week 3 part 2

Question 1

Pancytopenia

Answer 1

A DEFICIENCY OF BLOOD CELLS OF all LINEAGES (but generally excludes lymphocytes!)

Pancytopenia is NOT a diagnosis (it reflects a diagnosis)

Pancytopenia does NOT always mean bone marrow failure or malignancy

Question 2

What are the two mechanisms that cause pancytopenia?

Answer 2

Reduced production
OR
Increased destruction of cells

Question 3

Clinical Manifestations of Pancytopenia

Answer 3

Pancytopenia usually presents with signs and symptoms that relate to a reduction in a particular cell line:

1) Anemia
2) Thrombocytopenia
3) Neutropenia

Question 4

Thrombocytopenia

Answer 4

1. Defined as a platelet count of <150,000 cells/μ‎L.
2. Patients with platelet counts >100,000 cells/μ‎L often have normal bleeding times (unless platelet function is abnormal) and usually do not have symptoms.
3. Easy bruising may be noted as the platelet count approaches 50,000 cells/μ‎L.
4. Counts below 10,000–20,000 cells/μ‎L can be associated with petechiae, mucosal bleeding, hemarthrosis, and spontaneous internal bleeds.

Question 5

Neutropenia

Answer 5

1. Defined as an absolute neutrophil count of <1500 cells/μ‎L.
2. Predisposes patients to bacterial infections (however, patients usually present with symptoms related to anemia or thrombocytopenia first).
3. The risk for infection increases substantially after the neutrophil count falls below 500 cells/μ‎L.

Question 6

Common Causes of Pancytopenia (“PANCYTO”)

Answer 6

Paroxysmal nocturnal hemoglobinuria (PNH)

Aplastic anemia

Neoplasms and Near neoplasms

Consumption

Vitamin deficiencies (the “V” looks like a “Y”)

Toxins, drugs, and radiation therapy

Overwhelming infections

Question 7

PNH

Answer 7

A disorder of stem cells that results in an increased sensitivity to complement-mediated cell lysis. The etiology relates to a somatically acquired loss of the PIGA (phosphatidylinositol N-acetylglucosaminyltransferase subunit A) gene in hematopoietic progenitor cells. PNH can clinically manifest as an isolated Coombs test–negative intravascular hemolysis, a hypercoagulable state, and/or bone marrow aplasia.

Question 8

Aplastic anemia

Answer 8

Aplastic anemia is one of the misnomers in medicine because it involves a disorder of stem cells and therefore affects all cell lines. The etiology of idiopathic aplastic anemia is unknown, but an immune-mediated reduction in hematopoietic progenitors has been proposed.

Aplastic anemia is a condition that occurs when your body stops producing enough new blood cells. The condition leaves you fatigued and more prone to infections and uncontrolled bleeding.

Question 9

There are many causes of Aplastic anemia, what are the infectious causes?

Answer 9

Parvovirus B19 is the most frequently documented viral cause of aplastic anemia. Hepatitis, HIV, cytomegalovirus (CMV), and, Epstein-Barr virus (EBV) infections have also been seen; however, the specific type of hepatitis virus associated with aplastic anemia has not been identified.

Question 10

Fanconi’s anemia

Answer 10

Fanconi’s anemia is an autosomal recessive or X-linked disease that usually appears in childhood and is often associated with other congenital abnormalities (e.g., cardiac and renal malformations, hypoplastic thumbs, hyperpigmented skin). Fanconi’s anemia is associated with an increased risk for solid tumors and leukemias as well as aplastic anemia.

Question 11

Drug causes of aplastic anemia

Answer 11

Drugs and toxins. Chemotherapeutic agents, chloramphenicol, sulfa drugs, gold, nonsteroidal antiinflammatory drugs, certain antiepileptic drugs, ionizing radiation, benzene, and various other drugs have been associated with aplastic anemia.

Question 12

Idiopathic aplastic anemia

Answer 12

Despite an extensive workup, the cause remains unclear in a large number of patients. In these cases, the leading hypothesis is that a host immune response against hematopoietic progenitor cells leads to the aplastic anemia.

Question 13

What neoplasms cause pancytopenia?

Answer 13

Neoplasms (e.g., leukemia, metastatic malignancies) and near neoplasms (i.e., myelodysplastic syndrome) can cause pancytopenia.

