Transcript Acute Leukemia by Molly Miller

Acute Leukemia
Noon Conference
April 13, 2016
Why am I giving this talk?
• Acute leukemia is an emergency
• No one taught me how to manage acute leukemia
when I was a resident
• Bryan Hambley asked me to
Outline
• Obligatory pathophysiology/epidemiology discussion
• When to suspect acute leukemia
• Why is acute leukemia an emergency?
• Initial management of the newly diagnosed patient
i.e., how to avoid screwing up your admission (and minimize anxiety)
• Acute problems in patients receiving chemotherapy
VA wards, BMT cross-cover
Introduction
AML
AML
AML
ALL
AML
 differentiation
 proliferation
CML
CLL
MM
AML Classification
FAB
M0
AML w/minimal differentiation
M1
AML w/o differentiation
M2
AML w/differentiation
M3
acute promyelocytic leukemia
M4
myelomonocytic (AMML)
M5
a) monoblastic, b) monocytic
WHO
AML with recurrent genetic abnormalities
AML with MDS-related changes
Therapy-related AML/MDS
AML NOS
Myeloid sarcoma
M6
erythroblastic
Myeloid proliferation related to Down’s
syndrome
M7
megakaryoblastic
Blastic plasmacytoid dendritic neoplasm
Adapted from UpToDate
ALL Classification
FAB
WHO
L1
small, monomorphic
ALL with recurrent genetic abnormalities
L2
large, heterogeneous
ALL NOS
L3
Burkitt-type
T-cell ALL
Adapted from UpToDate
Acute leukemia statistics
Variable
AML
ALL
4.0
1.7
% new cancer diagnoses
1.3%
0.4%
Lifetime risk
0.5%
0.1%
65
39
25.9%
67.5%
New cases/year (per 100,000)
Average age at presentation
5-year overall survival*
SEER Data
Diagnosing acute leukemia
• Diagnosis is based upon bone marrow analysis (how many blasts?).
• A preliminary diagnosis may be made by flow cytometry on circulating
blasts (from peripheral blood) if a bone marrow biopsy is not possible.
Your job is not to diagnose acute leukemia. Your job is:
to suspect acute leukemia in the appropriate clinical setting,
to conduct the appropriate workup when you suspect acute leukemia,
and to provide the appropriate supportive care to acute leukemia patients.
When to suspect acute leukemia
• Hematologic abnormalities that may suggest acute leukemia:
Presentation
Differential Diagnosis
Leukocytosis
Infection
Acute stress
“Leukemoid reaction”
Medications – which ones?
Other hematologic malignancies (CLL,
CML, some lymphomas)
Bi- or tricytopenias
Infection
Medications – which ones?
Circulating blasts
Medications – which ones?
Leukoerythroblastic process
Leukemic blasts
• How to identify blasts
– Look at the peripheral smear
– Look at the differential for “% blasts”
– May be called “atypical lymphocytes” until verified by a pathologist
Can AML and ALL be distinguished by morphology alone?
Leukoerythroblastic smear
•
Etiology: release of immature
blood cell forms (blasts, nRBCs)
due to marrow infiltration,
marrow stress, or
extramedullary hematopoiesis
•
Associated disease states:
myelofibrosis, metastatic cancer,
granulomatous disease
(especially with superimposed
acute stress)
How could you distinguish between a leukoerythroblastic process and acute leukemia?
Clinical presentations of acute leukemia
Chief complaint is never: “I have an abnormal blood smear.”
Chief complaint
Reason
“Abnormal labs”
cytopenias, circulating blasts, sometimes bone marrow Bx
Malaise
pancytopenia, especially anemia and neutropenia
Infection
dysfunctional immune system
Bleeding
thrombocytopenia, DIC
Organ failure
leukostasis, tumor lysis syndrome, hypoxia
Why is acute leukemia an emergency?
Tumor lysis
Sepsis
Leukostasis
DIC
Tumor Lysis Syndrome (TLS)
blast
K+
Ca2+

