AN APPROACH TO “BAD BLOOD” AKA
ACUTE LEUKEMIA
Arif Ali Awan – R2 JGH
November 27th, 2014
IM Teaching
DISCLAIMER
Just a Resident
CASE
52F Nurse, 3 sisters
PMHx: HTN, hysterectomy
Meds: Hctz 12.5; NKDA
No family history
Presents with 6 week history of intermittent fever (upto 38.5), sore throat, malaise,
muscle pains, mild dyspnea went to GP, given NSAID’s and antibiotics
Developed small red dots especially on legs, gingival bleeding, worsening fatigue
Presented to Santa Cabrini WBC 279,000, Hgb 80 MCV = 90, Plat 25; 60%
peripheral blasts
Transferred to JGH.
THE FIRST THINGS YOU HAVE TO DO
Make sure patient not in DIC, TLS
Symptomatic leukostasis!
AML/APL or ALL
ACUTE LEUKEMIA
A disease in which immature heterogenous white blood cells multiply or accumulate
uncontrollably
Circulating “clonal” white blood cells.
Need to distinguish between AML (60-70%)/APL (5-8% of AML), ALL (~20%)
Hematologic emergency: fatal in weeks to months (Infection, bleeding)
AML: 16000 cases yearly in US, median age 70 y, 3-5/100,000 person-yr
ALL: total 6000 cases yearly in US, minority in adults
HISTORY
Common: fatigue, infection, bruising, bleeding
Leukostasis: Neuro (CN, altered MS), Resp, CVS
MSK: bone pain
Cardiac history, co-morbidities
Prior transfusions and pregnancies: allo antibodies
Drug allergies
Prior herpes simplex: prophylaxis
Pregnancy/menses: OCP; fertility preservation
Siblings?
Extramedullary: anywhere, gingiva
Skin (leukemia cutis or Sweet syndrome)
Performance status
RISK FACTORS
Risk factors:
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MDS
Myeloproliferative disorder
Prior chemotherapy
IR
Trisomy 21
Rare congenital syndromes (Klinefelter’s, Fanconi, dyskeratosis congenita)
Smoking RR 1.4
CT scans RR 1.2-1.7
Family history
Not cell phones!
PHYSICAL EXAM
Fever: treat as infection
Eyes: hemorrhages and or exudates up to half have ocular involvement.
Oropharynx: gingival involvement, dental caries, oral thrust
Organomegaly and LNs: uncommon in AML - think of ALL or CML in blast crises
Neuro: CN palsies, Altered MS.
Skin: pallor, infiltrative lesions, petechiae and echymoses, leukemia cutis (10-15%),
Sweet Syndrome
LEUKEMIA CUTIS
SWEET SYNDROME AKA ACUTE FEBRILE
NEUTROPHILIC DERMATOSIS
AML CNS INVOLVEMEMENT
uncommon ( 5-7%):
high circulating blast count,
M5
defer LP if high blast count and asymptomatic to
avoid contamination
defer LP to consolidation
IDENTIFYING LINEAGE: AML/APL, ALL
Morphology not always helpful
Flow cytometry
Immunostains
Cytogenetics
AML DIAGNOSIS
Blood and marrow (aspirate and biopsy)
Auer rods: rod like filaments of aggregated primary azurophilic granules
(most seen in M1 and M2)
> 20% blasts in BM/peripheral or recurrent cytogenetic abnormality
Special stains distinguish myeloid (MPO) from lymphoid (TdT)
Flow cytometry: help to distinguish lymphoid from myeloid (CD13, 33, 34,
117); establishes maturation
DO CYTOGENETICS!
ROUTINE LAB TESTING
CBC with differential and blood film
BUN, creatinine, lytes, uric acid, glucose
Liver enzymes, LDH
calcium profile
PT, PTT, fibrinogen, FDPs or D dimers
flow cytometry if blasts in blood
Beta-HCG
Type and Screen
Defer HSCT testing: HLA, CMV, Hep A/B/C/HIV/HTLV
LABORATORY FINDINGS
WBC: 20% > 100,000, 50% normal or reduced
Pancytopenia
Watch out for tumor lysis syndrome (hypoCA, HyperPhos, Acidosis, hyperK, increased
LDH, increased Uric Acid, renal failure).
