Back to basics!
Definition of Bone Marrow Failure?
--> Intrinsic disorder of the BM, resulting in:
1. Disrupted hematopoietic stem and progenitor cell homeostasis and function
2. Inadequate production of white blood cells, red blood cells, and/or platelets.
Happens as a result of acquired mutations in PIGA gene (Xp22.2).
How do you treat it?
-> Paroxysmal Nocturnal Hemoglobinuria (PNH).
-> Bone marrow transplant is the only definitive cure.
-> Complement inhibition - Requires lifelong therapy. It prevents hemolysis and thrombosis but does not affect the course of BM failure.
C5 inhibitors (Eculizumab, ravulizumab)
Copan (Iptacopan, Danicopan )and coplan drugs (Pegcetacoplan).
True/False
70% of Patients with Acquired Aplastic Anemia Will Develop Clonal Hematopoiesis
True.
Name some Acquired Bone Marrow Failure syndromes.
Acquired
-> Acquired Aplastic Anemia
-> Acquired Pure Red Cell Aplasia
-> Hypocellular MDS
-> Paroxysmal Nocturnal Hemoglobinuria
-> Transient Drug Suppression
-> Transient Infection Vitamin/Mineral Deficiency
Name an inherited BMF syndrome that is caused by defective telomere maintenance. Other clues in presentation- Dyskeratotic nails/hair, Leukoplakia/reticular rash, skin hypertrophy on hands/feet/ataxia, esophageal stricture/immune deficiency etc.
Dyskeratosis Congenita
Etiology: abnormal aging of BM stem cells through defective telomere maintenance
What is false about Diamond Blackfan Anemia ?
A. It is caused by mutations in Ribosomal Proteins.
B. It is associated with Congenital anomalies,Short stature, Cardiac/renal/GU, hand/limb, Craniofacial/neck abnormalitities.
C. 40% respond to corticosteroids; others require chronic transfusions.
D. ↑ eADA in>80%
E. All of them are correct.
E. All of them are correct.
Name some Inherited Bone Marrow Failure syndromes?
--> Diamond-Blackfan Anemia
--> Fanconi Anemia
-->GATA2 Haploinsufficiency
--> SAMD9/SAMD9L syndromes
-->Severe Congenital Neutropenia
--> Shwachman-Diamond Syndrome
--> Telomere Biology Syndromes
--> Thrombocytopenia Syndromes
Young male with increased bruising and fatigue, followed by a day of fever, no prior history except for recent viral gastroenteritis. No lymphadenopathy or hepatosplenomegaly on exam.
CBC shows pancytopenia, no blasts.
Bone Marrow Aspirate/Biopsy- Marrow Aplasia.
How do you treat it?
Acquired Aplastic Anemia
■ Idiopathic/Immune Mediated (75-80%)
■ Drug/chemical Effect (3-5%): chemotherapy, anti-epileptics, benzene exposure
■ Hepatitis Associated (10-15%): Non-typeable, autoimmune?
■ Viral Infection (5-10%): EBV, HIV, parvovirus.
Treatment
-> Only patients with severe [Bone marrow cellularity <25% and at least 2 of the following-ANC <500, plt <20K, retic <60K) or very severe acquired aplastic anemia (Fulfilling criteria for SAA +ANC<200) are typically eligible for transplant preferably Matched Sibling Donor Bone Marrow Transplant (MSD-BMT).
--> If HLA matched sibling, can do Immune Suppression as well as Haploidentical or Unrelated Donor SCT.
Immune Suppression Therapy
Q1 Supportive care prior to and during IST
Q2 Name some Immune Suppression Therapies used.
Supportive care prior to and during IST
Infectious disease prophylaxis:
-> Antifungals if ANC consistently < 500
-> HSV prophylaxis x 1 month (some centers)
-> Pneumocystis pneumonia prophylaxis: at least 3 months once IST starts.
Blood products:
-> Use leukoreduced and irradiated blood products
-> Maintain platelet count > 10K (higher during ATG), hemoglobin > 7-8 g/dL
Immune Suppression Therapy
--> Equine ATG
--> Prednisone
-->Cyclosporine A
Goal: gradual blood count recovery over the first 6-9 months
Why determine whether cause of aplasia is inherited or acquired?
--> Treatment approaches are different!
* Acquired Aplastic Anemia can be treated with immune suppression
* Inherited causes: Stem Cell Transplant (SCT) is the only cure
Other organ systems are affected!
--> Implications of inherited causes for other family members
* Family genetic counseling and donor testing
* Many BMF diseases have incomplete penetrance or variable disease onset
* Because inherited BMF is common in some scenarios Ex #1: >70% of Adolescent/Young Adult patients with Monosomy 7 MDS had germline GATA2 mutation*
- Most Common inherited BMF syndrome that results from Defective DNA repair and Oxidative stress, presents early in life with Congenital malformations such as Short stature, Café au lait, Hypoplastic thumbs, and microcephaly.
- How do you diagnose it?
- How do you treat it?
Fanconi Anemia
Diagnosis: chromosomal breakage study --> confirm with gene sequencing (NGS).
T/T-Androgens (Danazol, oxymetholone): Efficacy in ~50%
SCT only curative option
Gene therapy
Match the following disorder to its etiology.
A. Severe Congenital Neutropenia (SCN)
B. Cyclic Neutropenia
C. Shwachman-Diamond Syndrome (SDS)
-------------------------
A. Ribosome disorder
B. ELANE mutations
C. Misfolded Neutrophil Elastase
Severe Congenital Neutropenia (SCN)-Misfolded Neutrophil Elastase
Cyclic Neutropenia- ELANE mutations
Shwachman-Diamond Syndrome (SDS)-Ribosome disorder