Acute Leukemia: The Ultimate Hematological Emergency

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Acute LeukemiaThe Ultimate Hematological
Emergency

• Khaled el-Shami MBBCh PhD

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AML Incidence

• New cases each year 11,960
• Deaths each year 9000

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Biology of Leukemia 101

• Resistance to apoptosis (even when DNA is
  damaged)
• De-regulation of growth
• Differentiation block

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On presentation

• 1012 leukemia cells (1 liter volume).
• 70 of adults treated with induction
  chemotherapy will achieve remission.
• Remission Normal counts (platelets100K,
  ANC1000, transfusion independent, blasts
• 2-3 log reduction in the initial burden means 109
  cells (1 mL volume) remaining.
• Undetectable amidst normal marrow
• Enriched for leukemia stem cells.

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AML

• Causes
• De novo
• Solvents
• Radiation
• MDS/AML
• Age/time
• Alkylating agents, platinum, nitrosourea
• tAML
• Topoisomerase II inhibitors
• Anthracyclines
• Etoposide

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Hematopoietic Stem Cell
Years
Months
Weeks, Days
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Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
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Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
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Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
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Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
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Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
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Hematopoietic Stem Cell
Platelets
Red blood cells
White blood cells
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Hematopoietic Stem Cell
Platelets
Red blood cells
White blood cells
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Hematopoietic Stem Cell
Platelets
Red blood cells
White blood cells
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Hematopoietic Stem Cell
Acute Leukemia
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Hematopoietic Stem Cell
Chemotherapy
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Hematopoietic Stem Cell
Remission
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AML Working hypotheses

• AML is a stem cell disease
• The bulk cells circulating in peripheral blood
  are mostly non-dividing, partially differentiated
• Leukemia derived from more primitive (more
  multi-potent) stem cells will be harder to cure.
• The features of the bulk cells offer clues as to
  how primitive the leukemia stem cell is
• How much chemotherapy can you give?
• Not so much that the normal stem/progenitors in
  the body (gut, marrow, etc) cant recover.

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Questions on presentation

• Who should get a CR?
• Whose CR equates to a cure?

Characterize the AML at presentation
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AML

• Patient History
• Morphology
• FAB
• Prognostic?
• Clue to molecular abnormalities
• Flow Cytometry
• FISH
• Molecular studies

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FAB
FAB
Morphology
MPO
SE
Comment
NSE
M0 M1 M2 M3 M4 M5 M6 M7
Undifferentiated neg neg neg
primitive (bad?)
Min. different. pos neg neg
promitive (bad?)
Differentiated pos pos neg
t821
Differentiated pos pos neg
t1517 (APL)
Myelomonocytic pos pos pos
INV16/M4eo
Monocytic pos neg pos
11q23, FLT3
Erythroleukemia neg neg neg BAD
Megakaryocytic neg neg neg BAD
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AML Patient-specific prognostic features

• Antecedent hematologic disorder (e.g., MDS)
• MDS/AML is a SEPARATE disease, but is lumped in
  with all AML
• Can be diagnosed when patient presents with AML
  AML with trilineage dysplasia

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Hematopoietic Stem Cell
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Hematopoietic Stem Cell
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Hematopoietic Stem Cell
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Hematopoietic Stem Cell
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Hematopoietic Stem Cell
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Hematopoietic Stem Cell
MDS/AML
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AML Patient-specific prognostic features

• Antecedent hematologic disorder (e.g., MDS)
• MDS/AML is a SEPARATE disease, but is lumped in
  with all AML
• Can be diagnosed when patient presents with AML
  AML with trilineage dysplasia
• Increasing age (a continuous variable)
• Age 65, almost always incurable
• Often, age associates with MDS
• Prior chemotherapy
• Etoposide, anthracyclines- 11q23 (MLL gene)
• Typical time frame 6-24 months
• Alkylators, other chemo lead to MDS, take longer

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AML Leukemia-specific prognostic features

