Acute Leukemia: Treatment

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Acute Leukemia Treatment Historical General
Principles (AML) APL ALL Cases
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Acute Leukemia Treatment Historical Prior to
modern chemotherapy (1960s), average survival
with acute leukemia 2 months
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General Principles Individualized and risk
adapted Major supportive care component due to
natural history of the disease and due to
treatment toxicity Treatment with curative
intent involves sequential remission Induction
and post-remission phases
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General Principles Individualized and risk
adapted Individualized risk/benefit analysis.
Since conventional leukemia treatment is
associated with significant toxicity and
mortality (10-40), based on age, comorbidities,
disease biology etc., not all patients should be
treated aggressively.
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General Principles Individualized and risk
adapted Whereas even 10 years ago all patients
treated aggressively were treated identically
(overkill), due to a better molecular
understanding of disease biology, and better
prognostication (largely molecular and
cytogenetic) the intensity of treatment (and
hence the toxicity) is now tailored to the
individual case).
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General Principles Major supportive care
component Protean signs and
symptoms Patients may present with or develop
during treatment life-threatening
opportunistic infections (neutropenia) septic
shock, respiratory failure etc. severe
bleeding, often life threatening
(thrombocytopenia /- coagulopathy)
neurological symptoms (CNS infiltration or
bleeding) etc.
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General Principles Treatment with curative
intent involves sequential remission Induction
and post-remission phases
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Treatment of AML
Death
Death
Remission-Induction
Post-remission
CR
Cure
Refractory
Relapse
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Treatment of AML
Death
Death
Remission-Induction
Post-remission
CR
Cure
Refractory
Relapse
Chemotherapy x 2(3) Allotransplant Long-t
erm follow-up (with assessment of minimal
residual disease) Maintenance treatment?
Chemotherapy x 1
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Why Post-remission treatment?
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CR gt 60-70 Long-Term Survival (gt3 years) 15
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gt 50 of patients relapse
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Cure
Complete Remission
Post-remission Treatment
Pre-treatment
Relapse
1012 cells
lt 5 Marrow Blasts in Normocellular
Marrow Normal Peripheral Blood Counts No
Extramedullary Disease
Minimal Residual Disease (MRD)
109 cells
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Treatment of AML Remission-Induction Prognosti
c factors (who gets treated?) Drugs
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Remission-Induction Prognostic factors before
therapy Age (gt60 unfavourable median
68) Secondary leukemia (unfavourable) Comorbid
ities (unfavourable) Cytogenetics Favourable
Intermediate Poor risk Other elevated
LDH presentation LKC
Interrelated
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Induction chemotherapy Supportive care Clinical
trial No treatment
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Drugs Cytosine Arabinoside, Cytarabine,
Ara-C S-phase-specific cytotoxic
antimetabolite Metabolized intracellularly into
Ara-CTP DNA damage due to inhibition of a-DNA
polymerase, inhibition of DNA repair, and
incorporation into DNA. Anthracycline
(Daunorubicin, Mitoxantrone, Idarubicin) DNA
intercalation, inhibiting DNA synthesis and
DNA- dependent RNA synthesis. Cytotoxic
activity cell cycle phase non-specific, but
maximal in S-phase.
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Drugs Etoposide Cytotoxic topoisomerase II
inhibitor, inhibiting DNA synthesis. Affects
mainly the S and G2 phases
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Remission?
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Allotransplant Observation ? Maintenance
Induction Chemotherapy
Consolidation Chemotherapy x 2
CR
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Prognostic factors after therapy Age (gt60
unfavourable median 68) Comorbidities
Cytogenetics Favourable Intermediate P
oor risk Other Time to CR Number of
blasts on day 14-16 MRD
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Prognostic factors after therapy Age (gt60
unfavourable median 68) Comorbidities
Cytogenetics Favourable Intermediate P
oor risk Other Time to CR Number of
blasts on day 14-16 MRD
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So who gets transplanted ? (Who gets observed?)
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Autologous BMT in CR1 identical to chemotherapy
alone Allogeneic BMT vs. Autologous BMT
Allogeneic BMT vs. chemotherapy alone
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Allo BMT? Good Risk NO
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Allo BMT? Bad Risk YES
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Allo BMT? Intermediate Risk Maybe
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How to further stratify intermediate risk group?
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Intermediate Indeterminate Standard
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Normal, 8, 6, -Y, del(12p)
1/3
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• 2. Presence of specific mutations

