management of acute leukemia

1. ACUTE LEUKEMIA
MODERATOR :- DR.SUDHIR.SINGH
PRESENTER :- DR.VIJAY.P.RATURI

2. ACUTE MYELOID LEUKEMIA :-
• AML is characterized by uncontrolled proliferation
myeloid progenitor cells.
• Abnormal proliferation and aberrant differentiation of the
malignant cells leads to inhibition of normal hematopoiesis
• Characterization of transforming genetic events is
important in diagnosis , defining prognosis , planning t/t in
AML.

3. EPIDEMIOLOGY :-
• Incidence rate of AML in india is 3-5 cases/1 lac .
• AML accounts for about 15% - 20% of acute leukemia in
in children and adolescent & 80% in adult.
• Incidence of AML rises rapidly after age of 60
median age at diagnosis is 67 years.
Principle and practice of paediatric oncology 6e-

4. ETIOLOGY :-
• Pathophysiology mechanism are multiple , & are distinct
in different type of AML.
• Inherited genetic predisposition and environmental
mutagens such as radiation , drugs , & other toxin play a
role.
• Association of AML with variety of congenital disorder
eg:- ( down syndrome ).
• Large european population based study found no
significant familial aggregation for AML or MDS, it means
most pt with AML/MDS causative factor is environmental.

5. PATHOGENESIS :-
• It’s a complex multistep process that result from the
interaction of two different classes of mutation.
MUTATION
Impair cell differentiation
Resulting in clonal
expansion of myeloid
progenitor
1st class 2nd class
Abnormal cell proliferation
By activation of cellular
Proto oncogenes :-
• FLT3 tyrosine kinase
• RAS , c- kit
• Some molecular alteration in AML are distinct
chromosomal changes ( Translocation, inversion, deletion).

6. COMMON CYTOGENETIC AB-N & MUTATION IN AML
MUTATION IMPARING
DIFFERENTIATION
• t(8,21)
• t(15,17)
• Inv 16
• 11q23
• Rare – t(6,11) t(9,11)
t(6,9) inv 3
MUTATION THAT PROMOTES
PROLIFERATION
Proto oncogene mutation
• FLT3 activationg mutation
• RAS mutation
• C- kit muation
Tumour suppressor gene
Mutation
• P53
• retinoblastoma

7. RISK FACTOR FOR DEVELOPMENT OF AML :-
ENVIRONMENTAL EXPOSURE
• Benzene
• Ionizing radiation
• Smoking
GENETIC DISORDERS
• Down syndrome
• Bloom syndrome
• Fanconi anemia
• Ataxia telengectesia
• Klinefelter syndrome
PRE-EXISTING HEMATOLOGIC
DISORDER :-
• MDS
• Myelo proliferative disorders
• Aplastic anemia
TREATMENT ASSOCIATED
• Alkylating agents
(deletion chr 5 or 7)
• Topoisomerase 2
inhibitor ( changes
in chr long arm 11 )

8. CLINICAL FEATURES :-
• Patient with AML usually present with bone marrow
failure that causes symptoms of anemia , bleeding from
thrombocytopenia , neutropenic infection
• DIC is seen in APL ( acute promyelocytic leukemia)
• Leukostasis and hyperviscosity causing organ dysfunction
usually occur with blast cell count > 100000 /ul
• Rare but striking manifestation of AML includes Sweet
syndrome.

9. LABORATORY FINDINGS :-
HAEMATOLOGIC
• Increased WBC with blast in peripheral smear
• Anemia , thrombocytopenia , granulocytopenia, DIC
CHEMISTRY
• Hyperuricemia, Increased BUN and S.creatinine , high LDH
• Hypokalemia , hypercalcemia
• Spurious hypoxemia , hypoglycemia
IMAGING STUDIES
• Intracranial hemorrhage
• Thickened nerve sheath
• Lung infiltrates

10. CLASSIFICATION :- its mainly morphology based on
FAB to be more comprehensive
WHO classification
FAB classification of AML :-

13. DIAGNOSTIC EVALUATION:-
According to WHO ,diagnosis of AML require at least
20% myeloid blast in peripheral blood or bone marrow
Evaluation of patient with AML at diagnosis includes:-
• Blood count and inspection of blood smear
• BM aspirate & biopsy
• Cytogenetics
• Molecular analysis
• L.P if CNS symptom is present