ADDITIONAL INTERVENTIONS
CXR
ECG
TTE if risk factors
LP if symptomatic
BM asp and biopsy with cytogenetics and flow cytometry (subclassification, prognosis, tailoring
treatment): KIT, FLT3, NPM1, CEBPA
Broviac placement
Fertility preservation
Dentistry consultation if poor oral hygiene
Oncology/transplant nurse
Psychosocial support
AML - FAB
FAB subgroups based on the predominant cell type and to define the leukemia’s cell position in
the maturation sequence of that specific lineage, less common use nowadays
M0-M7
M0 Minimal differentiation (3%)
M1 Without maturation (15–20%)
M2 Maturation (25–30%)
M3 Acute promyelocytic leukemia (5–10%)
M4 Acute myelomonocytic leukemia (20%)
M4Eo Acute myelomonocytic leukemia with abnormal eosinophils (5–10%)
M5 Acute monocytic leukemia (2–9%)
M6 Erythroleukemia (3–5%)
M7 Acute megakaryocytic leukemia (5%)
AML
WHO
AML with recurrent genetic abnormalities
 t(8;21)- AML/ETO
 With abnormal bone marrow eosinophils and inv16 or t(16;16)
 11q23 abnormalities
AML with multilineage dysplasia
AML and MDS-therapy related
AML not otherwise categorized
++ atleast 20 different subtypes
AML TREATMENT
Goal: stabilize patient and then rapid restoration of normal BM function.
Induce Remission: Induction: reduces leukemia cell population from 1012 to 109
(MRD)
Prevent Relapse: Consolidation: 1-3 or more courses of chemo or BMT to eradicate
residual leukemia and allow for cure
Complete Remission: normal blood counts (ANC>1000, plt > 100,000, no pRBC
transfusion needs) and BM cellularity with < 5% blasts without leukemic phenotype
Cure?: relapse and death rates low after 3-4 years remission; 40% age < 60
Clinical trials
AML TREATMENT INDUCTION 7+3
1) Cytarabine (Ara C )
-continuous infusion x 7 days
-<60 yo 200 mg/m2; >60 yo 100 mg/m2
- Myelosuppresion: biphasic nadir 7-9 D, 15-24D, Rash, conjunctivitis, Mod. N/V, increased
LFT’s, ulceration, neurotoxicity (cerebellar dysfunction)
2) Anthracycline
-Daunorubicin 60-90 mg/m2 IV x 3 days
-Dose reduce with hepatic dysfunction (bilirubin)
- Myelosuppresion: nadir 10-14 D, cardiac toxicity, mucositis, red/orange urine, Mod. N/V,
increased LFT’s,
?? D14 Marrow
SUPPORTIVE CARE DURING INDUCTION
Febrile Neutropenia: treat find source otherwise prophylaxis (Levofloxacin) RR 0.66 reduced
mortality. NNT 30’ 60% identified source, 6% mortality (15% of cases fungal, 15% mixed,
5% bacteria)
IPA prophylaxis posaconazole NNT 20 mortality
Herpes Simplex Prophylaxis
Nutrition
HLA matched CMV neg, irradiated, leukodepleted transfusions (plt > 50000 APL)
?G-CSF no survival benefi
TLS: Allopurinal nearly all; Rasburicase if WBC > 100,000, T-ALL but not if G6PD def.
Beware transfusions with leukostasis.
