Acute Leukemia

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Acute Leukemia

• Noon Conference
• April 13, 2016

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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

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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

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Introduction
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AML Classification
FAB 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
M6 erythroblastic
M7 megakaryoblastic
WHO
AML with recurrent genetic abnormalities
AML with MDS-related changes
Therapy-related AML/MDS
AML NOS
Myeloid sarcoma
Myeloid proliferation related to Downs syndrome
Blastic plasmacytoid dendritic neoplasm
Adapted from UpToDate
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ALL Classification
FAB FAB
L1 small, monomorphic
L2 large, heterogeneous
L3 Burkitt-type
WHO
ALL with recurrent genetic abnormalities
ALL NOS
T-cell ALL
Adapted from UpToDate
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Acute leukemia statistics
Variable AML ALL
New cases/year (per 100,000) 4.0 1.7
new cancer diagnoses 1.3 0.4
Lifetime risk 0.5 0.1
Average age at presentation 65 39
5-year overall survival 25.9 67.5
SEER Data
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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.
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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
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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?
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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?
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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
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Why is acute leukemia an emergency?
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Tumor Lysis Syndrome (TLS)
blast
Laboratory Value Direction of change Mechanism
K ? tumor cell lysis
PO4 ? DNA release
Uric acid ? DNA release
Ca ? PO4 binding
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TLS Clinical Features
K
Ca2
K
PO4
uric acid
?
?
?
v
CaPO4
Ca2
?
arrhythmias
weakness
tetany
paralysis
acute renal failure
AMS
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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
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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

purines/pyrimidines
What blood test should you get before
administering rasburicase?
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TLS Prevention Treatment
Prophylaxis Rasburicase Hemodialysis
Everyone! Clinical tumor lysis syndrome (end-organ damage) Clinical tumor lysis syndrome (end-organ damage)
Everyone! Limited resources G6PD deficiency
Everyone! Limited time Rasburicase failure
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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 notyou 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

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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)
30203022. Salloum et al. (1998) BMT 21835-837.
Vasquez (2012) FSFB-CIDER Case of the Month.
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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

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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!)

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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!

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Neutropenic Fever

• Neutropenia
• ANC lt 500 or ANC lt 1000 with expected nadir lt 500
• Fever
• T gt 38C or T 38C x 1h

Empiric therapy
Add vancomycin
Add antifungal

• Hemodynamic instability
• PNA
• SSTI, CVC infection
• BCx with GP organism
• Colonized with MRSA or VRE

• Zosyn
• Meropenem
• Cefepime
• Ceftazidime

• Fever 4-7d after initiation of broad abx
  coverage
• no identified source of infxn
• Anticipate neutropenia gt 7d

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DIC

• Consumptive coagulopathy triggered by release of
  tissue factor from blasts

DVT CVA MI
ICH SDH pulmonary hemorrhage
Adapted from UpToDate
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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 gt 20-30K (50K if bleeding)
• Keep fibrinogen gt 150

Recognizing and treating DIC can save a patients
life!
Nur et al. (1995) Eur J Hem 55(2)78-82.
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DIC in APL (AML M3)

• APL has a unique molecular mechanism
• t(1517) ? PML-RAR fusion protein

Nur et al. (1995) Eur J Hem 55(2)78-82.
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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 lt 1 week
• APL patients are often treated empirically prior
  to definitive diagnosis
• Benefits outweigh risks (nothing to lose)
• When to suspect APL

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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

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Acute leukemia Admission Orders
Diagnostic workup
Tumor lysis
Leukostasis
Sepsis
DIC
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Acute leukemia Initial Management
Diagnostic workup
Tumor lysis
Leukostasis
Sepsis
DIC
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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 dont 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)
• Dont forget viral workup respiratory antigens,
  CMV, EBV

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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 gt 10K (especially gt 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
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Summary

• Acute leukemia is an emergency
• Blasts may not be recognized when pathologists
  are sleepingYOU 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 (its 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 (its
  our job to help you!)

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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