Question 14

Consumption cause of pancytopenia

Answer 14

i. Hypersplenism

ii. Immune-mediated destruction usually results in decreases of one or two cell lines but can also cause pancytopenia.

Question 15

What vitamin deficiencies cause panctopenia?

Answer 15

Vitamin deficiencies (e.g., vitamin B12 and folate deficiencies) should always be considered in patients with pancytopenia.

Question 16

Overwhelming infections that may cause pancytopenia

Answer 16

Sepsis, tuberculosis, or fungal infection can cause pancytopenia. HIV infection can also result in pancytopenia from the infection itself, superimposed infections, or medications used to treat the infection.

Question 17

Physical examination for pancytopenia

Answer 17

Carefully examine the spleen and lymph nodes. The presence of splenomegaly increases the likelihood of malignancy and essentially rules out aplastic anemia.

Question 18

Megaloblastosis in pancytopenia

Answer 18

increases the likelihood of vitamin B12 or folate deficiency, but can also be seen in other primary bone marrow disorders.

Question 19

Blasts in pancytopenia

Answer 19

implicate a possible myelodysplastic syndrome or acute leukemia.

Question 20

Leukoerythroblastic smear in pancytopenia

Answer 20

A leukoerythroblastic smear, which reveals early red blood cells and early white blood cells (WBCs) (i.e., bands, metamyelocytes, myelocytes), implies marrow invasion by malignancy, fibrosis, or infection. Teardrop cells (i.e., RBCs shaped like a teardrop from being “squeezed” out of the bone marrow) are frequently seen with leukoerythroblastosis.

Question 21

Pseudo–Pelger-Huet anomaly and pancytopenia

Answer 21

(i.e., neutrophils with bilobed nuclei) is seen in patients with myelodysplasia

Pelger-Huet anomaly (PHA) is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape (bilobed, peanut or dumbbell-shaped instead of the normal trilobed shape) and unusual structure (coarse and lumpy).

Question 22

Investigations to find the cause of pancytopenia (always assume caused by primary bone marrow failure util proven otherwise)

Answer 22

a. Patient history.
b. Physical examination.
c. Laboratory studies.
d. Peripheral blood smear (megaloblasts, blasts, leukoerythroblastic smear, Pseudo–Pelger-Huet anomaly)
e. Vitamin B12 and folate levels
f. HIV test.
g. Viral serologies.
h. PNH workup.
d. Bone marrow biopsy.

Question 23

Increased cellularity of bone marrow biopsy when investigating pancytopenia

Answer 23

suggests peripheral destruction (hypersplenism or an immune-mediated disorder) or inadequate differentiation (acute leukemia and myelodysplasia). PNH, acute leukemia, and some forms of myelodysplasia can demonstrate either a hypercellular or hypocellular marrow.

Question 24

Decreased cellularity of bone marrow biopsy when investigating pancytopenia

Answer 24

is the common finding in aplastic anemia, but can also be seen in PNH, myelodysplasia, and, occasionally, hypoplastic acute leukemia.

Question 25

Features of aplastic anemia

Answer 25

normochromic, normocytic anaemia
leukopenia, with lymphocytes relatively spared
thrombocytopenia
may be the presenting feature acute lymphoblastic or myeloid leukaemia
a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia

Question 26

Treatment for pancytopenia

Answer 26

Packed RBC transfusions are usually given to maintain the hemoglobin above 7 gm/dl

Platelet transfusions may be necessary to control bleeding or when the platelet count falls below 10,000 cells/μ‎L to reduce the risk for spontaneous bleeding

Granulocyte colony-stimulating factor (G-CSF) is sometimes used to increase neutrophil counts.

Broad-spectrum antibiotics

Question 27

Specific treatment for PNH and panctopenia

Answer 27

Eculizumab is a monoclonal antibody that binds to the C5 component of complement and inhibits complement activation. It has been demonstrated to reduce the rate of hemolysis, transfusion requirements, and rate of thrombotic complications in patients with PNH.

Question 28

Bone marrow transplantation in pancytopenia

Answer 28

Bone marrow transplantation may be curative but carries significant morbidity and mortality. Therefore, it is often only used for late-stage complications of PNH, including aplastic anemia, or acute leukemia, or in cases of eculizumab resistant PNH.

