Lecture 12: Leukocyte Disorders Part 1 Flashcards
What is a bone marrow biopsy/aspiration?
Drilling a hole into bone to obtain cellular contents of bone marrow.
What are CIs of bone marrow biopsy?
Severe bleeding disorders (DIC, hemophilia)
Thrombocytopenia is a relative CI.
What can we test with a bone marrow biopsy?
Histology
Cytogenetic testing
Flow-cytometry
What are the indications of a bone marrow biopsy?
Abnormal CBC diff with normal smear.
Evaluate progress of treatment
FUO
Unexplained splenomegaly
Testing iron if all other tests are inconclusive
Where do we NOT perform a bone marrow biopsy?
Areas with signs of infection, injury, or excess overlying adipose tissue (NO FATTY AREAS)
What is the preferred site for a BM biopsy/aspiration?
Posterior iliac crest
Alt is anterior iliac crest
What is the preferred site for a BM aspiration only?
Tibia (under general anesthesia, used for infants <1yo)
Sternum (2nd and 3rd ICS, older than 12yo + morbid obese)
What is the main cause of acute lymphoblastic leukemia (ALL)?
Chromosomal translocation
What is ALL?
Malignant disorder that originates in a single lymphocyte, resulting from an abnormal expression of genes.
It is the cell immediately after the common lymphoid progenitor.
What 4 things does ALL result in?
Rapid cell proliferation/self-renewal
Reduction in normal cell proliferation
Block in cell differentiation
Increased resistance in cell apoptosis.
Essentially, it stays as an immature lymphoblast, making more of itself. Since it stays immature, it does not enter apotosis easily.
How does ALL impair hematopoiesis?
Accumulation of the lymphoblasts within the bone marrow suppresses the normal hematopoiesis since there is limited room.
Once it builds up, the bone marrow releases the lymphoblasts elsewhere to other organs.
How likely is ALL due to genetics vs environment?
Genetics are only 5% of cases.
95% are due to environmental factors.
What are the environmental factors associated with ALL?
In utero radiation exposure.
Chemicals
High birth weight (increase insulin-like growth factor 1)
LACK OF EXPOSURE to infections in the first few weeks of life.
Who is ALL MC in ?
Children, usually DXd prior to 15yo.
What gender is ALL MC in?
Males by a little.
What is the MC symptom in ALL?
FUO (fever of unknown origin)
What 3 hematologic conditions are common in ALL?
Neutropenia
Anemia
Thrombocytopenia
What is the main cause of all the S/S in ALL?
The direct infiltration of marrow or other organs by leukemic cells.
When do most deaths due to ALL occur?
In adults.
What are significant S/S of ALL?
LAN (often all lymph nodes, not specific)
Bone pain (a deep pain at night that wakes them)
Early satiety (splenomegaly bc stomach is compressed)
Mediastinal mass
Painless testicular swelling/mass
What is leukostasis?
Hyperleukocytosis, aka WBCs > 100k that causes neurologic symptoms.
Leads to inadequate circulation.
How emergent is leukostasis?
Very!
Risk of ICH, that lasts even 1 week after reduction.
40% mortality in 2 days if not treated.
How would someone with ALL potentially describe their symptoms?
Deep aching pains at night
Getting full very easily
Dysphagia, persistent chest pain
General swelling of lymph nodes
What would an initial workup of ALL be?
CBC
CMP
Blood cultures
CXR
CT/MRI Brain (WITHOUT contrast)
What would I expect on a CBC of an ALL patient?
Decreased RBC, platelets, and neutrophils.
WBC could be low, normal, or high.
Why do we order a CXR for an ALL patient?
R/o pneumonia
Check mediastinal mass
Why do we order a brain MRI/CT?
Neurologic s/s
Leukostasis suspected
Case Study:
Further history reveals the patient has multiple febrile illness recently but no specific cause was identified. Mother has noticed that he has been less energetic than usual. On exam, you note the child has lost 5 lbs since last visit 6 mo ago. He has cervical, axillary, and inguinal LAN throughout, measuring 1.5-2.0cm.