14. PROGNOSTIC FACTORS :-
CLINICAL PROGNOSTIC FACTOR
• Age
• AML arising from pre- existing MDS
• T/t related AML
• Performance status
• Extra medullary disease , co- morbid conditions
LABORATORY BASED PROGNOSTIC FACTOR
• WBC > 20000u/l at presentation
• Cytogenetics
• Molecular genetic changes
• Multidrug resistance
• CD34 +ve blast

15. • Best predictor of long term outcome next to age are
chromosomal & molecular genetic finding in leukemic cells.
• Cytogenetic analysis is basis of stratification on pt in three
Risk groups with different responses to chemotherapy.
• Approx 40-50% pt have normal karyotype at time of
diagnosis and most of them fall into intermediate risk.
• Best studied mutation , internal tandem duplication of
FLT3 gene are found in approx 20-30% of AML pt.
• Outcome of younger AML pt has improved markedly over
last 3 decades due to advances in chemotherapy &
supportive care.

16. TREATMENT OF AML :-
• T/t plan in AML pt depends on age , performance factor ,
prognostic factors detected by cytogenetics, FISH, and
PCR.
• T/t for AML is divided into 2 phases :-
- remission induction
- post remission therapy
• Goal of remission induction is to achieve a CR defined by
criteria :-
- < 5% blast in BM
- absent extramedullary leukemia
- neutrophil count > 1000/ul
- platelet count > 1lac/ul

18. • It’s not surprising that clinical trials confirm an almost
100% risk of relapse when pt receive only induction
chemotherapy.
• Long term survival requires post remission t/t .
• Intensive chemotherapy given after achievement of CR
is termed as consolidation therapy

19. INITIAL MANAGEMENT :- Initial evaluation should
include following
• History and physical examination
• CBC with differential count
• Coagulation studies
• Serum chemistries with uric acid, calcium
• Evaluation of renal and liver function
• Hep B and C , HSV ,CMV , varicella , HIV serologies.
• BM aspirate for morphology, cytochemistry ,
cytogenetics , molecular genetic studies
• BM biopsy
• HLA typing of pt
• L.P in high risk pt with CNS symptoms
• chest radiograph and ECG

20. • Workup should be followed by discussion with the patient
about the diagnosis , prognosis , side effect of therapy ,
impact on life style , anticipated requirement for support
by family and friends.
• In elderly pt , decision to give only supportive t/t without
chemotherapy may be reached jointly by pt and attending
physician.
• Final outcome depends not only on choice of
chemotherapy but also on close monitoring ,prevention,
and management of complication.
• Pt should be monitored for side effect such as
cardiotoxicity due to anthracyclines or neurotoxicity from
high dose of cytosine arabinoside.

21. INDUCTION THERAPY :-
• The m.c used chemotherapy regimen consist of
1 or 2 cycles of combination of cytarabine 100-200
mg /m2 given by continous i.v infusion over 7 days
and 3 days of an anthracycline ( eg :- duanorubicin
60-90 mg /m2 , idarubicin 10-13 mg/m2 or
mitoxantrone 10-12 mg/m2 by iv bolus)
• This “ 3 + 7 “ regime result in CR rates of approx
70-80% in patients younger than 55 – 60 years.
• If leukemia persist in BM at day 14 or 21, a 2nd
identical or modified course of CT is given.

22. • High dose duanorubicin is now considered a new std care
in the initial t/t of patient < 65 years of age with good
performance status and adequate cardiac function.
• In a recent phase 3 trial ,pt were randomized to receive a
traditional induction 3+7 regimen or to receive same
regimen in combination with fractionated small dose of
gemtuzumab.
• Trial demonstrated significant advantage in event free
survival and DFS at 2 years for pt who were treated on
gemtuzumab arm.

23. POST REMISSION TREATMENT :-
• Nearly all patients in CR after induction therapy have residual disease
that without further management leads to relapse.
• Main strategies to prevent relapse is HDAC and allogenic or
autologous HSCT.
• Consolidation t/t improves survival in younger pt with AML
• Consolidation with HDAC using daily dose of 1-6 gm/m2 is the std
for patient younger than 60 years.
• Pt over the age 0f 60 years do not benefit from HDAC consolidation.
• Evidence has suggest 1-4 courses of HDAC are reasonable.
• For younger pt choice between HDAC and HSCT based on risk of relapse

24. HAEMATOPOIETIC STEM CELL TRANSPLANTATION:-
• High dose Marrow ablative c.t and total body irradiation
followed by autologous or allogenic stem cell rescue have
been widely used in AML.
• Autologous HSCT requires stem cell collection from pt
while in CR.
• Allogeneic HSCT are obtained from HLA matched siblings,
unrelated donors, and cord blood or haploidentical donors
• Multiple trials comparing std consolidation c.t with HSCT
have demonstrated that allo HSCT provides best anti-
leukemic therapy with the lowest risk of recurrence
followed by auto HSCT .