Question 29

Specific treatment for PNH in pancytopenia

Answer 29

1. The constant hemolysis and hemosiderinuria/hematuria can actually result in iron deficiency that may require iron replacement. Likewise, folate replacement is recommended in all patients with chronic hemolysis regardless of the cause.
2. Chronic anticoagulation therapy is indicated for all patients who have a history of thrombosis.
3. Eculizumab
4. Bone marrow transplantation

Question 30

Antithymocyte globulin

Answer 30

Antithymocyte globulin is usually the first-line pharmacologic treatment for patients with severe aplastic anemia. Two forms of the antibody exist (ATGAM, derived from horses, and thymoglobulin, derived from rabbits).

Question 31

Immunosuppressive agents in aplastic anemia

Answer 31

Immunosuppressive agents (e.g., cyclosporine) are used in conjunction with antithymocyte globulin and increase the likelihood of remission.

Question 32

Specific treatments for aplastic anemia

Answer 32

Transfusion support and antibiotics
Pharmacologic therapy
Antithymocyte globulin
Immunosuppressive agents 
Bone marrow transplantation

Question 33

Rituximab

Answer 33

Rituximab is a targeted cancer drug and is also known by its brand names MabThera, Rixathon and Truxima. It is a treatment for: chronic lymphocytic leukaemia (CLL) some types of non-Hodgkin lymphoma (NHL) some non cancer related illnesses.

Question 34

Rituximab mechanism of action

Answer 34

The direct effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and the indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy.

Question 35

Ofatumunab (Azerra).

Answer 35

Ofatumumab, sold under the brand name Arzerra among others, is a fully human monoclonal antibody to CD20, which appears to inhibit early-stage B lymphocyte activation.

Ofatumumab injection is used in chronic lymphocytic leukemia (CLL) in patients who have not received any treatments in the past.

Question 36

Obinutuzumab

Answer 36

Obinutuzumab is also known as Gazyvaro®. It is used to treat chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL). Monoclonal antibody against CD20

Question 37

Bortezomib

Answer 37

Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is generally used together with other medications. It is given by injection.

Question 38

Tyrosine Kinase Inhibitors (TKI) in CML

Answer 38

Imatinib, nilotinib, dasatinib, bosutinib and ponatinib.
Generally well tolerated
Achieve haematological, cytogenetic and molecular remissions in the majority of patients
Some patients can stop treatment without relapsing (treatment free remission leading to cure)

Question 39

Immune therapy in cancer

Answer 39

Allogenic bone marrow transplant (from a matched donor) is immune therapy.
T cells from the donor cause immune attack on cancer.
Graft versus Leukaemia or lymphoma Effect (GvL).
But also have immune attack of normal cells. Very toxic. Graft versus Host Disease (GVHD).

Question 40

Adoptive immunotherapy

Answer 40

Make the patients own immune cells recognise the cancer as foreign and attack it.
Avoids toxicity of graft versus host disease.
Most promising is CAR-T cell therapy.

Question 41

Chemo and radiotherapy

Answer 41

Damages DNA of cancer cells as it divides (mitosis).
Cell recognises it is damaged beyond repair and dies by process of apoptosis
Often involves a protein in the cell nucleus - P53
Mutations of P53 make it more difficult to treat with chemotherapy and radiotherapy.

Question 42

Cytotoxic drug classification

Answer 42

Cell cycle specific

Non-cell cycle specific

Question 43

Cell cycle specific agents:

Answer 43

1. Antimetabolites
   (impair nucleotide synthesis / incorporation)
2. Mitotic spindle inhibitors

Question 44

Antimetabolites examples

Answer 44

Methotrexate
inhibits dihydrofolate reductase

6-Mercaptopurine / Cytosine arabinoside / Fludarabine
incorporated into DNA

Hydroxyurea
impaired deoxynucleotide synthesis (ribonucleotide reductase)

Question 45

Mitotic spindle inhibitors examples

Answer 45

Vinca alkaloids such as vincristine / vinblastine

Taxotere (Taxol)

Question 46

Alkylating agents

Answer 46

chlorambucil / melphalan
bind covalently to bases of DNA (adducts)
produces DNA strand breaks (mutation) by free radical production
(cytotoxic cancer drug)

Question 47

Cytotoxic antibiotics

Answer 47

anthracyclines: daunorubicin / doxorubicin / idarubicin
DNA intercalation: reversible
impairs RNA transcription
strand breaks in DNA (free radicals)

