2. Presentations
1. Common
a) Hyperleukocytosis with circulating blasts
b) Pancytopenia ± circulating blasts
c) Generalized lymphadenopathy, hepatosplenomegaly, ± circulating blasts
2. Uncommon
a) Single lineage cytopenia with no circulating blasts
b) Extramedullary tumors
c) Relapse of bone marrow failure (inherited or acquired) syndromes
7. • Characteristics of lymphoblast:
- Intermediate sized cells
- Scanty agranular cytoplasm
- Round or slightly irregular nuclei
- Fine chromatin
- Inconspicuous nucleoli
8. FAB System defines 3 categories of lymphoblasts:
L1- small , scant cytoplasm with inconspicuous nucleoli
L2- larger, heterogenous in size, prominent nucleoli and more
abundant cytoplasm
L3- large, deep cytoplasmic basophilia, prominent cytoplasmic
vacuolation, morphologically similar to Burkitt lymphoma cells.
9. • Characteristics of myeloblast:
-large cells
- Cytoplasmic granules with or without auer rods
- Variable shaped nuclei with fine chromatin
- Auer rods are the only morphologic finding specific
for myeloblasts.
Based on the nature of granules, myeloblasts may be-
Type 1: Agranular or rare granules (M0,M6 and M7)
Type 2: Pauci granular (<15 primary azurophilic granules) M4,5
Type 3: granular (>20 granules and no golgi zone), M2,3
11. MPO- myeloid differentiation except very early myeloblast and monoblast
Sudan black- tends to track with MPO but less specific
Non specific esterase- monoblasts and monocytes
Specific esterase- cells of neutrophil lineage and mast cells
PAS- both lymphoid and myeloid
15. • Recurrent genetic abnormalities associated with specific
immunophenotypic patterns :
MLL rearranged ALL : CD10 - / CD 15+
Ph + ALL : CD 25 + , CD 13 +, CD 33 +
16. Prognostication
Myeloid
• Cytogenetics
• Molecular prognostic features
• Response to treatment
Lymphoid
• Age
• Gender
• Initial WBC
• Extramedullary disease
• Immunophenotype
• Ploidy
• Cytogenetics
• Response to treatment
• Nutritional status
18. Molecular prognostic features (ALL)
Favourable :
1. t(12;21)ETV6/RUNX1
2. Trisomy 4
3. Trisomy 10
4. HOX 11 rearrangement by
t(5;14)
5. T(8;14) MYC IgH
Unfavourable :
1.t(4;11)MLL/AF4
2. t(1;19) TCF3/PBX1
3.t(9;22) BCR/ABL1
4. Early T cell precursor
19. RESPONSE TO TREATMENT
• Significance of MRD in AML (Risk stratification and therapeutic
implications): MRD should be assessed after completing initial
induction therapy, before HCT, and additionally, at time points
based on the regimen used.
20. • Presence of MRD post-induction therapy and after HCT is associated
with increased risk of relapse and shorter survival in AML.
• The specified cut-off level for MRD defines two groups of patients-
“MRD positive” and “MRD negative”. Data regarding such risk
stratification with impact on therapeutic decision making are
evolving with no global consensus so far
21. MRD IN APL:
• Achievement of PCR negativity for at the end of consolidation
• Treatment should not be modified if PCR detects PML-RARA during
active treatment.
• Posttreatment, conversion of PCR negative to positive status for
PML-RARA (confirmed on a repeat sample) in BM or PB heralds
relapse.
• Early identification of molecular relapse helps to take immediate
action to reduce complications like bleeding; however, a significant
impact on clinical outcome has not been shown
22. MRD IN ALL:
• The response to initial therapy as assessed morphologically remains an
important prognostic marker but it is not sufficiently sensitive to assess the
depth of response
• MRD is quantified by molecular analysis of clone-specific immunoglobulin/T-
cell receptor (Ig/TCR) gene rearrangements.
• Alternatively, it can also be measured by quantitating the fusion gene
transcripts (BCR-ABL) or abnormal leukemia associated proteins (NPM1) by
PCR methods.
• More commonly however, MRD is assessed by multiparametric
flowcytometry.
23. • Multiparametric flowcytometry for MRD analysis is based on the
discrimination of ALL cells from the normal counterparts or, more
precisely, on the identification of the leukemia-associated aberrant
immunophenotype (LAIP).
24. Other prognostic features
• Adverse clinical prognostic features in AML include presence of
extramedullary disease, therapy related AML, history of prior
myelodysplasia, presence of other comorbid conditions, and poor
performance status.
• However, the greatest prognostic factor is the underlying leukemia
causing genetic defect.
