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Acute leukaemias othieno abinya
1. ACUTE LEUKAEMIAS: THE HARD
FACTS
N.A.OTHIENO-ABINYA, FRCP
DEPARTMENT OF CLINICAL MEDICINE AND
THERAPEUTICS,
UNIVERSITY OF NAIROBI
2. CONFLICT OF INTEREST
Life as a medical oncologist
used to be so simple before
2000! (EricP.Winer:
(19/09/2014),
3. But first things first!
I have got no conflict
of interest to declare.
4. EVERYTHING OLD IS NEW AGAIN
Cora B Sternberg and Andrea B Apolo on:
Modified M-VAC in neoadjuvant treatment of muscle
invasive bladder cancer
How about Jazz?
Today cancer treatments have gone high-tech.
AML too?
6. ACUTE MYELOID LEUKAEMIA
Unbridled proliferation of haematopoietic stem cells of
myeloid lineage resulting in marrow failure and patient death
unless successfully treated.
Cause of acute leukaemias is largely unknown but malignant
transformation is unlikely to be the result of a single event,
rather, multistep process.
7. Background
Multiple processes producing genetic damage secondary to
physical or chemical exposure in susceptible progenitor cells.
Incidence in the US is approximately 4.9/100,000
population/year.
About 75% of new acute leukaemia cases are in adults.
8. What causes you? Risks
Ionizing radiation
Occupational exposure to benzene and other chemicals
Cytotoxic chemotherapy, especially with alkylating agents
and topoisomease II inhibitors - AVOID DOING IT THE
AFRICAN WAY
Most patients have no credible aetiologic factors
9. Presentation
Mainly result of bone marrow failure:
Fatigue
Spontaneous bleeding
Fever
Others are: Weight loss, night sweats and lethargy.
Effects of tissue infiltration or circulating leukaemia cells.
Metabolic abnormalities
14. WHO Classification: Can we apply it? Is it
important? Can we improvise?
Acute myeloid leukemia with recurrent genetic
abnormalities
Acute myeloid leukemia with t(8;21)(q22;q22); RUNX1-
RUNX1T1
Acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16)
(p13.1;q22), CBFβ/MYH11
Acute promyelocytic leukemia with t(15;17)(q22;q12);
PML/RARA
Acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-
MLL
Acute myeloid leukemia with t(6;9)(p23;q34); DEK-NUP214
15. Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)
(q21;q26.2), RPN1-EVI1
Acute myeloid leukemia (megakaryoblastic) with t(1;22)
(p13;q13); RBM15-MKL1
Acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-
MLL
Provisional entity: Acute myeloid leukemia with mutated
NPM1
Provisional entity: Acute myeloid leukemia with mutated
CEBPA
16. Acute myeloid leukemia with myelodysplasia-related
changes
Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise specified
Acute myeloid leukemia with minimal differentiation
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic/monocytic leukemia
18. Diagnostic procedures: Are they
available to us all?
Baseline evaluation involves routine blood work:
complete blood count with differential
comprehensive metabolic profile, and coagulation studies.
19. This is necessary for determining diagnosis and prognosis.
Additional studies:
Chest radiography and echocardiography to determine a
patient's ability to receive potentially cardiotoxic
chemotherapy.
A cautious lumbar puncture may be needed if CNS
symptoms are identified.
Human leukocyte antigen (HLA) typing is needed if bone
marrow transplantation is being considered, and it should be
performed prior to myeloablation
20. Diagnostic evaluation
High index of suspicion
Physical evaluation
Blood and bone marrow
20% blasts, not 30% required for diagnosis
A bone marrow aspiration and biopsy should be evaluated by:
. cytochemistry
Immunophenotyping
Flow cytometry
Cytogenetics
21. Things used to be very simple!
TODAY
Flow cytometry immunophenotype
CD 34, 33,13,117 11b, 14
Cytogenetics
Molecular profiling
22. Cytogenetic risk stratification for overall
survival; Do we need it in Africa?
Favorable Risk
Balanced structural rearrangements
t(15;17) PMLRARA
t(8;21) RUNX1-RUNXT1
inv(16) CBFB-MYH11
Normal karyotype
Mutated NPM1 without FLT3-ITD
Mutated CEBPA
23. Intermediate risk
Balanced structural rearrangements
t(9;22) MLLT3-MLL
Cytogenetics abnormalities not classified as favorable or adverse
Adverse/Unfavorable Risk
Complex karyotype
Balanced structural rearrangements
inv(3) RPN1-EVI1
t(6;9) DEK-NUP214
t(v;11) MLL rearranged
25. Treatment steps
Induction = THE YOUNGER BROTHER OF MURDER.
Consolidation
Postconsolidation therapy
NCCN classifies patients into those <60 years and those ≥ 60
years.
This is controversial.
26. Views
AML should always be considered a medical emergency in
younger (age <60 years) adults, in whom each day of delay
in instituting definitive chemotherapy may compromise
survival.