• Leukocytosis (like age, a continuous variable)
• M4eo, M5
• When leukocytosis present, watch for
• CNS involvement
• leukostasis
• Cytogenetics
• FLT3 internal tandem duplication mutation
  (FLT3/ITD)

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Other prognostic features

• CNS involvement
• Performance status/co-morbid features
• Unusual or primitive features, esp biphenotypic
  morphology or extramedullary disease

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Cytogenetics

• Technique
• Needs dividing cells, so marrow usually better
• Complemented and extended by FISH and rtPCR
• FISH Fluorescence In Situ Hybridization
• Typically in metaphase cells, peripheral blood
  works fine- so ideal when marrow unavailable
• rtPCR- for 1517
• rtPCR for BCRABL in ALL

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Cytogenetics

• Good (thats a laugh)
• 1517
• 821
• M2, AML with differentiation, often with CD19
• Core binding factor
• INV16
• M4eo, basophilic eosinophils in marrow
• Watch for CNS disease
• Core binding factor
• These abnormalities typically trump bad risk
  cytogenetics.

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Cytogenetics

• Intermediate
• Normal
• One or two abnormalities

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Cytogenetics

• Bad
• Chromosome 7
• Chromosome 5
• Complex (3 or more)
• 11q23
• Any trisomy?

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FLT3

• Receptor tyrosine kinase (CD135)
• FLT3/ITD mutation constitutively activates
  receptor
• 23 of de novo AML
• FLT3 point mutation occurs in 7, less prognostic
• Patients typically present with
• Leukocytosis, packed bone marrow
• De novo
• M5
• Normal cytogenetics
• Normal or near normal CR rate
• Very high relapse rate, rarely responds to
  salvage therapy

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AML
12,000 cases/year
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12 AML patients

• Old, MDS- dies
• Old, MDS- dies
• Old, MDS- dies
• Old, MDS- dies
• Old, de novo?- dies
• Old, de novo?- dies

7. APL, cured 8. CBF, cured 9. 7-, dies 10.
FLT3/ITD, dies 11. Intermediate, cured 12.
Intermediate, dies
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AML therapy

• Cytarabine
• Infusional or high-dose
• Anthracycline
• Any will do- dauno, ida, mitoxantrone
• Other active agents
• Etoposide
• Cyclophosphamide
• Hydroxyurea
• 6MP/TG
• Topotecan

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Cytarabine

• S-phase selective
• Dose over days to hit cells moving into S-phase.
• Infusional or intermittent high dose
• Cytidine deaminase
• Toxicity
• Mucositis
• Scleritis
• Pain, red eyes
• Steroid eyedrops
• Cerebellar toxicity
• Predictors age, renal insufficiency

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Other agents..

• Anthracycline
• Cardiomyopathy
• Normally dose-dependent, but can be idiosyncratic
• Etoposide
• Mucositis

Induction therapy for AML (for the Oncology
Boards) Infusional cytarabine combined with an
anthracycline.
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73- the traditional regimen

• Cytarabine
• 100 or 200 mg/m2/day CI for 7 days
• Anthracycline
• 45 or 60 mg/m2 dauno or 12 mg/m2 ida IVP Days 1-3
• Day 14 marrow
• If aplasia (marrow recovery
• If residual leukemia, give 52 starting Day 21.
• If after counts are recovered and still residual
  leukemia, give second course of 73
• CR rate 75 (includes those needing 2 courses)
• No other induction regimen has been PROVEN to be
  better

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Other variants

• 73etoposide (ADE)
• DAT (or TAD if youre German)
• Follow on Day 21 with HAM
• Timed sequential therapy.
• Hopkins, plus occasional other sites around the
  world

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The day 14 marrow

• In the 73 regimen, if blasts are still present,
  treat with 52 (or 73)
• With timed sequential therapy, if blasts are
  present at day 14, plan for a transplant

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Who needs a lumbar puncture?