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2.i FLT3 mutations i. FLT3/ITD - internal
tandem duplication in JM domain -
activating - associated with high LKC -
20-25 ii. FLT3/TKD - activating point
mutation - second tyrosine kinase domain of
FLT3 - 7-10 iii. FLT3-JM-PM -
activating point mutation in JM domain -
2
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Should FLT3/ITD status define alloBMT?
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2.ii. MLL partial tandem duplications - partial
internal tandem duplication usually involving
exons 2-6 or 2-8 - 10 of AML with normal
cytogenetics - 90 of AML with (11)
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No difference in presentation features No
difference in CR rate
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2.iii. Nucleophosmin mutations - 50-60 normal
cytogenetics
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2.iv. other CEBPa - 15-20 of normal
cytogenetics - confers favourable
prognosis RAS - 10 of normal
cytogenetics - neutral KIT - 1 -
unknown
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• 3. Overexpression of specific genes

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3.i. ERG (ETS - Related Gene) - overexpression
25 normal cytogenetics
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Outcome of patients grouped by ETS-related gene
(ERG) expression into quartile 4 (Q4), the
uppermost quartile, and quartiles 1 to 3 (Q1-3),
the lower quartiles
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3.ii. BAALC (Brain And Acute Leukemia,
Cytoplasmic)
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Combinatorial analysis?
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Allotransplant Observation
Induction Chemotherapy
Consolidation Chemotherapy x 2(3)
CR
? Maintenance Chemo
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Prognostic factors after therapy Age (gt60
unfavourable median 68) Comorbidities
Cytogenetics Favourable Intermediate P
oor risk Other Time to CR Number of
blasts on day 14-16 MRD
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Monitoring MRD Stratification parameter Detectio
n of impending relapse Multiparameter flow
cytometry Detect low frequency aberrant
immunophenotype Quantitative PCR Detect
translocation-specific transcripts t(1517)
inv(16) t(821) Detect expression of
leukemia associated genes WT1 EVI1
usually expressed as log reduction from diagnosis
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Allotransplant Observation ? Maintenance
Chemo
Induction Chemotherapy
Consolidation Chemotherapy x 2(3)
CR
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Maintenance Chemotherapy ? No accepted role in
NA in non-M3 AML (but of key importance in APL
and ALL)
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Acute Leukemia Treatment Historical General
Principles (AML) APL ALL Cases
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Acute Leukemia Treatment Historical General
Principles (AML) APL ALL Cases
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APL While all of the general principles apply,
APL has several unique features - most curable
AML - most progress in outcome in last 15 years
of all AMLs
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APL - most deadly up front due to
life-threatening coagulopathy hemorrhage thr
ombosis retinoic acid syndrome
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APL - 10 - 15 of adult AML - median age 40
years - no increase in incidence with age -
increased incidence among Hispanics, Philipinos
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APL Prognostic factors - t(1517) confers good
prognosis - presence of additional cytogenetic
abnormalities does not alter this risk -
simultaneous presence of bad risk or complex
abnormalities do not confer bad risk in the
presence of t(1517) - RARa fusion partner
PZLF-RARa confers poor drug response - WBC
count gt10 bil/L (likely have FLT3/ITD
mutation) - Platelet count lt40 bil/L - CD56 ve
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Treatment - unique sensitivity to all-trans
retinoic acid (ATRA) and arsenic
trioxide - LKC lt 10,000 start ATRA day 0 and
daunorubicin day 5 - LKC gt 10,000 start
ATRA and daunorubicin simultaneously
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Treatment - typically no role for
alloBMT - maintenance LKC lt 10 bil/L, ATRA
x 1 2 years LKC gt 10 bil/L, ATRA
6-mercaptopurine methotrexate x 2
years - only AML in which autoBMT in CR2 as
good as alloBMT
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Treatment MRD assessment - following
induction, usually PCR ve - following final
consolidation, gt95 PCR -ve (PCR vity at
this point very bad) - following completion of
consolidation chemo, MRD assessment every 3
months for 2-3 years - if -ve PCR becomes ve,
chance of overt relapse within 1 year gt
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Acute Leukemia Treatment Historical General
Principles (AML) APL ALL Cases
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Acute Leukemia Treatment Historical General
Principles (AML) APL ALL Cases
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ALL While all of the general principles apply,
ALL has several unique features Adverse
prognostic factors Age gt 35 years gt 4 weeks to
CR LKC gt 30 bil/L (B lineage) LKC gt 100 bil/L
(T lineage) Cytogenetics Ph t(922) (30
adults) translocations involving MLL,
myc hypodiploidy (mostly pediatric)
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ALL Distinct biology lymphadenopathy,
splenomegaly much more likely mediastinal mass
common CNS disease much more common
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ALL Treatment of adult ALL is much more
complicated than that of AML - more
drugs doxorubicin cytarabine methotrex
ate vincristine/vinblastine L-asparagi
nase corticosteroids 6-mercaptopurine
- prophylactic CNS treatment
intrathecal chemo XRT - treatment
lasts several years in 3 week cycles of
alternating drugs, and with periodic CNS
treatment, and periodic dose intensification
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ALL In adults, alloBMT currently restricted to
Ph cases and to those with 11q23 abnormalities
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Acute Leukemia Treatment Historical General
Principles (AML) APL ALL Cases