What do these symptoms suggest? What are the key symptoms?
Febrile illness without cause = FUO.
Less energetic = possible anemia.
Lost 5 lbs = loss of appetite, early satiety, UNintentional weight loss
Generalized LAN = concern for systemic infection.
When are blood cultures generally ordered?
Signs of infection.
What are additional lab tests we could order to work-up ALL?
Peripheral smears
LDH
CT Chest with Contrast
What would I typically see on a smear for an ALL pt?
Pancytopenia with circulating lymphoblasts.
Why does LDH elevate in ALL?
Tissue destruction.
When would I order an LP for ALL? What am I looking for?
All patients with suspected ALL to check for CNS involvement.
+ Lymphoblast cells in CSF.
What would show up in a flow-cytometry test for an ALL patient?
ALL cells will express CD19 antigens and potentially CD10 antigens.
Lack of mature T-cell markers as well. (CD3, CD4, or CD8)
What would show up in a bone marrow aspiration & biopsy for an ALL pt?
> 20% lymphoblasts per the WHO.
This is the definitive diagnostic method for ALL.
What are the two treatments for ALL patients?
Induction chemotherapy
CNS prophylaxis
What is the goal of induction chemotherapy?
Remission induction via MULTI-DRUG chemotherapy.
How is CNS prophylaxis administered?
Intrathecal therapy at all stages.
What is intrathecal therapy?
Direct administration of chemotherapy via administration directly into the EPIDURAL space.
What should we do if ALL is highly suspected?
Refer to heme onc.
What is the post-remission therapy in young ALL pts able to tolerate chemo?
Readministration of the induction regimen in order to increase the time of remission.
Either intensified therapy or maintenance therapy.
Maintenance lasts 2-3 years, much longer.
When can an ALL pt undergo intensified post-remission therapy?
They must have normal hematopoiesis.
Lasts 4-8 months.
What is the post-remission therapy for older ALL pts who cannot withstand chemo?
Allogeneic stem cell transplant.
AKA all patients that are matching donors.
How is an allogeneic stem cell transplant given?
Person undergoes massive, intensive chemo to irradiate all their bone marrow.
They are then transfused with the donor stem cells over an hour.
How do we manage leukostasis in ALL pts?
Prophylaxis for tumor lysis syndrome via IV hydration and hypouricemia agents.
Emergent chemo and leukapheresis if leukostasis present.
Why is tumor lysis syndrome so dangerous?
Spillage of tumor contents can cause massive electrolyte abnormalities.
What is leukapheresis?
Removal of whole blood to remove the WBCs.
The blood is then retransfused into the patient.
What is the cure rate of ALL in children vs adults?
90% in children.
50% in adults.
If a patient with ALL relapses, when is it most likely to occur?
Within first 2 years.
Reappearance of leukemic cells at any site.
Where is the MC site of relapse for an ALL pt?
CNS.
Hence why we do intrathecal chemo.
What falls under good prognostic criteria for ALL?
- No chromosomal abnormalities
- Younger than 39
- WBC < 30k
- Complete remission within 4 weeks.
Damage to what cell is the cause of Chronic Lymphocytic Leukemia? (CLL)
B cells
What is the etiology of CLL?
Malignant lymphoid neoplasm characterized by accumulation of long-lived, functionally incompetent, small mature B cells.
Results in dysfunction in the maturation of B cells.
What are the B cells of CLL unable to do?
They DO NOT RESPOND to immunologic stimulation.
What are the epidemiology stats of CLL?
MC form of leukemia in the US!!
MC in elderly, 90% occur after age 50.
MC in white males.
How does CLL commonly present?
LAN (MC finding)
Recurrent infections (Pneumonia, HSV, HZV)
HSM (early satiety)
S/S of anemia/thrombocytopenia in advanced CLL.
How does a CBC of CLL appear?
WBC > 20k
Isolated absolute lymphocytosis is the HALLMARK SIGN.