• Anybody with a WBC50K
• Anybody with neurologic symptoms
• Anybody with ALL (including Burkitts)
• Anybody with M4eo
• Anybody with M5
• Wait until blasts are cleared from the blood
  before proceeding
• Contamination vs. seeding

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Consolidation

• Most common High dose cytarabine (HiDAc)
• Mayer 3g/m2 IV BID Days 1,3,5 for 3-4 cycles
• Several alternates (e.g., 1.5 g IV q12 x 6 days)
• Others auto or allo transplant
• Sometimes etoposide or anthracycline added to
  HiDAc

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?
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Remission duration determines likelihood of
success
1-6 months unlikely..
6-24 months a chance
Median time to relapse 10 months
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Acute Promyelocytic Leukemia

• t1517
• PMLRARa fusion- blocks transcription/differentiat
  ion
• High white count M3 variant typically FLT3/ITD
• FLT3/ITD common in APL, but no effect on outcome.
• Typically presents with low white count, DIC.
• Will try to die in first week, usually of
  bleeding.
• Induction with anthracycline, ATRA
• Watch for ATRA syndrome
• DONT check marrow at Day 14
• Will see promyelocytes
• Consolidation unclear, many are using arsenic
  chemo
• High survival rates
• 10 die during first week, 10 relapse.

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ALL

• New cases each year 3970
• Deaths each year 1490
• Treatment regimens
• Intense, prolonged, with lots of drugs
• CNS coverage
• Intrathecal
• Hi dose MTX and Ara C
• Prolonged maintenance

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• FAB L1 (85) smaller, high n/c ratio, indistinct
  nucleoli

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• FAB L2 (14) larger, more cytoplasm,
  pleomorphic, more distinct nucleoli

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• FAB L3 (1) cytoplasmic basophilia (Ig),
  vacuoles (Burkitts leukemia)

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ALL in adults

• Older patients do worse
• 30 Ph chromosome (Bad)
• T-cell ALL
• Classic case young male with mediastinal mass
• Bad in most other cases
• Here at Hopkins
• Hoelzer
• E2993
• Includes L-Asparaginase (nasty in adults)
• Transplant randomization
• HyperCVAD
• A, B, repeat 4 times
• A CHOP with hyperfractionated Cytoxan

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ALL patients age 30 and under

• Better outcomes using pediatric regimens (more
  intense, prolonged)
• Boissel et al J Clin Oncol 2003 21774

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Acute Leukemia Practice

• Its Friday night

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How the newly-diagnosed acute leukemia patient
will try to die on you

• DIC
• Leukostasis
• Sepsis
• Tumor lysis

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Initial maneuvers

• Assess the patient
• Are they febrile?
• Start Zosyn or equivalent. Not likely fungal
• Dyspneic? Coughing? Looks like pulmonary edema?
• Leukostasis is the most common reason
• Leukostasis can occur with WBC as low as 10K, but
  very common when WBC50K
• Urgent need to lower white count
• DO NOT TRANSFUSE
• Are they mentating?
• May be leukostasis or intracranial bleed
  (especially common in APL)
• Are they bleeding?
• Intraocular hemorrhage surprisingly common
• Cryoprecipitate, platelets, and, believe it or
  not, heparin

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Initial maneuvers

• Admission labs (standard order sets)
• Heme 8 w/diff
• Smear is available in minutes for review
• Chemistries, including uric acid, phosphate
• Tumor lysis labs and DIC labs
• Type and cross, HLA sample for platelets
• Blood, urine cultures
• PT/PTT, fibrinogen
• Replace fibrinogen with cryoprecipitate
• Replace if falling rapidly, if and
• Flow cytometry
• Can be used to quickly determine myeloid from
  lymphoid, determine likelihood of APL

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Leukostasis

• Two different kinds
• AML, WBC 50,000
• Some AMLs are stickier than others
• Leukostasis can occur with WBC of 10,000
• High leukocrit- simply very high white count
• Generally 300K, can be any kind of leukemia,
  CML, ALL, CLL
• The type of leukemia doesnt matter
• Usually acute, most commonly AML
• Treatment options
• Cyclophosphamide 60 mg/kg IV
• Leukapheresis
• Need a Shiley, typically femoral, call onc endo,
  give platelets
• Call the HATS attending, overall time to lower
  count 6-12 hours.
• Hydroxyurea
• 2 grams po q6 hours
• Phlebotomy (when desperate)