? CONTROVERSIAL
27. Give me CR with frontline
chemotherapy if you care for me.
28. Should we send all to clinical
trials?
2013 NCCN guidelines - all cases of AML excluding APL
should be treated in the setting of an appropriate clinical
trial.
t-AML - poor prognosis, with median survival of only 8
months and 5-year survival less than 10%.
29. Humble request please
Good hygiene
Availability of platelets and blood at very short notice
Availability of effective antimicrobials
Dedicated, well-informed personnel
Laboratory capability to recognize bone marrow in
remission.
ON AVERAGE 30 UNITS OF BLOOD IN FIRST 21 DAYS
30. Induction chemotherapy(Attempted
murder)
The goal is to reduce the number of leukemic cells, as well as
to return proper function to the bone marrow.
Treatment of older AML patients is controversial.
They often cannot tolerate the toxicities of intensive
remission induction chemotherapy.
Ordinarily, the treatment-related mortality is between 15%
and 30%.
Other less intensive regimens that may be used are oral
agents (such as hydroxyurea), low dose cytarabine, or one of
the hypomethylating agents (azacitidine or decitabine
31. 3/7
For 4 decades - a combination of an
anthracycline/anthracenedione and cytosine
arabinoside, the 3/7 protocol.
An anthracycline ie:
- daunorubicin at 45-90 mg/m2 days 1-3
- Doxorubicin 30-35 mg/m2 iv days 1-3
-Cytarabine at 100-200 mg/m2 civi days 1-7 consecutive
days.
Idarubicin or mitoxantrone at doses of 10-12 mg/m2.
32. Caveats
AMLs are quite heterogeneous and the prognosis remains
poor.
Substituting daunorubicin with another anthracycline, or
addition of 6-thioguanine or etoposide has not been
demonstrated to improve outcome.
Current mechanism targeted therapies are not changing the
outlook for AML significantly.
Moreover, 3/7 is quite toxic and support after its
administration is highly costly: KShs1.7 M in 21 days
33. Treatment-related statistics for
AML stratified by age
Age (years)
<60 ≥60
Induction chemotherapy 7 + 3 7 + 3
Postremission chemotherapy HiDAC 5 or 5 + 2
Complete response rates (%) 60-85 40-55
Treatment-related mortality (%) 5-10 20-30
5-year disease-free survival (%) 30 5-10
Those are responses from the west and North
34. Is 3/7 optimized?
Factors that appear to have been ignored in formulation of
AML protocols are numerous
Cell cycle kinetics appear to have been given blackout in
formulation of these protocols
The AML stem cell tends to be resistant to chemotherapy.
At any one time there are about 20% of myeloid leukaemia
stem cells (G0) cells.
35. Participation of Cyclin-dependent Kinases (CDKs), Cyclin-dependent Kinase Inhibitors
(CKIs) and Retinoblastoma protein (RB) in cell cycle control.
(+) CDKS (cyclins D1, D2, D3, and E) P53 BRAKES
D/Cdk4 CAK activation induction
D/Cdk6 (-) CKIs Kip/cip (p21, p27, p57)
Rb pRb INK4(P15, p16, p18, p19)
DRIVE E2F release
cdc25+ D/cdk5 p16
Release of transcription factor E2F cdk1 M D/cdk4 p15
E2F response cyc A/B cyc D1
genes transcribed G2 G1 Rb p21
p53
S D/cdk2 p27
Cell cycle E/cdk2
Progression cdk7+ cdk1/2 cyc E
(G1-S exit) cyc H Cyc A +cdc25
36. Post remission therapy
Aims to eradicate any residual disease in an attempt at cure.
Includes HiDAC for patients younger than 60 year - yields a
4-year disease-free survival rate of 44%, but carries with it a
5% treatment-related mortality.
HiDAC failed to improve the outcome of patients older than
60 years
Can be associated with cerebellar, ophthalmologic, and
gastrointestinal toxicity, particularly in patients over the age
of 60 years.
37. Allogeneic bone marrow
transplantation: No free rides!
Is an additional option for postremission therapy in adults
with AML.
For adverse cytogenetics in patients < 60 years and for
whom an HLA-matched sibling or matched unrelated donor
is available.
This procedure is not without risk; it has an associated 20%
to 25% treatment-related mortality rate.
38. For paediatric ALL, survival outcomes have dramatically
improved over the last several decades mainly due to:
- advances in the understanding of the molecular genetics and
pathogenesis of the disease
- incorporation of risk-adopted therapy
-availability of new targeted agents.
39. With current treatment regimens, the cure rate among
children with ALL is about 80%.
The long-term prognosis for adults with ALL however
remains poor, with cure rates of only 30-40%.
40. Outcome of AML
Poor in older people because of:
Poor stem cell reserve
Higher frequency of co-morbidities
Intrinsic resistance to chemotherapy
Dismal in our country because of total lack of even the bare
minimum.
WHAT IS THE WAY FORWARD?