Bone Marrow Failure

Diseases: Including
MDS, AA, PNH
Lauren Cosolo, RN, BScN, MN
Outline
• Review bone marrow failure and disease
• Discuss Myelodysplastic syndrome, pathophysiology, clinical
presentation, diagnosis, treatment
• Discuss Aplastic Anemia, clinical presentation, diagnosis,
treatment
• Discuss PNH, pathophysiology, clinical presentation, diagnosis,
treatment
• Review nursing considerations for bone marrow failure
diseases
 Bone Marrow Failure
• Ineffective hematopoiesis causing pancytopenia and the
inability to produce healthy blood cells
• Pancytopenia= reduction in blood counts red cells, white
cells, platelets

Scheinberg, DeZern, Steensma,

Image taken from: http://www.lookfordiagnosis.com/mesh_info.php?term=Myeloid+Cells&lang=1 2016; Hoffbrand & Moss, 2016
 Bone Marrow Failure Diseases
• Disorders resulting in cytopenia (low blood counts) due to
decreased bone marrow production
• Can be congenital (inherited) or acquired disorders

Congenital Acquired

• Fanconi anemia • Acquired Aplastic

• Diamond Blackfan Anemia
anemia • Myelodysplastic
• Dyskeratosis Syndrome (MDS)
congenita • Paroxysmal
Nocturnal
Hemoglobinuria
(PNH)
Young, 2014; Zhang, 2016
 Myelodysplastic Syndromes (MDS)
• Clonal disorders of hematopoietic stem cells characterized by
increasing bone marrow failure in association with dysplastic
changes (cells look abnormal) in one or more cell lineages

• Simultaneous proliferation and apoptosis of hematopoietic

cells (ineffective hematopoiesis) leading to hypercellular bone
marrow but pancytopenia in peripheral blood

Pathologyoutline.com
Pathophysiology of MDS
• There is an abnormal regulation of proliferation,
maturation and survival of hematopoietic stem cells due
to genetic changes
• A number of genetic changes/mutations are associated with MDS
• Changes in the expression of genes, such as hypermethylation
contributes to the development or progression of MDS
• Resulting in suppression of gene transcription

• As the disease progresses, maturation of stem cells are further

impaired with increased survival of myeloblasts
Prevalence and Risk Factors
• MDS usually develops in older adults >60 years old with median age of 72-76
years
• More common in males than in females
• MDS relatively common disease
• 4-7 estimated new cases/100,000 each year

Risk Factors:
• Older age
• Male
• Exposure to environmental factors (benzene)
• Smoking
• Previous chemotherapy or radiation treatment

Buckstein & Wells, 2008

Etiology
De novo MDS Treatment-related MDS

• Idiopathic • Chemotherapeutic agents

• Environmental exposure • Radiation therapy
• Benzene, solvents,
agriculture chemicals
• Smoking
• Autoimmune disorders
• Viral illnesses
• Inherited genetic
abnormalities
• Other benign hematologic
diseases

Devine, 2013; Aster & Stone, 2018

Clinical Presentation
• Patients with MDS typically present with peripheral blood
cytopenias
• Patients range from being asymptomatic with an incidental CBC
finding to having symptoms and complications related to the
previously unrecognized cytopenia
• Majority of MDS patients present with red cell lineage dysplasia
(anemia)

• Signs and Symptoms include:

• Fevers, infection from neutropenia
• Petechiae, ecchymosis, bruising, bleeding from thrombocytopenia
• Fatigue, SOB, palpitations, weakness, exercise intolerance, dizziness,
pale complexion, cognitive impairment as result of anemia
Diagnosis
• Diagnosis of MDS dependent on:
1. Quantitative changes in blood elements (cytopenias)
2. Evidence of dysplasia in peripheral blood smear and marrow

• History
• Signs and symptoms
• Past medical history + comorbidities
• Blood transfusion history
• Prior chemotherapy/radiation treatment
• Family history
• Medications
• Exposure to chemicals