K+
 uric acid  PO
4
CaPO4
Laboratory Value
 Ca2+
Direction of change
Mechanism
K+

tumor cell lysis
PO4

DNA release
Uric acid

DNA release
Ca++

PO4 binding
TLS: Clinical Features
K+
Ca2+

K+
 uric acid  PO
4
CaPO4
arrhythmias
weakness
paralysis
acute renal failure
 Ca2+
tetany
AMS
TLS: Diagnosis
TLS Type
Definition
Primary
Spontaneous
Secondary
Treatment-induced
Laboratory
≥ 2 laboratory abnormalities OR
≥ 25% change in 2 values from baseline value
Clinical
Laboratory TLS + end-organ damage
TLS: Prevention & Treatment
•
Prevention: Fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids,
fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids,
allopurinol
•
Treatment: rasburicase or HD
allopurinol
K+
purines/pyrimidines
uric acid
rasburicase
allantoin
What blood test should you get before administering rasburicase?
TLS: Prevention & Treatment
Prophylaxis
Rasburicase
Hemodialysis
Clinical tumor lysis syndrome (end-organ damage)
Everyone!
Limited resources
G6PD deficiency
Limited time
Rasburicase failure
TLS: Pearls
• 4 laboratory abnormalities: K+, PO4, uric acid, Ca++ (all  except Ca++)
• Make sure uric acid samples are collected on ice!
–
values will be falsely low if not…you could miss the diagnosis or be treating ineffectively!
• Order G6PD screen early
• Look for signs of end organ damage in case treatment is needed
• Everyone should get fluids and allopurinol unless contraindicated
Leukostasis
•
High blast count  hyperviscosity   tissue perfusion
•
Systems affected: CV (MI), pulm (ARDS), GI (bowel ischemia), CNS (CVA, retinal hemorrhage)
Retinal hemorrhage in 49 yo with
mantle cell lymphoma s/p filgrastim
CT head in pt with AML; Bx showed
leukocyte plugs
CXR in pt presenting with AML;
CT + BAL  Dx
Algharras et al. (2013) J Clin Diagn Res. 7(12): 3020–3022. Salloum et al. (1998) BMT 21:835-837. Vasquez (2012) FSFB-CIDER Case of the Month.
Leukostasis: Diagnosis and Treatment
• Leukostasis is a clinical diagnosis.
–
–
–
–
There is no specific WBC cutoff to establish Dx or decide treatment
Pathologic diagnosis is rarely available
Rely on clinical judgment and investigation of appropriate DDx
Ex: MI could be secondary to anemia, DIC, underlying CAD
• Medical management
– Steroids, hydrea can rapidly decrease WBC count
– Risks: tumor lysis syndrome, hydrea can worsen other cytopenias
• Leukapheresis
– Requires line placement, transfusion medicine consultation
– Contraindicated in APL
hematology
consultant
transfusion
medicine
consultant
Leukostasis: Pearls
• Leukostasis is a clinical diagnosis
– You may be the first to suspect it!
– Consider alternative diagnoses in your differential…
• Treatment can be lifesaving, and may be medical or by apheresis
– Involve consult teams early!
• Leukostasis makes transfusion risky
– Transfusion further increases viscosity (but hydration decreases it!)
Sepsis
• Patients with acute leukemia are immunodeficient
– Neutropenic
– Dysfunctional bone marrow  dysfunctional immune system
• Culture on admission, even if asymptomatic and afebrile
– Fast fever spikes are common, better to stay ahead of the curve!
• Calculate the ANC even in the setting of elevated WBC count
– Low ANC may be “hiding”
• Fever is an emergency in the neutropenic patient!
Neutropenic Fever
• Neutropenia
– ANC < 500 or ANC < 1000 with expected nadir < 500
• Fever
– T > 38°C or T = 38°C x 1h
Empiric therapy
• Zosyn
• Meropenem
• Cefepime
• Ceftazidime
Add vancomycin…
Add antifungal…
• Hemodynamic instability
• PNA
• SSTI, CVC infection
• +BCx with GP organism
• Colonized with MRSA or VRE
• Fever 4-7d after initiation of
broad abx coverage
• no identified source of infxn
• Anticipate neutropenia > 7d
DIC
• Consumptive coagulopathy triggered by release of tissue factor from blasts
ICH
SDH
pulmonary hemorrhage
DVT
CVA
MI
Adapted from UpToDate
DIC
• Occurs in ~10% of patients with acute leukemia
– At diagnosis
– After initiation of chemotherapy
• Screen all patients by sending:
– Coags
– Fibrinogen
– D-dimer
• How to manage:
– Monitor coags and fibrinogen even after initiation of chemotherapy!
– Keep plts > 20-30K (50K if bleeding)
– Keep fibrinogen > 150
Recognizing and treating DIC can save a patient’s life!