+/- decreased RBC, platelets
Bonus: What is normal WBC range?
5k-10k
How does a peripheral smear of CLL appear?
Small mature lymphocytes.
+ Smudge cells
Prolymphocyte (precursor to a small lymphocyte)
What does flow-cytometry reveal in a CLL patient?
Abnormal B-lymphocyte surface antigens
Generally used to confirm the diagnosis of CLL.
Is a bone marrow biopsy/aspiration required to diagnose CLL?
NO!
It may still be performed.
What is the difference in lymphocytes in ALL vs CLL?
ALL has lymphoBLASTS
CLL has MATURE lymphocytes.
ALL is also more common in children.
CLL is more common in elderly.
What does low-risk/stage 0 CLL present as?
Lymphocytosis alone.
Lymphocyte >15k and > 40% lymphocytes in bone marrow.
What does stage 1 CLL look like?
Lymphocytosis with enlarged node in any site.
Moderate risk.
What does stage 2 CLL look like?
Splenomegaly or hepatomegaly or both.
Moderate risk.
What does stage 3 CLL look like?
Anemia (Hgb < 11)
High risk
What does stage 4 CLL look like?
Thrombocytopenia (< 100k)
High risk
Modified Rai clinical system for staging CLL (Picture)
What is the management for low-risk CLL?
Observation
What are the treatment options for moderate-high risk CLL?
Multidrug chemo
Allogeneic stem cell transplant (uncontrolled on chemo)
Splenectomy (refractory splenomegaly and pancytopenia)
Which of the treatment options for CLL is considered curative?
Allogeneic stem cell transplant.
What is included in chemotherapy for CLL to decrease the duration of neutropenia?
Growth factors.
What are the complications of CLL?
Obstructive LAN
Aggressive Large cell lymphoma (Richter syndrome)
AIHA or thrombocytopenia.
What are the symptoms of richter syndrome?
Weight loss, fevers, night sweats, muscle wasting, increasing HSM, and LAN.
What is acute myelogenous leukemia?
AML is a malignant disease of the bone marrow resulting from an arrest in the early development of myeloid precursors.
What are the 4 pathophysiology concerns of AML?
Rapid proliferation of myeloblast WITHOUT DIFFERENTIATION into mature cells.
Abnormal myeloblasts are resistant to apoptosis
Accumulation of myeloblasts in marrow, blood, spleen, liver
Reduction of normal hematopoiesis due to marrow accumulation
What are myeloblasts?
The precursor to all the granulocytes and monocytes.
What is the pathogenesis of AML?
Chromosomal translocation and other genetic mutations.
What are the main etiologies of AML?
Myelodysplastic syndrome (MC risk factor)
Trisomy 21, Bloom’s syndrome, Fanconi anemia
Environment
Chemotherapy
What is MDS/myelodysplastic syndrome?
A bone marrow disease of unknown etiology that causes progressive cytopenia over years.
MC in older pts.
What are the epidemiology stats of AML?
70 y/o median onset.
MC in white males in developed countries.
Almost looks sounds like AMS, which is what older people get
What does a CBC of AML look like?
Decreased RBC, platelet and neutrophils.
WBC can be anything.
What does a peripheral smear of AML look like?
Mostly myeloblasts.
Auer rods (CONFIRMATIVE DIAGNOSTIC)
What is an Auer Rod?
Eosinophilic needle-like inclusion in the cytoplasm of myeloblasts.
It is a unique finding of abnormal fusion of primary granules.
What lab test can distinguish AML from ALL?
Flow cytometry.
Myeloid antigens will appear in AML.
When is an LP indicated for AML?
Symptomatic patients only.
CNS infiltration is typically RARE.
When is a brain MRI/CT indicated for AML?
Leukostasis/neurologic symptoms.
How do we manage AML?
Induction chemotherapy
Post-remission therapy.
CNS involvement will use intrathecal chemo.
Leukostasis will require leukapheresis and other tx.