• Physical Exam
• Investigating for evidence of cytopenias
• Integumentary
• Mucous membranes
• Bleeding- epistaxis, gum bleeding, hemoptysis, hematuria, prolonged menstruation, melena
• Fatigue
• Vital signs
• Presence of fevers, infections
• Presence of splenomegaly
Diagnostic Investigations
• Initial workup for MDS:

Blood work • CBC with blood smear, reticulocyte count, iron TIBC Ferritin, LDH level,
EPO level
• Initial workup to rule out other causes of cytopenia

Peripheral Blood • Dysplasia in red and white blood cells and platelets
Smear

Bone Marrow • Aspirate will allow to evaluate morphology of hematopoietic precursors

and blasts and cytogenetics (Identification of abnormal chromosomes (ie.
Biopsy and 5q- del) and for prognosis)
• Biopsy will show cellularity (usually increased, sometimes hypocellular
Aspirate bone marrow seen in MDS)

• Findings can suggest clonality and presence of MDS

Flow Cytometry • Used especially when dysplasia is minimal and cytogenetics is normal
 WHO Classification of MDS
Subtype Peripheral blood Bone marrow % blasts

Refractory anemia Anemia Unilineage erythroid <5

dysplasia (in >10% cells)
Refractory neutropenia Neutropenia Unilineage granulocytic <5
dysplasia
Refractory Thrombocytopenia Unilineage <5
thrombocytopenia megakaryocytic dysplasia
Refractory anemia with Anemia Unilineage erythroid <5
ring sideroblasts (RARS) dysplasia >15% erythroid
precursors are ring
sideroblasts
Refractory cytopenia with Cytopenia Multilineage dysplasia <5
multilineage dysplasia +/- ring sideroblasts
(RCMD)
Refractory anemia with Cytopenia Unilineage or 5-9
excess blasts type 1 multilineage dysplasia
(RAEB-1)
Refractory anemia with Cytopenia Unilineage or 10-19
excess blasts type 2 multilineage dysplasia
(RAEB-2)
MDS associated with Anemia, normal or high 5q31 deletion, anemia, <5
isolated del (5q-) platelet count hypolobulated
megakaryocytes
IPSS-R
Parameter Categories and Associated Scores
Cytogenetic risk Very good Good Intermediate Poor Very poor
group

0 1 2 3 4
Marrow Blast ≤2% >2-<5% 5-10% >10%
proportion

0 1 2 3
Hemoglobin ≥10g/dL 8-<10g/dL <8 g/dL

0 1 1.5
ANC ≥0.8 x 109/L <0.8 x 109/L
0 0.5
Platelet Count ≥100 x 109/L 50 - 100 x 109/L
<50 x 109/L

0 0.5 1
Risk Category Risk Score
Very low ≤1.5
Tool is only helpful at time of diagnosis Low >1.5-3
Tool is used to estimate life expectancy Intermediate >3-4.5
for NEWLY diagnosed patients with High >4.5-6
MDS Very high >6
IPSS-R
Prognosis
• Factors that predict outcome include:
• WHO classification
• Complex karyotype (>3 chromosome abnormalities)
• Chromosome abnormalities
• Blast proportion
• Cytopenias

• Even low risk MDS has significant morbidity and mortality

including transfusion requirements and associated complications
• Worsening of pancytopenia, acquisition of chromosomal
abnormalities, increase in number of blasts are poor prognostic
indicators
• Therapy related MDS is an extremely poor outlook
Treatment
• Dependent on:
• Patient’s age
• Performance status
• Prognostic score
• WHO classification
• comorbidities

• Determine treatment goals with patient and family, including

achieving hematologic improvement, reducing transfusion
requirements, delaying transformation to leukemia, improving
survival and maintaining quality of life

Devine, 2013
Low Risk MDS Treatment Options
(IPSS Low Risk/Int Risk-1)
• For patients that are asymptomatic watchful waiting and monitor
Q3-6 months

• Symptomatic Treatment options

• Medications for anemia (ESA, lenalidomide), neutropenia (antibiotics,
GCSF), thrombocytopenia (antifibrinolytics)
• Immunosuppressive therapy (ATG, Cyclosporine)
• Supportive Care (transfusion support, iron chelation)

