Bone Marrow Failure states

- Aplastic anemia
- Myelodysplastic syndrome (MDS)
- Pure red cell aplasia (PRCA)
- Myelophthisis (20 myelofibrosis)
 Aplastic anemia
- BM failure that arises from injury to or abnormal
expression of the stem cell
(hypoplastic BM/pancytopenia)
- Men and women are affected equally, but biphasic age
distribution (with the major peak in the teens and twenties
and a second rise in older adults).
- mechanisms:
- an antibody directed against an antigen on stem cells
or
- an immune mechanism
(T- lymphocytes suppress/destroy stem cell proliferation).
- Causes: - congenital
- SLE
- chemotherapy/radiotherapy
- toxins: benzenes, tolune, insecticides
- drugs: CAF, phenylbutazone, Au, sulfa
- viruses
• hepatitis (non-A, non-B, & non-C)
• EBV
• Parvovirus 19
• HIV-1 (AIDS)
- immune diseases
- pregnancy
- PNH
- idiopathic
Clinical features
- Bleeding: the most common
early sx
- Sx of anemia
- Infection: unusual 1st sx
- Restriction of sx to
hematologic system
- Laboratory features
aplastic anemia (severe)if >1:
• neutrophil <500/mcL
• platelets <20,000
• BM cellularity <20%
• cRetic count <1%
- Large RBCs (MCV)
- BM readily aspirated but
dilute
- Dx: pancytopenia + fatty BM
 Pancytopenia
causes
 BM disorder
 Aplastic anemia
 MDS
 acute leukemia
 MF
 infiltrative diseases (lymphoma, myeloma, Ca)
 megaloblastic anemia
 nonmarrow disorders
 hypersplenism
 SLE
 infections (TB, AIDS, leishmaniasis, brucellosis)
Treatment
supportive (most)
• transfusion (RBC, platelets)
• antibiotics
in severe cases + young <50: allogenic BMT
(HLA-matched)
elderly (>50): - immunosuppressive + anti-thymocyte
globulin (ATG) + cyclosporin (or tacrolimus)
high dose immunosuppressive with
cyclophosphamide, 200mg/kg
androgens (oxymetholone) 2-3mg/d

Course & prognosis

rapidly fatal if not treated

The major prognostic determinant is the blood count.
ABMT: durable complete response 80%
ATG Rx: partial response 60%
long-term responders: good prognosis
In the era of effective immunosuppressive therapies, absolute numbers of reticulocytes
(>25,000/uL) and lymphocytes (>1000/uL) may be a better predictor of response to
treatment and long-term outcome.
 MDS
(Old names: preleukemia, dysmyelopoietic syndrome, oligoblastic leukemia, refractory anemias)
- a heterogeneous group of hematologic disorders
- xed by cytopenias associated with a dysmorphic (or
abnormal appearing) and usually cellular bone marrow
- consequent ineffective blood cell production.
- usually idiopathic
- may be after cytotoxic chemotherapy
- no specific chromosomal abnormality
- contains heterogenous syndromes (FAB,1983)
 without excess BM blasts = refractory anemia with or
without ringed sideroblasts
 with excess blasts (RAEB 5-19% blasts)
 with proliferative syndrome = CMML (monocytosis)
>1000/mcL
- WHO classifcation, 2002
Clinical
Dysplasia in the bone marrow and peripheral smear are hallmark feature
- Usually > 60 yrs
- 1st diagnosed because of abnormal counts
- fatigue, infection, bleeding
- course indolent
- wasting illness
(fever, wt, loss, general debility)
- splenomegally may be present
Lab
- Marked anemia
- MCV: N / increased
- macro-ovalocytes
- WBC: N/ decresed
- neutropenia common
- deficient granules or bilobed nucleus
(Pelger-Huet)
- myeloid series: left shifted
- platelet : N/decreased; hypogranular platelet
-BM: - xically hypercellular
- erythroid hyperplasia
- sign of abnormal erythropoisis
- megaloblastic features
- nuclear budding
- multinucleated erythroid precursors
- ringed siderblasts
- dwarf megakaryocyte with
a unilobed nucleus
- variety of cytogenic abnormality
(5q- syndrome, monosomy 7)