27. OTHER PROGNOSTIC FACTORS IN ALL
• Girls have better prognosis. Probable reasons :
• - risk of testicular relapse in boys
• - higher incidence of T ALL in boys
• - lower incidence of hyperdiploidy in boys
28. ploidy
• Hyperdiploidy: 51 - 67 chromosomes, is seen in approximately 30%
childhood cases
• >67: Near tetraploid, associated with T ALL OR RUNX2+ B ALL
• Hypodiploidy : chromosome number < 44
• near haploidy (24-31 chromosomes)
• low hypodiploidy (32-39 chromosomes)
• high hypodiploidy (40-44)
31. Therapeutic approach to a patient of AL
Induction therapy
Achievement of Remission
Consolidation therapy
Supportive care
• Prevention and
treatment of
infections
• Blood products
• Tumor lysis
syndrome
• Consolidation
chemotherapy
• Allogeneic SCT
Maintenance therapy
Treatment of relapse
32. Initial treatment: depends on risk
categorization
• AML – Induction/Consolidation (chemo or AlloSCT)
• ALL- Induction/consolidation/cranial
prophylaxis/reintensification/MT
• APL- Induction (chemo or chemo free)/consolidation± MT
33. Supportive care
• Tumor lysis syndrome
• Infection prophylaxis and management
• Blood products
34. Tumour lysis syndrome: CAIRO BISHOP
DEFINITION
• Laboratory TLS : >=2 values
above upper limit or 25%
above baseline within 3 days
before or 7days after giving CT
in the setting of adequate
hydration & hypouricemic
agent-
Uric acid - 8mg/dL
Potassium6meq/L
Phosphorus6.5mg/dL
Calcium7mg/dL
• Clinical TLS : laboratory TLS + 1
of the following that was not
attributable to a therapeutic
agent
S.Creatinine 1.5 times upper
normal limit
Cardiac arrythmia/ sudden
death
Seizure
35. Grading of TLS :
0 1 2 3 4 5
s.Creatinine <1.5 x ULN 1.5 x ULN >1.5-3 x ULN >3-6 x ULN >6 x ULN Death
Cardiac
Arrythmia
None Intervention not
indicated
Non urgent medical
intervention
Symptomatic &
incompletely controlled
medically or controlled
with device (e.g
defibrillator)
Life threatening (eg.heat
failure,
hypotension,syncope,shock
Death
Seizure None 1 brief
seizure;seizure(s)
well controlled by
anticonvulsants or
infrequent focal
motor seizuresnot
interfering with ADL
Seizure in which
consciousness is
altered;poorly
controlled;breakthrough
seizures despite medical
intervention
Seizure of any kind which are
prolonged, repetitive or
difficult to control (e.g. Status
epilepticus, intractable
epilepsy)
Death
36. Prophylaxis for TLS:
IV HYDRATION :
1.Choice of fluid – Standard fluids containing saline and dextrose
2. Rate – approximately twice the maintenance OR 2-3L/m2 ( or
200mL/kg in children <= 10kg)
3. Target urine output- 80 to 100ml/m2 / hour ( 2mL/kg/hour but 4-
6ml/kg/hour if child is <=10kg)
4.Diuretics can be used to maintain urine output provided renal
function is normal and there is no hypovolemia/obstructive
uropathy ( preferred- frusemide because of additional potassium
excretion)
37. 5. Duration of hydration – depends on disease condition and clinical
status
HYPOURICEMIC DRUGS
1. ALLOPURINOL – Preferred for initial management
Limitations- does not reduce pre existing serum uric acid
- may increase serum concentration of other purines(6MP
dose reduction required
-interaction with cyclophosphamide, high dose MTX,
amoxicillin, ampicillin, frusemide
-hypersensitivity reactions
38. • Dose – 50 to 100mg/m2 every 8 hours (maximum 300mg/m2 / day)
Or 10mg/kg/day in 3 divided doses (Dose to be reduced to 50% in
the setting of AKI)
2. Rasburicase- for the initial management of patients at high risk for
TLS, this is preferred over allopurinol especially in those with
impaired renal /cardiac function
Contraindication – G6PD deficiency
Dose- 0.15mg/kg for 1-5 days
39. • URINARY ALKALISATION
Not preferred for the following reasons-
- No data demonstrating its efficacy
- Potential risk of calcium phosphate deposition in the kidney, heart
and other organs in the setting of hyperphosphatemia once tumour
breakdown begins.
40. TREATMENT OF ESTABLISHED TLS
• 1.Hydration
• 2. Rasburicase
• 3.management of specific electrolyte abnormalities
41. INFECTION PROPHYLAXIS
• Fever in neutropenic leukemic patients is a medical emergency
• Empiric broad spectrum antibiotic to be started as early as possible
after drawing blood cultures
• antibiotic selection to be guided by patient’s presentation and
institutional pattern
• IDSA recommends empiric monotherapy with antipseudomonal
beta – lactam agent such as cefepime, meropenem, imipenem or
pipercillin- tazobactum
42. • Gram positive coverage (eg vancomycin ) to be added in:
suspected central venous catheter related infection
skin/soft tissue infection
pneumonia
hemodynamic instability
It may be stopped after 2-3 days if there is no evidence of gram
positive infection
43. • Empirical antifungal should be considered in patients who have
persistent fever after 4-7 days of a broad spectrum
• Oral ulcers may be due to herpes simplex or Candida spp. Thus
aciclovir and/or fluconazole may be added in such situation
• The choice of antifungal for empiric therapy depends upon- which
fungi are most likely to be causing infection as well as toxicity
profiles and cost
44. 1. For persistently febrile patients who have not been receiving
antifungal prophylaxis and who have no obvious site of infection,
caspofungin is preferred since Candida spp is most likely
2. those with pulmonary nodules, invasive mould suspected and
choice is voriconazole
45. • Central venous Catheter removal :
1.catheter related bloodstream infection caused by S.aureus, P.