• Allo-SCT assessment
• Delayed allo-SCT offers maximal life expectancy as long as transplant
occurs before transformation to leukemia
• Eligibility ultimately decided by transplant center
• Often SCT is not an option to due to patients’ older age or
comorbidities Mdsclearpath.org
Disease Progression
• Potential indicators of progression to high risk MDS
• Worsening cytopenia
• New cytopenia
• Appearance of blasts
• Rising LDH
• Systemic symptoms (fever, weight loss)

• Specific evaluation of higher risk MDS

• Bone marrow aspiration and biopsy
• Flow cytometry
• Cytogenetics

Mdsclearpath.org
Treatment Options for High
Risk MDS
• Goal of treatment:
• Change natural history of MDS
• Defer AML transformation
• Improve survival for patients with MDS

• Treatment Options:
• Hypomethylating agents (azacitidine, decitabine) (usually
standard of care, however not a cure for MDS)
• Chemotherapy
• Allogeneic Stem Cell Transplant
• Supportive Care/ Palliative Care
• Clinical Trial

Mdsclearpath.org
Supportive Care
• All patients should receive supportive care as it is adjunct to chosen
therapy
• Patients with cytopenias and associated symptoms can receive
supportive care

• Transfusion support
• Red cells or platelets
• CMV negative
• Nursing Management:
• Identify symptoms of anemia, monitor CBC, monitor for fluid overload and
advocate for diuretic
• Assess response to platelet transfusions (platelet refractoriness) and PRBCS
(Hgb)
• Monitor for SE of transfusions
• Iron overload
Mdsclearpath.org
Iron Overload Management
• Iron Chelation Therapy
• Deferoxamine SC daily dose of 1,000–2,000 mg (20–40 mg/kg/day)
should be administered over 8–24 hours, using a small portable
pump capable of providing continuous mini-infusion.
• SE: allergic reaction, ocular and ototoxicity, cardiac dysfunction
• pretreatment hearing and visual exam
• Defersirox Initial dose 20 mg/kg body weight daily, orally, taken on an
empty stomach 30 minutes prior to meals.
• SE: GI hemorrhage, hepatic/renal failure, cytopenias, diarrhea, n/v, abdo
pain
• Deferiprone
• SE: agranulocytosis
• Measure ANC, interrupt if ANC <1.5
 Impact of MDS on Patients/Families
• Quality of life is complex, individually defined for patients
living with MDS
• Includes physical, social, emotional, practical and spiritual aspects

• Aging, comorbidities, fatigue, and uncertain illness trajectory

affects the quality of life of patients

• Oncology nurses are in an appropriate position to monitor the

impact of the illness and treatment on patients and their
quality of life through systematic assessment, providing
appropriate interventions, referrals and ongoing support

Thomas, Crisp & Campbell,2012

 Aplastic Anemia
• Pancytopenia (low blood counts) as a result of hypoplasia of
bone marrow
• Can be inherited or acquired, majority are acquired

• Reduction in number of hematopoietic stem cells and an

immune reaction or error in the remaining stem cells causing
them to not divide or differentiate appropriately to populate
bone marrow
Image: Medical-dictionary.thefreedictionary.com; Hoffbrand & Moss, 2016
 Prevalence and Etiology
• Affects primarily children (with children, majority are
inherited), young adults or adults >60
• More common in people of Asian descent
• 2-12 new cases/million each year

Etiology:
• Inherited or acquired
• Most cases are idiopathic
• Exposure to chemicals, drugs, viruses, radiation, immune
diseases

Incekol & Ghadimi, 2015; Hoffbrand & Moss, 2016

Clinical Features
• Present with signs and symptoms of pancytopenia

• Most frequent symptoms:

• Bruising
• Bleeding gums
• Epistaxis
• Menorrhagia
• Symptoms of anemia (Pallor, headache, palpitation,
SOB/dyspnea, fatigue, foot swelling)