25. RISK BASED APPROACH TO AML :-
<A> BETTER RISK AML :- pt with better risk karyotype t(8,21)
or inv 16 ,NPM1 mutation do well
with either intensive consolidation chemotherapy or auto
HSCT . long term DFS of 60-70% can be achieved.
<B> POOR RISK AML :- pt with poor risk or FLT3- ITD as well
as patients with secondary AML have
very poor prognosis .if HLA matched donor is available ,
these patient should be evaluated for HSCT as soon as
possible.
- pt with FLT3- ITD should be considered for clinical trials
with FLT3 tyrosine kinase inhibitor such as midostaurin,
lestaurtinib , sorafenib, quizartinib.

26. <C> INTERMEDIATE RISK AML :- t/t is complex in the largest
& most heterogeneous
prognostic group of patient with normal cytogenetics ,
no molecular marker or marker of unknown impact on
therapy.
- Allo – HSCT , consolidation chemotherapy , & auto HSCT
are considered of equivalent benefit.
- recent meta analysis revealed allogenic HSCT has
significant relapse free survival and OS benefit for
intermediate risk AML as compared to non allogenic HSCT
therapies.

27. TREATMENT OF ACUTE PREMYELOCYTIC LEUKEMIA :-
• APL is well defined disease entity with overall better
prognosis than other AML subgroups.
• It’s a first example of leukemia in which therapy directed
against the leukemogenic event , the t(15,17) resulting in
PML-RAR fusion transcript, leads to improved outcome.
• With better management of associated coagulopathy and
the introduction of ATRA & ATO ,APL now represent the
most curable subtype of AML with cure rate of > 90%
quoted in large clinical trials.

28. • The most widely tested t/t for APL consisted of a
combination of ATRA & anthracycline based c.t for
induction ,followed by at least 2 courses of anthracycline
based c.t and ATRA for consolidation , and maintenance
therapy with intermittent ATRA alone.
• Its is now established that ATO is more effective agent in
APL than ATRA ( north american intergroup trial).
• Despite the introduction of ATRA and improvement in t/t
of coagulopathy ,bleeding remain imp cause of death .
• Coagulopathy is t/td with FFP, fibrinogen , platelets with
goals fibrinogen > 150mg/dl and platelets > 30000/ul.

29. • APL differentiation syndrome is associated with both
ATRA & ATO. It is characterised by pleural & pericardial
effusion ,weight gain , edema , dyspnoea, fever.
• Its t/td with i.v administration of dexamethasone at a dose
of 10mg twice daily.
• Goal of induction and consolidation therapy should be the
attainment of PCR negativity for PML – RAR rearrangement
as a persistence of such minimal residua disease (MRD)
predicts relapse.

30. TREATMENT OF RELAPSED AND REFRACTORY AML:-
• Unfortunately , AML relapses in majority of patients.
• Approx 25% of younger pt are refractory to std induction c.t
.pt with recurrence AML experience lower CR rates with
reinduction chemotherapy compared to initial t/t.
• Therefore, pt with relapsed and refractory Aml are
candidates for clinical trials
• Pt with CR > 12 months, reinduction with HDAC containing
regimen,since it can achieve a CR rate of 50-60% .
• Pt with short CR ,priority is t/t on a clinical trials.

31. ACUTE LYMPHOBLASTIC LEUKEMIA :-
• Approx 3-4 cases/lac of ALL are diagnosed each year In
INDIA ,more than half of them in children.
• Currently children & adults with ALL have DFS rates
of 50-80% respectively.
EPIDEMIOLOGY :-
• ALL is most common paediatric malignancy approx
25% of childhood cancer.
• ALL occurs between ages of 2-5 years & after 50yr
• Slight male predominance
• Highest in hispanic children , caucasians have 2 fold
increased risk as compared to african- american
Division of paediatric oncology , Deptt of paediatric, AIIMS , delhi .

32. ETIOLOGY & RISK FACTOR :-
• Some conditions predispose to ALL most notably
trisomy 21(down syndrome) risk increased by 15fold
• EBV infection is implicated in minority of cases of
mature b cell ALL.
• Acquired chromosomal ab-N confined to
lymphoblast are found in > 90% cases , including
aneuploidy ( M.c hyperdiploidy) and /or
translocation in some cases are prenatal in origin.