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Leukostasis

• Blood transfusion can kill a patient in
  leukostasis
• Do NOT write for the PRBCs until satisfied that
  leukostasis isnt an immediate issue
• Watch for leukostasis once transfusion therapy is
  initiated.
• Initial transfusions should be SLOOOOW
• Platelet tranfusions generally tolerated.
• Often needed for procedures

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Tumor Lysis Diagnosis

• Most common in ALL
• EXPECT severe tumor lysis in Burkitts.
• Can be seen in any acute leukemia
• Uric acid, phosphate, K, Cr
• tumor lysis labs on standard order sets
• Organ failure, especially kidneys

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Initial Maneuvers for Acute Leukemia Patients

• Initial treatment
• Hydration (or not, if in leukostasis)
• Allopurinol
• Phosphate binder (amphojel)
• Transfusions (if not in leukostasis)
• RBCs, platelets
• Antibiotics?
• Cryoprecipitate? Heparin?

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Initial maneuvers

• Flow Cytometry
• Sample of whole blood in green or purple top
• RBCs lysed, WBC pellet washed.
• Antibodies with fluorochrome labels added.
• Stained cells analyzed by FACS
• Whole process can be done in two hours.

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Flow cytometry

• Myeloid?
• CD13, CD33
• Lymphoid?
• CD19, CD5, CD7
• APL?
• CD33, HLA-DR negative

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Is this APL?

• Typical findings
• Low white count
• Low fibrinogen, abnormal coags
• Lots of purple granules
• But watch out for the microgranular variant
• Findings on flow cytometry
• CD13, CD33 positive, DR negative

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Is this APL?
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If you think this might be APL

• Start all-trans retinoic acid (ATRA)
• 40 mg/m2 divided BID
• If WBC high (often FLT3), count may rise further
  with differentiation.
• Hydrea or daunorubicin concurrently
• Watch for DIC
• Follow fibrinogen, give cryoprecipitate if
• Heparinize10 units/kg, no bolus.
• After ATRA started, watch for ATRA syndrome
• Rising WBC count
• Cardiopulmonary distress, weight gain
• Treat with steroids, Hydrea or daunorubicin

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Time for the marrow
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What to order for a new leuk

• Aspirate and core biopsy.
• Aspirate lets you see the morphology, the core
  gives cellularity.

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Core Biopsy
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Aspirate

• Marrow (with spicules present) smeared on a
  slide, stained with Wright/Giemsa
• Used to determine morphology of cells
• On a slide, marrow can be visualized directly by
  examining areas near spicules of bone.
• In a tube, the aspirate consists of some mixture
  of marrow and blood

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What to order for a new leuk

• Aspirate and core biopsy.
• Aspirate lets you see the morphology, the core
  gives cellularity.
• Flow cytometry.
• Differential for new patient just starting
  therapy
• Cytogenetics
• Marrow vs peripheral blood
• Krieger vs Griffin lab
• FISH

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Purine Catabolism Pathway
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Risk Factors for Tumor Lysis Syndrome

• Characteristic Risk Factor
• __________________________________________________
  __________
• type Burkitt's lymphoma
• Lymphoblastic lymphoma
• Diffuse large-cell lymphoma
• ALL
• Chemoresensitive highly
• proliferative solid tumors
• Tumor burden/extent of disease Bulky disease
  (10 cm)
• Elevated LDH ( 2x ULN)
• Elevated WBC (25,000/µL)
• Renal function Preexisting renal failure
• Oliguria
• Baseline uric acid Baseline serum/plasma uric
  acid 450 µmol/L (7.5 mg/dL)

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Guidelines for Management of TLS
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Leukostasis in a Flt3 AML
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Mechanisms of intervention of leukemic cells in
the activation of blood coagulation
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What to order for a new leuk

• FLT3
• Procurement
• PCR
• 1517
• BCRABL