What are the two types of stem-cell replacement therapies for post-remission AML?
You can use allogeneic or autologous stem cell transplant for AML post-remission.
It is preferred to use ALLOgeneic stem cells.
What are the good prognosis factors for AML?
Age < 60
Remission induction after first chemo.
What is chronic myeloid leukemia? (CML)
Disorder characterized by dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with NORMAL DIFFERENTATION.
What is the cause of CML?
Translocation of the philadelphia chromosome, aka 9 to 22.
How does translocation of 9 to 22 cause CML?
Genetic defect known as bcr/abl occurs.
bcr/abl produces a protein that has overactive tyrosine kinase activity.
What does tyrosine kinase do?
Controls cell growth, differentation, metabolism, and apoptosis.
When does CML usually occur?
55 y/o
What is the only etiology of CML?
Increased risk with exposure to ionized radiation (DOSE RELATED)
What are the 3 phases of CML?
- Chronic: WBCs proliferate
- Accelerated: Additional cytogenetic abnormalities occur
- Terminal blast crisis: immature myeloid cells rapidly proliferate (FATAL)
In what phase are most CML diagnoses made?
Chronic phase, phase 1.
85% of diagnoses are found incidentally and patients tend to stay in it for 3-5 years.
What is the MC first symptom noted by CML patients?
Fatigue and weight loss.
What is the cause of pruritis, diarrhea, flushing, and GI ulcers in CML?
Overproduction of HISTAMINE by basophils.
Pruritis = histamine binding to nerves?
Diarrhea = irritation
Flushing = vasodilation
GI ulcers = histamine releases gastric acid
How does the accelerated phase of CML present?
FUO
Bone pain
Marked splenomegaly
Acute leukemia signs: anemia, neutropenia, thrombocytopenia
What is the most common PE finding in CML?
Splenomegaly.
You can also see hepatomegaly and LAN.
How does a CBC for a CML patient in the chronic phase present?
WBC in the 100k-150k range.
Granulocytosis with marked increase in mature neutrophils, with a mild increase in basophils and eosinophils.
Why do we not immediately treat a WBC of >100k for leukostasis?
We need symptoms to be sure.
CML presents with hyperleukocytosis with no neurologic symptoms.
How does a CBC for a CML patient in the accelerated phase present?
Reduced platelets, RBC, increase in myeloblasts.
How does a peripheral smear for a CML patient in accelerated phase present?
Peripheral blast cells and promyelocytes
What is leukocyte alkaline phosphatase?
LAP is found in leukocytes.
We will see LOW LAP because the granulocytes are RESISTANT to apoptosis.
AKA cells aren’t dying, so they don’t release LAP.
How does a bone marrow aspiration/biopsy present for a CML patient?
Hypercellular with increased granulocytes and progenitors.
> 20% blasts means they are in blast phase.
What is a PCR used for in CML patients?
Identifying the bcr/abl segment within the philly chromosome.
What is the standard therapy for a CML patient in phase 1/chronic phase?
SINGLE DRUG CHEMO.
Tyrosine kinase inhibitor, inhibiting the cells addiction to tyrosine kinase.
Targets CML death more than regular cells.
What are the types of remission we can see in standard therapy for CML?
- Hematologic remission within 3 months. Normal CBC/PE.
- Cytogenetic remission within 6 months. Normal chromosome with < 10% philly cells.
- Molecular remission within 1 year. Negative PCR for bcr/abl segment.
How long do we continue therapy for CML after we reach molecular remission?
2 years!
How do we treat the accelerated/blast phase of CML?
TKI + multidrug chemo
Consider allogeneic stem cell transplant. Also indicated if TKI doesn’t work.
TKI = tyrosine kinase inhibitor.
What should we be monitoring for CML patients in regards to phase transition between chronic to accelerated?
Progressive splenomegaly
Inadequate decreases in granulocytes with standard therapy.
Blast cells and promyelocytes in peripheral smear
Anemia, Basophilia, and thrombocytopenia.
