1. MULTIDISCIPLINARY APPROACH
TO THE MANAGEMENT OF
LEUKEMIAS- AML/MDS
DR. R. RAJKUMAR M.D., D.M.
ASST PROF
MADURAI MEDICAL COLLEGE &
CONSULTANT MEDICAL ONCOLOGIST

2. CASE HISTORY
MR. X 68/M
PRESENTING C/O FEVER, FATIGUE - 20DAYS
O/E– pallor +
Comorbidities- Nil
P.S. 1
COMPLETE HAEMOGRAM-
HB—7.6
TOTAL WBC COUNT -1300
D.C. – P-20%, L-76%, E- 04%, M-00%
PLATELET—1.04 LAKHS/cu mm
PACKED CELL VOL- 25.7%
MCV- 101.8 fl
MCH- 30.0 pg
RED BLOOD CELL COUNT- 2.53 million

3. LAB0RATORY VALUES
UREA- 30.0
CREATININE- 0.90
TOTAL BILIRUBIN- 0.70
DIRECT- 0.30
INDIRECT-0.40
SERUM ELECTROLYTES
SODIUM- 149
POTASSIUM- 4.0
CHLORIDE-106

4. PERIPHEREAL SMEAR
RBCS SHOW MICROCYTES AND
NORMOCHROMIC NORMOCYTE
WBCS SHOW LEUKOPENIA. OCC ATYPICAL
CELLS SEEN.PLATELETS ARE REDUCED.
BONE MARROW
PARTICLES: APARTICULATE
CELLULARITY: HYPOCELLULAR
MEGAKARYOCYTES: NOT SEEN
NONERYTHYROID:ERYTHROID RATIO
>100:1

5. BONE MARROW
DIFFERENTIAL COUNT:
BLASTS: 73%
PROMYELOCYTES: 00%
MYELOCYTES: 01%
METAMYELOCYTES: 01%
POLYMORPHS: 02%
LYMPHOCYTES: 23%
PLASMA CELLS: 00%
EOSINOPHILS : 00%
MONOCYTES:00%
ERYTHROID: 00%

9. BONE MARROW
MORPHOLOGY: Blasts are 2-3 times the size
of lymphocytes with high N:C ratio, opened
up chromatin , 1-2 conspicuous to
prominent nucleoli, nuclear foldings,
nuclear groovings and moderate agranular
basophilic cytoplasm with absence of auer
rods.
IMPRESSION:
SUGGESTIVE OF ACUTE MYELOID
LEUKEMIA.

10. QUESTION
1. Cytochemistry
2. Periphereal blood flowcytometry
3. Bone marrow flowcytometry
4. All the above

11. FLOW CYTOMETRY

12. FLOW CYTOMETRY

16. QUESTION
FURTHER EVALUATION-
1. B.M. CYTOGENETICS - FISH
2. MOLECULAR DIAGNOSTICS-RT PCR
3. L.P.
4. 1&2
5. ALL THE ABOVE

18. AML Classification
FAB Classification
M0 Minimally differentiated
M1 Without maturation
M2 With maturation
M3 Acute promyelocytic leukemia
M4 Acute myelomonocytic leukemia
M5 Acute monoblastic leukemia
M6 Acute erythroleukemia
M7 Acute megakaryoblastic leukemia
2008 WHO Classification

19. AML ALOGORITHM

23. Prognostic/predictive factors in
AML
Factor Comment
Age Major impact at diagnosis
WBC Continuous variable
Prior therapy or MDS? Karyotype may be more important
Extramedullary disease Variable
Day 14 blast count Higher percentage worse
# cycles of induction One better than two
Cytogenetic/molecular profile Major Impact at diagnosis
Gene expression profile Can further subdivide patients
MicroRNA expression Needs validation by other groups
Gene sequencing Future application
MRD detection at CR ??; seems like it should be useful

26. Molecular Profiles of
Cytogenetically Normal AML
Döhner H, et al. Blood. 2009 Oct 30. [Epub ahead of print]. This research was originally published in Blood. © 2009
the American Society of Hematology.

