MKSAP 1: Hematopoietic stem cell and their disorders Flashcards
Name the bone marrow failure syndromes
Aplastic anemia
Pure red cell aplasia
Neutropenia
What are the characteristics of aplastic anemia?
a condition characterized by pancytopenia with associated neutropenia, anemia and thrombocytopenia and a severely hypocellular bone marrow (<10%)
What the main etiologies of aplastic anemia?
Toxic, viral or autoimmune mechanisms
Define severe plastic anemia from very severe aplastic anemia?
Severe aplastic anemia has two or more of the following:
- ANC 200-500/uL
- Platelet count < 20K/uL
- absolute reticulocyte count <40K/uL
Very severe aplastic anemia has two or more the above except with ANC <200
What are some drugs that can cause aplastic anemia?
NSAIDs, beta-lactam abx, antiepileptic drugs and psychotropic meds
What is the dominant cause of adult AA?
autoimmunity as autoreactive T cells attack pluripotent HSCs and cause aplasia
What is first line therapy for aplastic anemia?
cyclosporine and antithymocyte globulin leads to control in 70% of adults. Allogeneic HSCT is a potentially curative therapy and should be considered for those younger than 50 with compatible donors
What are the 3 disorders that are acquired defects of the hematopoietic stem cell?
aplastic anemia
paroxysmal nocturnal hemoglobinuria
myelodysplastic syndromes
What is PNH?
Acquired disorder in which erythrocytes lack membrane proteins CD55 and CD59 required to stabilize complement leading to episodic intravascular hemolysis
What is the cardinal feature of pure red cell aplasia?
Severe anemia without an adequate reticulocyte response. Examination of bone marrow shows an absence of erythrocyte precursors
What is the mechanism for PRCA?
predominantly T cell autoimmunity or direct toxicity to erythrocyte precursors
List causes of PRCA
Parvovirus B19 Thymoma Autoimmune disease Lymphoid lukemia and lymphomas Solid tumors Drugs (phenytoin, isoniazid) Pregnancy Anti-EPO antibodies in patients receiving EPO
What specific subset of patients are susceptible to parvovirus B19 infection causing PRCA? What treatment may they require?
sickle cell anemia patients
Can cause severe anemic crisis
IVIG may hasten viral clearance
What diagnostic test is required to diagnose PRCA? What else does it exclude?
Bone marrow examination
Also excludes secondary causes of PRCA such as CLL or non-Hodgekin lymphomas
How do leukemias and lymphomas cause PRCA?
Immune mediated mechanisms
Name the T cell lymphoproliferative disorder that is associated with PRCA, is associated with RA, diagnosed by peripheral blood smear and shows lymphocyte CD57 positivity on flow cytometry
How can it be treated?
large granular lymphocytosis
Treated with methotrexate
define felty syndrome
clinical triad of RA, splenomegaly and neutropenia
How is thymoma excluded as a cause of PRCA?
CT scan of the chest
How are idiopathic causes of PRCA treated?
Immunosuppression with prednisone either administered alone or with cyclosporine or cyclophosphamide
What are the possible general causes of isolated neutropenia?
Hereditary, toxic or immune causes
What are the general categories of toxicities to cause neutropenia?
viral, bacterial or meds
Name the viruses that can cause neutropenia?
Acute HIV, CMV and EBV
What specific bacterial infections can cause neutropenia?
Rickettsial infection or overwhelming bacterial infection
What meds can cause neutropenia?
Cytotoxic chemos, NSAIDs, carbamazepine, phenytoin, PTU, cephalopsorins, Bactrim and psychotropic drugs
What immune related disorders can cause neutropenia?
Connective tissue disease such as SLE and RA
What is the main difference between aplastic anemia and the myelodysplastic syndromes?
Dysplastic (difficult formation) marrow of MDS is most commonly hypercellular. A full bone marrow yields low blood counts bc cells are ineffectively formed and limited survival
What are some etiologies of MDS
Past radiation or chemo but more commonly a primary process
What is the dreaded complication of MDS
Conversion to AML
LEFT OPEN FOR WHO Classification of MDS
LEFT OPEN FOR WHO Classification of MDS
What are patient characteristics to detect MDS?
MDS increases with age. Suspect in patients with macrocytic anemia or pancytopenia in whom B12 and folate have been excluded. Basophilic stippling or Howell Jolly bodies and dysplastic neutrophils
What is the scoring system used for MDS and what does it incorporate?
International Prognostic Scoring System (IPSS-r) weighs percentage of marrow blasts, cytogenetics of the marrow and peripheral blood cytopenias
What are the 2 treatment goals for MDS?
1) Relieve transfusion dependence
2) Prevent transformation to AML
What is the approach with a patient considered low risk MDS?
No treatment at all or infrequent transfusions
What is the approach with a patient considered high risk or very high risk?