• Infections are common and frequently life threatening

Incekol & Ghadimi, 2015; Hoffbrand & Moss, 2016

Diagnosis
• Blood work
• CBC with diff, B12, folic acid, LFT, LDH, chem panel, coags
• Pancytopenia early on

• Bone Marrow Aspirate and Biopsy

• Bone marrow is profoundly hypocellular, marrow space is
composed mostly of fat cells and marrow stroma

• Flow cytometry
• To detect coexisting disorders

• Cytogenetics
• Rule out MDS and congenital disorders
Classification

Severe Very Severe Non-Severe

• Presence of • ANC <0.2 • Not fulfilling

2-3 severity
parameters: criteria
• ANC <0.5 • Chronic
• Platelets <20 needs >3
• Reticulocytes months
<1%
 Treatment
• very severe & severe aplastic anemia stages require treatment as this
category has a high mortality rate

• HCT ( hematopoeitic stem cell therapy)

• Dependant on age, functional status and availability of donor

• Immunosuppressive therapy
• ATG (Antithymocyte globulin)
• Horse ATG administered IV over 4 days
• Requires pre-medication with tylenol/ benadryl to decrease infusion reactions
and serum sickness reaction
• Requires daily steroids to reduce risk of serum sickness
• Risk for anaphylaxis- keep anaphylaxis kit at bedside during infusion
• Cyclosporine
• SE: HTN, renal insufficiency, Mg deficiency, gum hyperplasia
• Requires BP, Cr monitoring, regular dental care

Larratt, powerpoint; Longo, 2017

Serum Sickness
• Occurs 1-2 weeks after initiating treatment of ATG

• Flu-like illness, rash and arthralgia

• Treatment: steroids
Supportive Care
• Transfusions
• RBC, platelets
• Irradiated Blood

• Treatment of Infections
• Empiric therapy with broad spectrum antibiotics
• Growth factors as prophylaxis for repeated infections

• Infection Prevention and Monitoring

• Patient education on preventing infections and monitoring for
fever and signs and symptoms of infection
Paroxysmal Nocturnal Hemoglobinuria
(PNH)
• Acquired hemolytic anemia

• Characterized by:

Hemolysis

Venous
Pancytopenia
Thrombosis

Longo, 2017
Pathophysiology
• Acquired mutation in PIG-A gene in hematopoietic stem cell
• If mutation proliferates the result is a clone that is deficient in
cell surface proteins known as glycosylphospatidylinositol-
anchored proteins (GPI-AP)
• The GPI-AP proteins act as receptors, complement regulators
and adhesion molecules
• CD55 and CD59 which are two GPI-AP that protect red blood
cells from complement activity are not present on the surface
of the PNH red blood cells, which leaves these cells extremely
sensitive to complement-mediated destruction

Young et al., 2009

Prevalence
• Same frequency in men and women
• Rare disease
• Prevalence estimated at 5/1,000,000
• Can present in small children or older adults, most patients
are young adults
 Clinical Presentation
Anemia
• Results from a combo of hemolysis and bone marrow failure

Thrombosis
• Common sites: intraabdominal( hepatic, portal, mesenteric,
splenic) and cerebral veins with hepatic vein thrombosis
(Budd-Chiari syndrome)

Gastrointestinal
• Abdominal pain, esophageal spasm, dysphagia

Other Manifestations
• Gross hemoglobinuria, renal tubular damage
Brodsky, 2014
 Diagnosis
• Blood work
• CBC with diff
• Liver profile, bilirubin
• LDH
• Reticulocyte count

• Urinalysis
• Hemoglobinuria

• Flow Cytometry
• Identify the GPI-AP deficient peripheral blood cells

Parker et al., 2005

Treatment
• Supportive Care
• Transfusions
• Folic acid/iron supplements
• Treatment of complications (eg. Thrombosis)

• Biotherapy
• Ecullizumab (Solaris)

• Allogenic SCT for young patient with severe PNH

• Primary prophylaxis for thrombosis

Longo, 2017
Nursing Considerations for
Bone Marrow Failure Diseases
• Comprehensive assessment of patient and management of side
effects