33. CLINICAL FEATURES:- Presenting sign and symptoms
are always caused by lympho-
Blastic infiltration of b.m with blood count abN
COMMON SIGN & SYMPTOMS
• 70% hepatomegaly
• 60% fever
• 50% fatigue
• 50% lymphadenopathy
• 40% bleeding
• 40% bone or joint pain
• 20% anorexia
• 10% abnormal pain
SITES OF INVOLVEMENT
• 100% Bone marrow
• 10% Ant Mediastinal mass
• 5% CNS
• 2% Testicular
• < 5% others eg:- eye, skin,
pericardium, pleura,
kidney , brain, ovary,
intussusception

34. EMERGENCY PRESENTATION INTERVENTION
• leukostasis
• Neutropenia with fever/infection
• Thrombocytopenia
• DIC
• Tumour lysis syndrome
• Airway obstruction , SVC syndrome
• CNS manifestation
• Ocular involvement
• Spinal cord compression
• O2 , leukapheresis
• Broad spectrum i/v A/B
• Platelet transfusion
• FFP, cryoprecipitate
• Iv hydration , allopurinol or
rasburicase , supportive mx
• Corticosteroids & radiation
• Corticosteroids & radiation
• Radiation
• Corticosteroids & radiation

35. LABORATORY FEATURES :-
• The diagnosis is confirmed by demonstration of
lymphoblasts in the blood or BM.
• Blast morphology can be classified in three category
(L1,L2,L3) according to FAB.
• L3 is of clinical & prognostic significance because
L3 is indicative of mature b cell or burkitt type ALL.
• Majority of ALL is of precursor B cell (pre B cell),
10-20% is T-cell,< 5% is mature B-cell or burkitt type.
• L.P is required to evaluate the possibilities of meningeal

36. CLASSIFICATION :-
FAB MORPHOLOGY
- L1 : homogenous blast , minimal cytoplasm
- L2 : increased nuclear heterogeneity , prominent nucleoli
- L3 : basophilic cytoplasm with prominent vacuolization
BONE MARROW
- M1 : <5% blast
- M2 : 5% - 25% blast
- M3 : > 25% blast
CEREBROSPINAL FLUID CYTOLOGY
- CNS-1 : no blasts
- CNS-2 : wbc < 5/ul with blasts
- CNS-3 : wbc >5/ul with blasts , or symptomatic CNS involvement (eg
cranial nerve palsy)

37. PROGNOSTIC FACTORS :-
• Age is a strong prognostic determinant .
• Outcome is inferior in infants and adults in comparison to
children.
• T-cell and mature B-cell disease have historically had
lower DFS rates than pre B-cell ALL.

38. RISK GROUP ASSIGNMENT IN B-cell precursor ALL:-
STANDARD RISK HIGH RISK
age 1-9 10-35
WBC <30,000- <50,000 >30,000 - > 50000
CNS Negative Positive
chromosomes t(12,21) 11q23,t(1:19)
double or triple trisomy t(9,22)
4/10/17
DNA index hyperdiploidy hypodiploidy
T/t response RER SER

39. TREATMENT :-
• Therapy is based on clinicopathologic features, & t/t
should be directed by physician familiar with subtype.
• Therapy should be started as soon as possible after the
diagnosis.
• T/t is based on phenotype and prognostic factors and
include the following phases :-
- induction
- consolidation
- CNS sterilization
- maintenance for a total of 2-3 years

40. COMMON T/T REGIMENS FOR PRE B-CELL ALL & T-CELL ALL
INDUCTION REGIMEN (WEEK 1-4)
3 DRUGS :- <a> prednisolone 40-60mg/m2 or dexa 6mg /m2
PO * 21-28 days ( day 0 , 28)
<b> vincristine 1.5mg/m2/dose iv weekly * 4 doses ( day 0,7
, 14,21O)
<c> e-coli asparaginase 6000- 10,000 iu/m2/dose im * 6-9
dose 3d /week * 2-3 week
<d> IT methotrexate(or triple t/t with hydrocort & cytarabine)
4 DRUG :- add the following to above
<a> doxorubicin 25-30mg/m2/dose or duanorubicin 25-45mg
/m2/dose iv weekly * 4 doses