Require treatment at diagnosis
What are the therapies for MDS?
allogeneic HSCT in fit younger patients or chemotherapy such as asacytidine and decitabine
Name the myeloproliferative neoplasms
CML Polycythemia vera Essential thrombocytopenia Primary myelofibrosis Eosinophilia and Hypereosinophilic syndromes
How do the MPNs present?
unusual thromboses, massive splenomegaly
constitutional symptoms such as fevers, chills, weight loss and night sweats
What cancer do all MPNs have a gradual connection to?
Each has a chronic phase that may progress at varying frequency to AML
How might a patient with CML present and what would be seen on peripheral blood smear?
Present with constitutional symptoms and splenomegaly , fatigue, early satiety and progressive weight loss
Granulocytic leukocytosis is seen on CBC and earlier myeloid forms such as metamyelocytes, myelocytes and less than 5% blasts are present on peripheral smear
What is the main indicator for extreme granulocytic leukocytosis?
the leukemoid reactions, >50K WBC
Can also be caused by sepsis and Cdiff
What is the genetic cause of CML?
The Philadelphia chromosome leading to fusion gene BCR-ABL encoding a mutant tyrosine kinase. Necessary and sufficient to diagnose CML
What is the guideline for treatment of CML compared to ET and PMF?
Therapy is required at diagnosis otherwise can lead to transitional accelerated phase or progress to an overt blast crisis
What are the percentages of leukemias arising from CML?
AML (80%)
ALL (20%)
What is the treatment for CML?
Tyrosine kinase inhibitors
1st gen - imatinib
2nd gen - nilotinib or dasatinib
What side effect needs to be monitored for tyrosine kinase inhibitors?
QT interval prolongation
What are the unique side effects of dasatinib?
Pericardial and pleural effusions and associated with pulm arterial HTN
No TKI is safe in pregnancy
What are the therapeutic options for CML in pregnancy?
Close observation without therapy or interferon alfa
Progression of CML is due to medication nonadherence and/or TKI resistance. What new TKI has been approved and what side effects need monitored?
Ponatinib overcomes some TKI resistance
Thromboembolic complications
These drugs also cost 100K a year and need assistance obtaining
What is polycythemia vera?
A disorder of myeloid/erythroid stell cell that causes erythropoietin independence proliferation of erythromcytes, analogous to the Philadephia chromosome in CML
Activating mutation of JAK2 (JAK2 V617F)
When is PV suspected?
Hgb > 18.5 in men or greater than 16.5 in women after 2nd causes excluded
What is the common underlying cause of 2nd erythrocytosis and what is it commonly due to?
Elevated erythropoietin level and most common hypoxemia
What are some 2nd causes of 2nd erythrocytosis?
Hypoxemia: COPD, sleep apnea, congenital heart disease, intrapulmonary shunting, elevated altitude, renal artery stenosis
Elevated erythropoietin: renal cell carcinoma, hepatocellular carcinoma, uterine fibroids
What clinical features distinguish MPNs?
pruritus after a warm bath, intermittent heat, redness and pain of palms and soles, hepatosplenomegaly, elevated WB and platelets and unusual thormboses
What lab findings are classic for PV?
Elevated serum B12 causes by increased levels of transcobalamin III produced in proliferating leukocytes
Hyperuricemia as a consequence of DNA turnover
What uncommon clots should prompt evaluation for PV?
Hepatic vein thrombosis or portal vein thrombosis
What are the treatment options for PV?
Therapy for PV is required at diagnosis.
Low dose aspirin decreases arterial and venous clot risk
Phlebotomy is the mainstay of therapy and can be used in addition to aspirin in patients younger than 60 years w/o previous thromboembolic event. Goal is Hct <45%
Hydroxyurea can be used in conjunction with phlebotomy in patients older than 60 years or those with previous thromboembolic events
What can be seen in PV patients in response to their treatment and in peripheral blood smear as PV progresses to fibrotic stage?
Decreasing phlebotomy or hydroxyurea requirements and increasing splenomegaly.
Peripheral smear with teardrop cells, nucleated erythrocytes and immature myeloid forms
When is essential thrombocytopenia suspected?
Platelet count of greater than 600K detected on 2 or more occasions at least 1 month apart in the absence of secondary causes
What are the secondary causes of ET and what is the most common?
IDA is the most common followed by reactive states due to infection or inflammation
What symptoms may be present in ET?
Digital ischemia, erythromelalgia, tranient ischemic attack, visual disturbances, venous thromboembolism, or bleeding
What score can be used ot risk stratify patients with ET?
The INternational Prognostic Score for ET. Many patients may be observed
What patients are considered low risk with ET and can be observed?
younger than 60 years, no previous thrombosis, WBC < 11K
What treatment options are indicated for ET?
Platelet lowering therapy is indicated for any patients at high risk. Hydroxyurea is well tolerated in older patients and considered 1st line in nonpregnant patients.
Anagrelide is an agent that prevents megakaryocyte budding but may cause fluid retention and exacerbation of CHF
Interferon alfa is the only platelet lowering agent safe in pregnancy
Plateletpheresis may be employed emergently to temporarily decrease platelet counts in symptomatic patients with extreme thrombocytosis, usually greater than 1 million
How does ET compare to other MPN in terms of AML and symptoms?