- treatment
- blood transfusions + Fe chelation
- myeloid granulocyte factors (G-CSF) + EPO 30,000 U, sc
- Cytotoxic drugs
- Lenalidomide, 10mg/d
- Azacitidine
- Decitabine
- immunosuppressive (ATG, cyclosporin, anti-CD52 monoclonal antibody – Campath)
- allogenic stem cell transfusion – curative
- hematopoeitic growth factors (HGF)
Course & prognosis
- Ultimately fatal
- cure rate: 30-60%
- most die of infection/ bleeding
- pts with refractory anemia may survive many yrs
(risk of leukemia: <10%)
- Those with excess blasts or CMML: short survival
(<2 yrs) & higher (20-50%) risk of developing
acute lekemia
- full deletion of C5 and C7: poor prognosis
 Pure red cell aplasia
- Rare
- autoimmune disease against erythroid precursors
- the unaffected lineages (myeloid & platelet) appear
quantitatively and qualitatively normal
- idiopathic
- SLE, CLL, lymphoma, thymoma
- drugs: phenytoin, CAF
- in response to viral infection
- papovirus
- anemia: often severe, NCNC
- low/absent reticulocytes
- RBC morphology : N
-BM: normocellular, erythroid precursors are markedly
reduced or absent
- treatment:
• stop offending drug
• resection of the tumor( eg, thymoma)
• high –dose iv Ig (eg, papovirus – related)
• immunosuppressive therapy:
o glucocorticoids
o ATG + cyclosporine (tacrolimus)
o anti-CD20 monoclonal antibody (Daclizumab)
- The presence of erythroid colonies has been considered
predictive of response to immunosuppressive therapy in
idiopathic PRCA.
 Myeloproliferative Disorders
- share an origin in a multipotent hematopoietic
progenitor cell
- overproduction of one or more of the formed elements
- without significant dysplasia
- a predilection to extramedullary hematopoiesis, myelofibrosis
- transformation at varying rates to acute leukemia
- Classification (WHO)
• Chronic myelogenous leukemia (CML), bcr-abl–positive
• Chronic neutrophilic leukemia (CNL)
• Chronic eosinophilic leukemia (CEL), not otherwise specified
• Polycythemia vera (PV)
• Primary myelofibrosis (PMF)
• Essential thrombocytosis (ET)
• Mastocytosis
• Myeloproliferative neoplasms, unclassifiable
 PV
• overproduction of all the 3 hematopoeitic cells lines (most RBC)
• autonomous production of erythroid cell in the BM
• independent of EPO
• mutation in JAK2 autoinhibitory, pseudokinase domain of the
tyrosine kinase, 95%
Clinical features
- Sxs related to expanded plasma volume & increased blood
viscosity
- headache, dizziness, tinnitus, blurred vision, fatigue
- aquagenic pruritus
- epistaxis
- male predominance (60%)
- median age: 60yrs
- plethora & engorged retinal vessels,
- spleen always enlarged (75% palpable)
- thrombosis is the commonest complication
- high incidence of acid-peptic disease
Lab features
- Hct >60%
- WBC 10,000-20,000/mcL
- platelets > 1,000,000/mcL
- basophilia + eosinophilia
- BM: hypercellular
panhyperplasia
absent Fe store
- Vit B12
- hyperurecemia
Treatment
- Phlebotomy
- 1 unit/week
- target : Hct <45% in men & <42% in women
- myelosuppressive therapy
- indication: - high phlebotomy requirement
- thrombocytopenia
- intractable pruritus
- HU, 500-1500mg/d
- anaglinide
- aspirin (75-81mg)
- allopurinol: uric acid >10mg%
- antihistamines
Prognosis
- survival : 11-15 years
- may arrest MF/CML
- AML (5%)
 ET
other designations:
essential thrombocythemia
Idiopathic thrombocytosis
primary thrombocytosis,
hemorrhagic thrombocythemia
- Uncommon
- unknown cause
- marked proliferation of megakaryocytes in BM leading to elevation of the platelet count
- mutation of JAK2 (50%)
Clinical features
- median age of presentation: 50-60 yrs
- wt loss, low-grade fever, weakness
- headache, dizziness
- increased platelet count
- thrombosis most common
- erythromelalgia
- splenomegaly 25%
Lab
- Platelet 2,000,000/mcL
- WBC <30,000/mcL + immature myeloid forms
- Hct: N
- BF: large platelets
- BM: megacaryocytes
Treatment
- HU 0.5-2g/d
- anaglide 1-2mg/d
- aspirin
- plateletphresis
Course & prognosis
- Indolent
- average survival: >15yrs
- late course fibrotic BM + massive splenomegaly
- 10-15% risk of progression to MF after 15 yrs, 1-5% to AML over
20 yrs
ET- BM
 PMF
 other designations :
 idiopathic myelofibrosis
 agnogenic myeloid metaplasia
agnogenic myeloid metaplasia
myelofibrosis with myeloid metaplasia
• a clonal disorder of a multipotent hematopoietic
progenitor cell
• of unknown etiology
• characterized by marrow fibrosis, extramedullary
hematopoiesis, and splenomegaly
- the least common chronic MPD
- night sweats, fatigue, and weight loss are common
presenting complaints
- In adults >50
- usually insidious in onset
- present with fatigue (anemia), abdominal fullness (splenomegally)
- unusual: bleeding, bone pain
- splenomegally invariable & massive
- heptomegaly 50%
- anemia + progressive thrombocytopenia bleeding
- Exuberant extramedullary hematopoiesis can cause:
• ascites
• portal, pulmonary,intracranial hypertension
• intestinal or ureteral obstruction
• pericardial tamponade
• spinal cord compression
• skin nodules
Lab
- Anemia
- WBC variable
- platelet variable
- peripheral blood
- significant poikilocytosis
- tear drop forms
- nucleated RBC
- myeloid features shifted to immature forms
- platelet morphology bizzare (giant degranulated form)
- megakaryocyte fragments
- BM: - dry tap
- fibrosis, reticulum fibers
collagen
- No specific chromosomal
abnormality.
50% express the JAK2 mutation
Treatment
- Mild form: no Rx
- transfusion
- thalidomide / lenalidomide
- allogenic BMT
- EPO
- splenectomy
Course & prognosis
• increasing marrow failure with transfusion dependent anemia and
increasing organomegaly
• can evolve from a chronic phase to an accelerated phase
• About 10% transform to an aggressive form of acute leukemia
• prognostic factors for disease acceleration:
o anemia, leukocytosis, thrombocytopenia,
o the presence of circulating myeloblasts,
o older age,
o the presence of complex cytogenetic abnormalities, and
o constitutional symptoms (unexplained fever, night sweats, or weight loss).