41. 5- DRUG : add the following to above
<a> cyclophosphamide 800-1200 mg/m2/dose iv * 1 dose
RESPONSE EVALUATION
DAY 14 B.M
- M1 : rapid early responder
- M2 or M3 : slow early reponder
DAY 28 B.M
- M1 : remission ,continue with post induction regimen. if
MRD is present ,may be allocated to higher risk group
- M2 or M3:- induction failure ,salvage re induction required

42. POST INDUCTION REGIME :-
PRETREATMENT CRITERIA:-
- ANC > 750/ul , platelets > 75000/ul
- ALT < 2times the upper limit , direct bilirubin normal for age
- serum creatinine normal for age
- no active infection or life threatening organ dysfunction
CONSOLIDATION ( WEEK 5)
STANDARD BERLIN- FRANKFURT- MUBSTER STUDY GROUP ( BFM)
- cyclophosphamide 1000mg/m2/dose iv * 2 dose
- mercaptopurine 60mg/m2 /dose PO once daily * 28 day
- cincristine 1.5mg/m2/dose iv * 4 doses
- cytarabine 75mg/m2/dose iv
- IT methotrexate weekly * 4dose

43. AUGMENTED BFM :-
- above STD BFM + ecoli asparaginase 6000 iu/m2/dose i.m
* 12 doses , 3 dose /week
CAPIZZI :-
- Cytarabine 3000mg/m2/dose iv * 4 doses weekly
- l – asparaginase 6000 iu/m2/dose im at hour 42 following
cytarabine
IFOSPHAMIDE/ETOPOSIDE :-
- Etoposide 100mg/m2/dose iv * 5 doses
- Ifosfamide 1.8mg/m2/dose iv * 5doses
INTERIM MAINTENANCE:-
commonly employed between consolidation and delayed
intensification/reinduction courses.

44. DELAYED INTENSIFICATION / REINDUCTION :
- Dexamethasone 10mg/m2/d in divided doses PO * 14-28 day
- vincristine 1.5mg/m2/dose iv weekly * 5 doses
- doxorubicin 25-30mg/m2/dose iv weekly * 3 doses
- cyclophosphamide 1000mg/m2/dose iv
- 6-thioguanine 60mg/m2/dose PO once daily * 14 days
- cytareabine 75mg/m2/dose iv
- IT methotrexate * 2 doses
MAINTENANCE /CONTINUATION REGIME :-
repeat cycles to complete 24-36 month of total t/t
- prednisolone 40-60mg/m2/d or dexamethasone 6mg/m2/d
in divided dose PO * 5day every 28 day
- vincristine 1.5mg/m2/day iv evry 4 week
- mercaptopurine 75mg/m2/dose PO once daily
- methotrexate 20mg/m2/dose PO once weekly
- IT methotrexate every 4-12 week for 1-2 yr of t/t

45. INTRATHECAL CHEMOTHERAPY:-
• Single agent IT methotrexate has been the std t/t
• Triple agent IT C.T is sometimes employed especially for
those with high risk disease, CNS leukemia or meningeal
relapse.
• To facilitate CNS delivery, the volume of CSF removed should equal
the volume administered and pt should remain in prone position for
30 min.
INDUCTION SCHEDULE :-
- CNS 1 : every 2 week * 2 doses
- CNS 2 or CNS 3 : weekly * atleast 4 doses
MAINTENANCE SCHEDULE :-
- every 4-12 week for 1-2 year of t/t
CONSOLIDATION SCHEDULE :-
- every 1-4 week

46. EXTRAMEDULLARY LEUKEMIA :-
• Current chemotherapy regimen are associated with low rates of
extra medullary relapse in both the CNS & testes.
• Pt with extramedullary relapse also require systemic therapy .
• Radiation is currently preserved to treat CNS leukemia
RADIATION GUIDELINES :-
• CNS radiation should be avoided in children <2 year of age
• Radiation dose should be based on specific indication & overall t/t.
SITE TOTAL DOSE (CGY) FRACTIONAL DOSE (CGY)
CRANIUM 1200- 2400 150-200
SPINE 600-1200 150-200

47. MANAGEMENT OF RELAPSE :-
• Chance of cure decreases after relapse.
• Attaining a second remission is critical & often times can
be achieved with standard 4 or 5 drug induction regimens.
• For those with bone marrow relapse and CR1 duration of
> 18-36 month ,approx 35% will achieve prolonged DFS
with intensive re-treatment.
ALLOGENIC STEM CELL TRANSPLANTATION:-
• Pt with HLA matched sibling donors , allogenic SCT in 2nd
CR is standard care.

48. Thank you…