New cytogenetic abnormalities or myelofibrosis in BM biopsy.
What is the prognosis for CML?
100% survival rate at 9 years if they responded to the TKI.
What is multiple myeloma?
MM is a neoplastic proliferation of plasma cells overproducing a nonfunctional, monoclonal immunoglobulins.
What is the pathogenesis of MM?
Preceded by a premalignant plasma cell proliferative disorder known as monoclonal gammopathy of undetermined significance. (MUGS)
What does MUGS come from?
Abnormal plasma cell response to antigenic stimulation.
What are the epidemiology stats of MM?
Median onset of 65 yo.
Most common in african american males, rather than white males.
What are the 5 pathophysiologies of MM?
- Proliferation of neoplastic plasma cells in the bone marrow results in DIMINISHED HEMATOPOIESIS.
- Neoplastic plasma cells are monoclonal, resulting in LACK OF ADEQUATE IMMUNOGLOBULIN RESPONSE to infection.
- Neoplastic plasma cells increase osteoCLASTIC acitivty, bone tumor formation, and hypercalcemia
- Neoplastic plasma cells secrete an antibody called myeloma proteins, which are harmful to the KIDNEYS, NERVES, and other organs.
- Infiltration of plasma cells in tissues, leading to plasmacytomas.
How does MM typically present?
MC is skeletal symptoms, esp in the axial skeleton.
Bone pain in the back, hips, and ribs
Spinal cord compression
Pathologic fractures
Hypercalcemia causing skeletal destruction
How does MM affect BM?
Anemia
Neutropenia
Thrombocytopenia
How does MM affect the kidney?
Reduced kidney function or failure.
PROTEINURIA
Oliguria
How does MM present neuro-wise?
Radiculopathy or neuro deficits
Peripheral nerve compression, MC is median nerve (carpal tunnel syndrome)
What do plasmacytomas do?
Cause bleeding and obstruction.
Affects many organs.
What kind of CBC would I expect in MM?
Pancytopenia
What would I see in a smear of a MM patient?
RBC Rouleaux formation.
What would I expect in a CMP of a MM patient?
Hypercalcemia (osteoclastic)
Elevated BUN/Cr (M-proteins)
What would I expect in a BM biopsy/aspiration of a MM patient?
Infiltration of monoclonal plasma cells by morphologically ABNORMAL cells.
What would I see in a protein electrophoresis of MM?
+ Paraprotein (M-protein)
What would I see in a urine protein electrophoresis of MM?
+ Bence Jones protein
BJ protein
What would I see in a quantitative immunoglobulin level of MM?
Suppression of the NON-myelomatous immunoglobulins (IgG, IgM, IgA)
What test do I run for prognostic testing of MM?
Beta-2 microglobulin.
Elevated is directly related to the tumor burden.
What am I looking for in an XRAY of MM?
Lytic lesions or pathologic fractures in the skull, spine, or long bones.
What is a CT scan used for in MM?
Monitor for neoplastic bone disease.
What is a MRI spine used for in MM?
Assess spinal nerve compression.
How do we manage MM?
It is incurable.
The goal is palliative.
What is the treatment protocol for MM?
Triple agent chemo for induction.
Autologous stem cell transplant after chemo if pt is younger.
Localized radiation for bone pain related to tumor formation.
How do we manage pathologic fractures in MM?
Stabilize bone
Irradiate lesion
How do we manage vertebral body collapse in MM?
Spinal ortho for kyphoplasty or vertebroplasty
How do we manage spinal cord compression in MM?
IV steroids to reduce swelling.
Radiation therapy
Consult neurosurgery
How do we manage bone disease/hypercalcemia in MM?
Bisphosphonates if renal function intact.
Drug: IV Reclast
AKA having the bone reabsorb the calcium
How do we manage anemia in MM?
EPO therapy if persistent and no other possible etiologies.
How do we manage renal impairment in MM?
Plasmapheresis to remove M-proteins/paraproteins.
What is the median survival rate for MM?
3 years ):
