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Acute Leukemia: The Ultimate Hematological Emergency

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Acute Leukemia: The Ultimate Hematological Emergency. Khaled el-Shami MBBCh PhD. AML: Incidence ... Surrender. AlloBMT. Clinical. trial. Risk stratify. Good ... – PowerPoint PPT presentation

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Title: Acute Leukemia: The Ultimate Hematological Emergency


1
Acute LeukemiaThe Ultimate Hematological
Emergency
  • Khaled el-Shami MBBCh PhD

2
AML Incidence
  • New cases each year 11,960
  • Deaths each year 9000

3
Biology of Leukemia 101
  • Resistance to apoptosis (even when DNA is
    damaged)
  • De-regulation of growth
  • Differentiation block

4
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.

5
AML
  • Causes
  • De novo
  • Solvents
  • Radiation
  • MDS/AML
  • Age/time
  • Alkylating agents, platinum, nitrosourea
  • tAML
  • Topoisomerase II inhibitors
  • Anthracyclines
  • Etoposide

6
Hematopoietic Stem Cell
Years
Months
Weeks, Days
7
Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
8
Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
9
Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
10
Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
11
Lifespan
Hematopoietic Stem Cell
Decades
Years
Months
Weeks, Days
Platelets
Red blood cells
White blood cells
12
Hematopoietic Stem Cell
Platelets
Red blood cells
White blood cells
13
Hematopoietic Stem Cell
Platelets
Red blood cells
White blood cells
14
Hematopoietic Stem Cell
Platelets
Red blood cells
White blood cells
15
Hematopoietic Stem Cell
Acute Leukemia
16
Hematopoietic Stem Cell
Chemotherapy
17
Hematopoietic Stem Cell
Remission
18
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.

19
Questions on presentation
  • Who should get a CR?
  • Whose CR equates to a cure?

Characterize the AML at presentation
20
AML
  • Patient History
  • Morphology
  • FAB
  • Prognostic?
  • Clue to molecular abnormalities
  • Flow Cytometry
  • FISH
  • Molecular studies

21
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
22
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

23
Hematopoietic Stem Cell
24
Hematopoietic Stem Cell
25
Hematopoietic Stem Cell
26
Hematopoietic Stem Cell
27
Hematopoietic Stem Cell
28
Hematopoietic Stem Cell
MDS/AML
29
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

30
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)

31
Other prognostic features
  • CNS involvement
  • Performance status/co-morbid features
  • Unusual or primitive features, esp biphenotypic
    morphology or extramedullary disease

32
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

33
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.

34
Cytogenetics
  • Intermediate
  • Normal
  • One or two abnormalities

35
Cytogenetics
  • Bad
  • Chromosome 7
  • Chromosome 5
  • Complex (3 or more)
  • 11q23
  • Any trisomy?

36
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

37
AML
12,000 cases/year
38
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
39
AML therapy
  • Cytarabine
  • Infusional or high-dose
  • Anthracycline
  • Any will do- dauno, ida, mitoxantrone
  • Other active agents
  • Etoposide
  • Cyclophosphamide
  • Hydroxyurea
  • 6MP/TG
  • Topotecan

40
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

41
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.
42
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

43
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

44
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

45
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

46
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

47
?
48
Remission duration determines likelihood of
success
1-6 months unlikely..
6-24 months a chance
Median time to relapse 10 months
49
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.

50
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

51
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52
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53
  • FAB L1 (85) smaller, high n/c ratio, indistinct
    nucleoli

54
  • FAB L2 (14) larger, more cytoplasm,
    pleomorphic, more distinct nucleoli

55
  • FAB L3 (1) cytoplasmic basophilia (Ig),
    vacuoles (Burkitts leukemia)

56
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

57
ALL patients age 30 and under
  • Better outcomes using pediatric regimens (more
    intense, prolonged)
  • Boissel et al J Clin Oncol 2003 21774

58
Acute Leukemia Practice
  • Its Friday night

59
How the newly-diagnosed acute leukemia patient
will try to die on you
  • DIC
  • Leukostasis
  • Sepsis
  • Tumor lysis

60
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

61
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

62
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)

63
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

64
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

65
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?

66
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.

67
Flow cytometry
  • Myeloid?
  • CD13, CD33
  • Lymphoid?
  • CD19, CD5, CD7
  • APL?
  • CD33, HLA-DR negative

68
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69
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

70
Is this APL?
71
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

72
Time for the marrow
73
What to order for a new leuk
  • Aspirate and core biopsy.
  • Aspirate lets you see the morphology, the core
    gives cellularity.

74
Core Biopsy
75
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

76
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

77
Purine Catabolism Pathway
78
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79
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)

80
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81
Guidelines for Management of TLS
82
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83
Leukostasis in a Flt3 AML
84
Mechanisms of intervention of leukemic cells in
the activation of blood coagulation
85
What to order for a new leuk
  • FLT3
  • Procurement
  • PCR
  • 1517
  • BCRABL
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