ET is the least likely to progress to AML or secondary fibrosis and least likely to present with symptomatic splenomegaly or constitutional symptoms
What is primary myelofibrosis?
Is an MPN that does not present with a dominant blood count elevation rather it is a clonal myeloid disorder characterized by abnormal proliferating megakaryocytes that prodcue excess fibroblast growth factor which causes marrow fibrosis and leads to extramedullary hematopoiesis
What can be describe on a bone marrow aspiration in PMF? What happens to LDH and uric acid?
“dry tap”
LDH and uric acid are elevated
What are the extramedullary hematopoesis sites?
Spine or lymph nodes
What symptoms can be seen in PMF?
fever, chills, night sweats, and malaise, early satiety, weight loss and abdominal discomfort
When is treatment required in PMF and what does it entail?
Treatment required for symptomatic splenomegaly, worsening cytopenias and constitutional symptoms
Allogeneic HSCT in younger patients
Treatment is palliative otherwise, splenectomy is perilous
Hydroxyurea
Jak2 inhibitor ruxolitinib
What is the differential for eosinophilia?
C - collagen vascular disease (Churg Strauss)
H - helminthic infection (strongyloides)
I - idiopathic hypereosinophilic syndrome
N - neoplasia (lymphomas)
A - allergy, atopy, asthma, also drug induced (carbamazepine, sulfonamides)
What are hypereosinophilic syndromes? Describe primary and secondary
Disease characterized by eosinophilia with a count > 1,500 and eosinophilic infiltrates of the tissues resulting in organ damage in addition to systemic symptoms such as fever, chills, night sweats and weight loss
Primary - an MPN with moelcular activation of platelet derived growth factor receptor without a known stimulating factor
2nd - polyclonal expansion in response to identified stimulus such as parasitic infection
What is the medication indicated for eosinophilic syndromes?
Glucocorticoids have dramatic lytic effect but long term use in HESs is problematic
What is the greatest risk factor for AML?
Age, mean age of presentation is 67
What is the diagnostic criteria for AML?
Requires 20% or more myeloblasts in either the peripheral blood or the marrow
What are the symptoms on labs in AML?
Anemia, thrombocytopenia and neutropenia
90% myeloblastic, 10% lymphoblastic in adults; reverse in children
What syndrome can develop in AML and what intervention needs to be considered>?
Hyperleukocytosis syndrome including hypoxemia and mental status change from stasis of immature cells in small capillary networks. Leukapheresis
What are the acute decisions that need to be determined acutely in suspected acute leukemia?
- Confirm acute leukemia
- AML vs. ALL (auer rods on blood smear, confirmed on flow cytometry)
- Exclude APL (Clinically suspected with DIC, classically with promyelocytes and prominent Auer rods, microgranular variant evaluated by flow cytometry; administer ATRA)
- AML - not APL (Begin induction therapy with cytosine arabinoside and an anthracycline)
- ALL (Philadelphia chromosome + or -)
What is the greatest influence on survival in AML?
genetic profile of the leukemic cells
What are the favorable AML genetic risk profiles?
T(8;21)
inv (16)
t(15;17)
What are the high risk genetic risk profiles in AML?
complex (>5 abnormalities), -5, -7, del(5q), 3q abnormal
What is APL? What is the defining clinical clue, the genetic defect and the indicated treatement even before confirmation testing?
Acute promyelocytic leukemia DIC t(15;17) All-trans retinoic acid (ATRA) Sometimes in combination with chemotherapy, or more recently, ATO (arsenic trioxide)
What syndrome can develop from ATRA and ATO? What is the treatment?
Differentiation syndrome -> characterized by hypoxemia, pulmonary infiltrates and fever
Stop meds and give steroids
What is the indicated treatment for non-APL AML?
7 day course of cytarabine and 3 day course of anthracycline
Less toxic regimen is azacitidine or decitabine
What is the main difference in presentation in patients with ALL compared to patients with AML?
frequent involvement of the CNS requires staging by CSF and prophylaxis with intrathecal chemotherapy
How is ALL defined?
25% lymphoblasts in the blood or bone marrow
What are the biochemical test features of ALL?
terminal deoxynucleotidyl transferase positive and
myeloperoxidase negative
What are predictors of poor outcome in ALL?
Advanced age B cell vs T cell disease > 30K blasts at diagnosis Poor risk cytogenetics the philadelphia chromosome t(9;22)
What drug is indicated in Philadelphia positive ALL?
Tyrosine kinase inhibitor dasatinib
What are the 2 recombinant growth factors used in common clinical practice?
G-CSF - to stimulate production of neutrophils in autoimmune neutropenia to hasten neutrophil recovery after cytotoxic chemo and for HSC mobilization.
Recombinant erythropoietin - ACD in CKD patients if iron, B12 and folate levels replete
What are the targets before treatment for ESA in CKD?
transferrin sat > 20% and serum ferritin > 100