Question 48

Cytotoxic drugs: general side effects (immediate)

Answer 48

Affects rapidly dividing organs

Bone marrow suppression
Gut mucosal damage
Hair loss (alopecia)

Question 49

Cytotoxic drugs: examples of drug specific side effects

Answer 49

Vinca alkaloids: neuropathy
Anthracyclines: cardiotoxicity
Cis-platinum: nephrotoxicity

Question 50

Cytotoxic drugs: long term side effects

Answer 50

Alkylating agents - Infertility, Secondary malignancy

Anthracyclines - cardiomyopathy

Question 51

Neutropenic sepsis definition

Answer 51

Neutropenic sepsis is defined by NICE as a neutrophil count of 0.5 × 109 per litre or lower, plus one of the following:

Temperature ≥ 38°C or
Other signs or symptoms consistent with significant sepsis
Neutropenic sepsis is the most common medical emergency amongst oncology and haematology patients, who can present with, or rapidly progress to haemodynamic instability. Therefore, rapid assessment and administration of empirical antibiotic therapy can be lifesaving.

Question 52

Signs of neutropenic sepsis

Answer 52

Temperature ≥ 38°C or
Other signs or symptoms consistent with significant sepsis
Neutropenic sepsis is the most common medical emergency amongst oncology and haematology patients, who can present with, or rapidly progress to haemodynamic instability. Therefore, rapid assessment and administration of empirical antibiotic therapy can be lifesaving.

Question 53

Antimetabolites mechanism of action

Answer 53

Antimetabolites act by replacing the natural building materials needed for DNA and RNA synthesis. This prevents DNA replication, halting cell reproduction.4,5,6

Antimetabolites act on the S phase of the cell cycle.

Question 54

Pyrimidine antagonists mechanism of action (cytotoxic drugs)

Answer 54

Pyrimidine antagonists inhibit thymidine synthase. This prevents the synthesis of the thymidine nucleotide, halting DNA replication.

Gemcitabine: used in pancreatic and ovarian cancer
5-FU: used in colorectal, gastric and pancreatic cancers
Cytarabine: used in lymphoma and leukaemia

Question 55

Palmar plantar erythrodysesthesia (PPE) - cytotoxic drug side effect

Answer 55

PPE is a painful erythematous rash occurring over the palms, fingers and soles of the feet. Lesions are typically clearly demarcated and painful. Skin breakdown and blistering typically develop as the condition progresses.

This is typically a dose-related side effect.

Question 56

Purine antagonists (cytotoxic drugs)

Answer 56

Purine antagonists inhibit enzymes used in the production of purines, preventing the synthesis of adenosine and guanine.

Examples of agents in this class include:

6-mercaptopurine and prodrug azathioprine: used in acute lymphocytic leukaemia
Fludarabine: commonly used in low-grade lymphomas

Question 57

Alkylating agents mechanism of action

Answer 57

Alkylating agents act directly on DNA strands and cause cross-linking of DNA and RNA strands. This results in permanent modification of the DNA structure leading to programmed cell death.

These agents act on multiple phases of the cell cycle. All of these agents are known to cause significant myelosuppression.

Question 58

Platinum agents as cyotoxic drugs

Answer 58

Examples of platinum agents include cisplatin, carboplatin and oxaliplatin. Each agent contains a platinum ion, surrounded by organic ligands, that carries out its action on DNA strands. These agents are commonly used in the management of ovarian, colorectal, lung and bladder cancers.

Question 59

Vinca alkaloids mechanism of action and uses

Answer 59

Examples of agents in this class include vincristine, vinblastine and vinorelbine. These agents are commonly used in solid tumours (including Wilms tumour and neuroblastomas) and lymphomas (Hodgkin’s and non-Hodgkin’s).

Vinca alkaloids act by binding on the b-tubulin units and prevents microtubule polymerization. This prevents spindle formation and the cell cycle arrests during metaphase.

Question 60

BCR-ABL tyrosine kinase inhibitors

Answer 60

BCR-ABL tyrosine kinase inhibitors
Examples in this class include imatinib and which is commonly used in the management of chronic myeloid leukaemia.

Question 61

Brunton kinase inhibitors

Answer 61

Ibrutinib is in this class and is used in the management of chronic lymphocytic leukaemia. It is associated with cardiotoxicity, hepatotoxicity and myelosuppression.