• Monitoring for signs and symptoms of cytopenias including fatigue,

bleeding, infection, etc. and providing appropriate interventions

• Addressing patient’s supportive care needs

• Education for patients and families on understanding the disease

and its manifestations, treatment modalities and the adverse
effects from treatment

• Connect to hospital and community resources

AAMAC
• Telephone and e-mail patient-to-patient support
• Educational material on Aplastic Anemia, MDS & PNH
• Quarterly newsletter
• Patient Tracker
• Local support group meetings
• Grants for medical research and education
• Website, Facebook, Marrowforums

http://www.aamac.ca/
References
• Devine, H. (2013). Myelodysplastic syndromes. In M. Olsen & L. Zitella (Eds.), Hematologic
Malignancies in Adults (51-74). Pittsburgh, Pennsylvania: Oncology Nursing Society.
• Buckstein, R. & Wells, R. (2008). Myelodysplastic syndromes (MDS). Retrieved from: https://
sunnybrook.ca/uploads/Myelodysplastic_Syndromes.pdf
• Burgoyne, T. & Knight, A. (2000). Myelodysplastic syndromes. In M. Grundy (Ed.), Nursing in
Hematological Oncology (21-30). London, UK: Baillere Tindall Royal College of Nursing
• Celgene. (2010). Vidaza azacitidine for injection.
• Thomas, M.L., Crisp, M., & Campbell, K. (2012). The importance of quality of life for patients living
with myelodysplastic syndrome. Clinical Journal of Oncology Nursing, 16(3), 47-57
• Van de Loosdrecht, A. A., & Westers, T. M. (2014). Flow Cytometric Immunophenotyping in
Myelodysplasia: Discovery and Diagnosis. Blood, 124(21), SCI-24. Accessed June 24, 2018. Retrieved
from http://www.bloodjournal.org/content/124/21/SCI-24.
• Incekol, D. & Ghadimi, L. (2015). Princess Margaret cancer centre: malignant hematology: self-
learning booklet. 3rd edition.
• Longo, D.L. (2017). Harrison’s hematology and oncology. New York: McGraw-Hill Education
• Brodsky, R. A. (2014). Paroxysmal nocturnal hemoglobinuria. Blood, 124, 2804-2811
• Parker, C. et al. (2005). Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood,
106, 3699-3709
• Young, N.S. et al. (2009). The management of paroxysmal nocturnal hemoglobinuria: recent advance
in diagnosis and treatment and new hope for patients. Seminars in Hematology, 46(1), S1-S6
References
• Hoffbrand, A.V. & Moss, P. A.H. (2016). Hoffbrand’s Essential Haematology. West
Sussex, UK: Wiley & Sons, Ltd.
• MDS Clear Path. Mdsclearpath.org
• Scheinberg, P., DeZern, A.E. & Steensma, D.P. (2016). Acquired bone marrow
failure syndromes: aplastic anemia, paroxysmal hemoglobinuria, and
myelodysplastic syndromes. Retrieved from:
http://ash-sap.hematologylibrary.org//
content/2016/489.extract?utm_source=TrendMD&utm_medium=cpc&utm_ca
mpaign=American_Society_of_Hematology_Self-Assessment_Program_TrendM
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• Young NS. Young N.S. Young, Neal S.Bone Marrow Failure Syndromes Including
Aplastic Anemia and Myelodysplasia. In: Kasper D, Fauci A, Hauser S, Longo D,
Jameson J, Loscalzo J. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo
J Eds. Dennis Kasper, et al.eds. Harrison's Principles of Internal Medicine, 19e
New York, NY: McGraw-Hill; 2014.
http://accessmedicine.mhmedical.com/Content.aspx?
bookid=1130&sectionid=79731602. Accessed August 01, 2018.
• Zhang, L. (2016). Inherited and acquired bone marrow failure syndromes: in the
era of deep gene sequencing. Journal of Leukemia, 4(4)