Aeruginosa, Candida or rapidly growing non tuberculous
mycobacteria
2.catheter related bloodstream infection with fungi other than
candida spp
3. complicated infections like tunnel infection, port “pocket”
infection
46.
47.
48. BLOOD PRODUCTS
• Blood products in the form of PRBC and platelet are required in
large amounts especially during induction phases
• Hemoglobin is required to be maintained at 7g/dL
• Prophylactic platelet transfusions are required at levels of
<20,000/cumm with fever, sepsis and <10,0000/cumm without
fever/sepsis.
• Therapeutic platelet transfusions: irrespective of PLT counts
49. TREATMENT OF ALL
• Induction
• Consolidation
• Cranial prophylaxis
• Reintensification
• Maintenance Therapy
50. INDUCTION
1. Aim – remission
Peripheral blood values must be within normal limits and bone
marrow should be of normal cellularity with <5% blasts
2. Induction therapy has 2 phases –
a) Remission induction :
Drugs used- Prednisolone, Vincristine, L-asparaginase,
Daunorubicin
b) Post – remission induction:
Drugs used- Cyclophosphamide, Cytarabine, 6MP
52. CRANIAL PROPHYLAXIS
• Reason – CNS acts as a sanctuary site where leukemic cells
undetected at diagnosis are protected by blood brain barrier
• Modalities of CNS prophylaxis :
radiation
intrathecal chemotherapy
high dose systemic chemotherapy
54. MAINTENANCE
• Drugs used – 6MP daily, weekly methotrexate with or without
vincristine and steroid
• Duration- 2 to 3 years
• These protocols offer CR rates of over 95%, 5 yr EFS of 80-85% and
5 yr survival rates of over 90%.
• The rationale behind the use of long-term low dose chemotherapy
as maintenance treatment is the elimination of slowly growing
subclones that persist after the intensive phases of treatment.
56. ELN risk stratification by genetics
RISK CATEGORY GENETIC ABNORMALITY
FAVOURABLE 1. t(8,21)(q22,q22.1), RUNX1- RUNX1T1
2. inv(16) or t(16,16)(p13.1,q22), CBFB-MYH11
3. mutated NPM1 without FLT3- ITD or with FLT3-ITDlow
4. biallelic mutated CEBPA
INTERMEDIATE 1. mutated NPM1 and FLT3-ITDhigh
2. wild type NPM1 without FLT3- ITD or FLT3-ITDlow
3. t(9,11)(p21.3,q23.3), MLLT3- KNMT2A
4. cytogenetic abnormalities not classified as Favourable or Adverse
ADVERSE 1. t(6,9)(p23,q34.1), DEK-NUP214
2. t(v,11q23.3), KNMT2A
rearranged
3. t(9,22)(q34.1,q11.2), BCR-ABL1
4. inv(3) or t(3,3)(q21.3,q26.2),
GATA2 -EVI1
5. -5 or del(5q), -7, -17/abn(17p)
6. Complex karyotype, monosomal
karyotype
7. Wild type NPM1 with high
FLT3-ITD
8. Mutated RUNX1 or mutated
ASXL1 or mutated TP53
57. • Intensive Chemotherapy for AML is divided into remission induction
and post remission therapy.
• Standard remission induction regimens: for all AML subtypes,
excluding APL include 7 days of infusional cytarabine and 3 days of
anthracycline , commonly known as “ 7 + 3 ” chemotherapy.
• Post-remission therapy: Patients who achieve remission will
ultimately relapse within a few months unless additional therapy is
given. Any medically fit patient who achieves CR is a potential
candidate for post-remission therapy
58. • Following post-remission treatment options are available:
1. Consolidation Chemotherapy: High dose Ara-C (doses ranging from 6-
18gm/m²/cycle). Number of cycles may vary from 2-4.
• Chemotherapy consolidation can be offered only in patients with favourable
or intermediate cytogenetic risk categories
2. Allogeneic Stem cell transplantation
59. • APL should be regarded as a medical emergency. The patients with
suspected APL should be immediately started on ATRA@
25mg/m²/d
61. • APL is risk stratified into 3 categories based on WBC count and
platelet count at diagnosis:
Low: WBC < 10x10 /l, and Platelet > 40 x 10 /l
Intermediate:WBC < 10x10 /l, and Platelet < 40 x 10 /l 9
High:WBC > 10x10 /l
In low and intermediate risk categories induction regimens containing
ATRA and ATO used
62. • Anthracycline -high risk disease
ATRA + chemotherapy induction
• The consolidation consists of ATO + ATRA even in high risk patients
• maintenance therapy with ATRA, 6MP and oral methotrexate in
high risk patients.
