song ni meg. Speaking of downloads, sinong may Light Grenades ng Incubus? Parip/burn/copy naman! Please, please please? Ganda eh (para sakin lang kahit na pangit ang ibang review nun). Eto lyrics ng isang song dun Love Hurts by Incubus from Light Grenades

Tonight we drink to youthAnd holding fast to truthI don’t want to lose what I had as a boyMy heart still has a beatBut love is now a featAs common as a cold day in LASometimes when I’m alone, I wonderIs it a spell that I am

underKeeping me from seeing the real thing?Love hurts…But sometimes it’s a good hurtAnd it feels like I’m aliveLove singsWhen it transcends the bad thingsHave a heart And try me, ‘cause without love I won’t surviveI’m fettered and abusedI stand naked and accusedShould I surface this one man submarine?I only want the truthSo tonight we drink to youthI’ll never lose what I had as a boySometimes when I’m alone, I wonderIs it a spell hat I am underKeeping me from seeing the real thing?Love hurts… But sometimes it’s a good hurtAnd it feels like I’m aliveLove singsWhen it transcends the bad thingsHave a heart and try me,‘Cause without love I won’t survive!

Iaia: (umalis na siya eh) Hi friends! Hi charmed ones! Blessed be!