Nur et al. (1995) Eur J Hem 55(2):78-82.
DIC in APL (AML M3)
• APL has a unique molecular mechanism
– t(15;17)  PML-RAR fusion protein
Nur et al. (1995) Eur J Hem 55(2):78-82.
DIC in APL (AML M3)
• DIC is more common in APL than in any other acute leukemia
– APL blasts release tissue factor, cancer procoagulant, annexin II
• Without treatment, APL patients die of bleeding complications in < 1 week
• APL patients are often treated empirically prior to definitive diagnosis
– Benefits outweigh risks (“nothing to lose”)
• When to suspect APL:
Clinical presentation:
•
hemorrhage, DIC
Blast morphology:
•
abnormal promyelocytes, prominent cytoplasmic granules,
bilobed nuclei, Auer rods
DIC and APL Pearls
•
Evaluate coags and fibrinogen on every suspected acute leukemic patient and replete
aggressively!
– Continue to monitor during chemotherapy
•
APL patients classically present with DIC and are at high risk of bleeding complications
•
Treatment with ATRA may be initiated prior to confirmation of diagnosis
– Involve hematology consult service early if any suspicion of APL
•
Invasive procedures (e.g., central lines) and leukapheresis are contraindicated in APL
– Procedures  excessive bleeding
– Leukapheresis is associated with sudden death
Acute leukemia: Admission Orders
Diagnostic workup
CBC, peripheral smear, flow
rule out/work up other conditions
Tumor lysis
K+, PO4, uric acid, Ca++, LDH
ECG, BUN/Cr, physical exam
Leukostasis
CBC/diff
CT head, CXR, eye exam
Sepsis
Blood cultures, neutropenic fever tx
low threshold for prophylactic abx
DIC
Coags
Fibrinogen
Acute leukemia: Initial Management
Diagnostic workup
Flow cytometry, bone marrow biopsy
Ancillary studies to r/o other diseases
Tumor lysis
Tumor lysis labs TID, prophylaxis for
everyone, treatment if indicated
Leukostasis
Monitor CBC
Monitor for ischemia
Sepsis
Frequent VS, f/u cultures, ANC daily,
rapid abx for neutropenic fever
DIC
Daily coags, fibrinogen
Keep plts > 20-30, fibrinogen > 150
Treatment complications: common
• Volume overload
–
–
–
–
Pts are aggressively hydrated during chemotherapy for 2 reasons: _______, _______
Continuation of hydration + diuresis preferred over stopping fluids
Prevention: DAILY WEIGHTS DAILY WEIGHTS DAILY WEIGHTS DAILY WEIGHTS
Treatment: diurese (may need a drip), hold fluids if necessary
• Electrolyte wasting
– K, Mg, PO4
– May require repletion multiple times per day
– Monitor lytes frequently and don’t forget to check Mg (especially when repleting K)
• Infection
– Work up and treat promptly
– Neutropenic patients may not show signs of infection (e.g., pulmonary infiltrates)
– Don’t forget viral workup: respiratory antigens, CMV, EBV
Differentiation Syndrome (APL)
• Mechanisms
– Cytokine release from differentiating APL blasts – “cytokine storm”
– Migration and tissue deposition of differentiating APL blasts
– Increased integrin expression  endothelial adhesion  capillaritis  leak
• Presentation
– Associated with WBC > 10K (especially > 30K)
– Symptoms: fever, hypoxia, pleural or pericardial effusion, renal failure, hypotension
• Treatment
– Dexamethasone 10 mg BID x3-5 days with taper
– Consider holding ATRA
Call the hematology fellow with any concerning symptoms in an APL patient!
Dr. Carlos Silva, UpToDate
Summary
• Acute leukemia is an emergency
– Blasts may not be recognized when pathologists are sleeping…YOU may be the first to
recognize and treat acute leukemia!
• If you know the 4 emergent syndromes, management becomes manageable!
–
–
–
–
Tumor lysis: prophylaxis for everyone, treatment for some
Leukostasis: look for signs of end-organ ischemia (it’s a clinical diagnosis!)
Sepsis: ANC can hide in high WBC counts, treat fever early
DIC: coags and fibrinogen for everyone
• Leukemia treatment can be complicated by volume overload, electrolyte
wasting, and infection
– daily weights, DIURESIS, daily BMPs, daily Mg, prompt treatment of neutropenic fever
• If you feel overwhelmed, call hematology (it’s our job to help you!)
Acknowledgments
• BMT faculty
–
–
–
–
–
–
–
Paolo Caimi, MD
Brenda Cooper, MD
Marcos de Lima, MD
Hillard Lazarus, MD
Jane Little, MD
Ehsan Malek, MD
Benjamin Tomlinson, MD
• Hem/onc fellows
–
–
Carlos Silva, MD
Masumi Ueda, MD
• BMT patients