Psychosocial
AML TREATMENT CONSOLIDATION
High dose cytarabine/Ara-C (HiDAC)
3g/m2 x 6 doses
For 3-4 cycles
No proven role for maintenance therapy in AML compared to ALL
If relapse: salvage chemotherapy, re-induction, clinical trial, ?autologous transplant
HSCT/TRANSPLANT
Allogenic matched related donor better than unrelated donor
Unfavourable prognosis – 20% increased survival 27 vs 7 % at 5 year
Intermediate risk – 6 to 10% increased survival
COMPLICATIONS: LEUKOSTASIS
WBC > 50,000 (AML > ALL)
Neurological: visual disturbance, headache/dizziness, TIA/CVA
CVS: MI
Resp: dyspnea, infiltrate on chest X-ray
Treatment: hydroxyurea, chemo, leukapheresis
TUMOR LYSIS SYNDROME
ALL > AML
First sign incr. LDH, low Ca
Then hyperkalemia, hyperphosphatemia, increased uric acid, renal failure, cardiac
arrhythmias
AML PROGNOSIS
Age (> or <60); > 60 worse
secondary AML
blast count > 100,000
response to induction chemotherapy
APL better prognosis
CYTOGENETICS
Favourable
Intermediate
Poor
Karyotype
t(15,17), t(8,21); inv(16)/t(16:16)
Molecular modifications
NPM1 (FLT3 neg), CEBPA
(biallelic)
Normal; includes -y, +8, +21, +22, CEBPA
-5/del(5q), -7/del (7q), t(6,9),
FLT3
11q23, 3 or more abnormalities
Over 23 genes mutated
AML PROGNOSIS
55-70% achieve CR with induction
50-70% will relapse during the first 18-24 months
allogeneic transplant an option in select few with sibling (preferable)
no role for maintenance chemotherapy
APL
Excellent prognosis once treatment started (higher mortality prior), younger ~ 30’s
Remember DIC/severe thrombocytopenia/CNS bleeding
t (15;17); t(11;17): PML-RAR α aberrant fusion protein blocks myeloid
differentiation.
Treated with:
Induction: All-trans retinoic acid (ATRA) + anthracycline (nearly all patients CR)
Consolidation: ATRA or Arsenic trioxide (ATO)
Maintainence: ATRA, 6-Mercapto-purine, oral methotrexate
Auto-HSCT if relapse.
APL - 2
Watch out for differentiation syndrome (25-40%):
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fever, edema, stomatitis,
Hypotension
dyspnea, ARDS
renal/liver failure
Treated with high dose steroids (Dex 10 mg IV BID), temporary cessation ATRA/ATO
Other AE: electrolyte imbalances, QT prolongation, rash, pain, increased LFT’s,
hearing loss (ATO)
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Only ~ 1000 adult cases/year in US
Similar presentation to AML
Hepatosplenomegaly and LNs more common
Leukocytosis less common
CNS involvement (15%) and relapse more common
Mediastinal mass in T cell ALL: CXR, CT chest
TLS more common than AML, can be spontaneous
TdT stain (ALL), MPO (AML)
LP, testicular exam
Philadelphia chromosome
ALL
B-cells (~80%): CD10, 19, 20
L1=Early Precursor B-ALL
subtype represents 25-30% of adult cases
L2= Pre-B ALL
representing 70% of cases
L3/Burkitt’s=B-ALL
subtype accounts for 1-2% of adult cases
T-ALL (~ 20%): CD2, 3, 5, 7, 4, 8, 38
Particularly aggressive
ALL TREATMENT
Borrowed from pediatric protocols
Overall survival 40%
PH chromosome ALL in 30%: poor prognosis
treatment 4 components over 2-3 years:
 Induction, consolidation, CNS prophylaxis and maintenance
 Mainly outpatient
 Allo BMT for PH + ALL or relapsed disease
Prognosis:
Good: children, pre-B WBC < 30,000, T-ALL < 100,000, rapid CR, t(12,21), hyperdiploidy
Bad: Ph chromosome changing with TKI-inhibitors, t(4,11), MLL/11q34 translocation
BACK TO OUR PATIENT
AML with leukemia cutis, FLT3 negative, intermediate cytogenetics
Given hydroxyurea (4g/day) initially
LP positive blasts
Induction chemotherapy complicated by:
1) Febrile neutropenia secondary CLA-BSI with VRE bacteremia
2) Severe Mucositis: MMW, pink lady, dilaudid
3) 15% weight loss: nutrition
4) Mild increased in liver enzymes
Day 28 bone marrow: CR
Received consolidation
Awaiting Allo-HSCT
FUTURE DIRECTIONS
Autologous Chimeric antigen receptor T-cells targeting CD19
Used in relapsed/refractory ALL: CR 90%, sustained response 67% of patients and
response seen up to 24 months.
SUMMARY
Acute leukemia: emergency
AML/APL vs ALL
Leukostasis: symptomatic ?urgent treatment
Treatment: Feb. Neut, TLS, transfusions, Anti-microbial prophylaxis
Watch out for adverse effects due to chemotherapy
REFERENCES
DynaMed: AML, ALL, APL
Pocket Oncology 2014