27. Heterogeneity within Cytogenetically
Normal AML Category
Gene Mutation Prognostic Impact
NPM1 Favorable in absence of
Flt3 ITD
Flt3 ITD/allele ratio Unfavorable
Flt3 TKD Controversial
CEBPA Favorable
MLL PTD Unfavorable
Ras Neutral
WT-1 Controversial
Runx1 Unfavorable

28. Impact of Gene Expression in
Cytogenetically Normal AML Category
Gene Impact of
Overexpression
BAALC Unfavorable
ERG Unfavorable
MN1 Unfavorable
Mir181 Favorable

29. Current State of AML Therapy
• Excluding the roughly 20-30% of good
risk patients, 40-90% of younger
patients (age 18-59) achieving
remission are destined to relapse

30. Current State of AML Therapy
• Excluding the roughly 20-30% of good
risk patients, 40-90% of younger
patients (age 18-59) achieving
remission are destined to relapse
• All but a very select subset of older
AML patients (> 60) will die due to
relapsed or refractory disease

31. QUESTION
Which of the following option would be
your choice for initial treatment in this
patient
1. 3+7 regimen
2. high dose cytarabine+ idarubicin
3. ADE(3+7+Etop)
4. 3+7 plus cladribine
5. Low dose cytrabine

34. Recent Randomized Trials of Dose-
Intensification in AML
• ECOG E1900: daunorubicin 90 mg/m2 x 3 superior to 45
mg/m2 x 3 in pts < 60 yrs[1]
– But not in patients with adverse cytogenetics, FLT3-
ITD, or aged 50 yrs or older
• HOVON: daunorubicin 90 mg/m2 x 3 = 45 mg/m2 x 3 in
pts ≥ 60 yrs[2]
– But superior in patients aged 60-65 yrs
• ALFA-9801: idarubicin 12 mg/m2 x 3 and x 4 superior to
daunorubicin 80 x 3 for CR[3]
– But not for EFS and OS
• MRC AML15: more durable CR in patients receiving
FLAG-Ida than ADE/DA[4]
– But higher initial toxicity
• HOVON: high-dose cytarabine = intermediate-dose
cytarabine in induction[5]
– Unknown whether intermediate dose = “standard
dose”
1.

35. QUESTION
Which Consolidation Regimen would you
choose?
1. 3-4 cycles of high dose cytrabine
2. 5+2 regimen
3. Allogenic stem cell transplantation
4. Autologous stem cell transplantation

43. Current Role of Allografts for
AML Patients <60 years in CR1

44. Current Role of Allografts for
AML Patients <60 years in CR1
• Adverse risk cytogenetics
– Most agree allograft appropriate
consolidation at least up to 55-60 years of
age

45. Current Role of Allografts for
AML Patients <60 years in CR1
• Adverse risk cytogenetics
– Most agree allograft appropriate consolidation at
least up to 55-60 years of age
• Favorable risk cytogenetics
– No role in general
• Intermediate risk cytogenetics
– This is where it gets complicated
– Recent meta-analyses suggest benefit
• Cornellison et al, Blood, 2007
• Koreth at al, JAMA, 2009

46. BMT versus Conventional therapy for
AML with normal cytogenetics
Schlenk RF, et al. New Engl J Med. 2008;358:1909-1918. Reprinted with permission © 2009 Massachusetts Medical
Society.

47. What recommendations should
be made for Flt3 ITD group?
• Should all of these patients be referred for
allograft? On what basis?

48. Lestaurtinib Midostaurin Tandutinib
QuizartinibSunitinib Sorafenib
Prescott H, et al. Expert Opin Emerg Drugs. 2011;16:407-423.
FLT3 Kinase Inhibitors

49. What defines a “suitable donor” allograft for a
high risk AML patient in first remission?
 Matched sibling: Yes
 Matched unrelated donor: Yes
 Mismatched unrelated donor (KIR mismatched?)
– Cooley et al, Blood, 2009
 Mismatched umbilical cord blood?
– Gutman et al, BBMT, 2009
 Haploidentical related?
– Perugia approach (ex vivo T-cell depletion)
– Hopkins approach (in vivo alloreactive T-cell depletion)

52. Acute Promyelocytic Leukemia (M-3)
• A) a severe bleeding tendency due to
fibrinogenopenia and disseminated intravascular
coagulation
• (B) accumulation of abnormal promyelocytes in bone
marrow and chromosomal translocation
t(15;17)(q22;q21)
• (C) with the resultant fusion transcripts between PML
and RAR detected by FISH using PML-RAR dual-
color, dual-fusion translocation probes
• D) Schematics representing the formation of 15;17
reciprocal chromosomal translocations and fusion
transcripts

57. ROLE OF SUPPORTIVE CARE
Will you use G-csf in AML ?
1. Prophylactically
2. Myelosupresssion following chemo
3. Fear of Clonal Myeloproliferation
Will you use ESA ?
1. HB- <10%
2. HB- <8%
3. Only if donor unavailable