MULTIDISCIPLINARY APPROACH

TO THE MANAGEMENT OF

LEUKEMIAS- AML/MDS

DR. R. RAJKUMAR M.D., D.M.

ASST PROF

MADURAI MEDICAL COLLEGE &

CONSULTANT MEDICAL ONCOLOGIST

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

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

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

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%

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.

QUESTION

1. Cytochemistry

2. Periphereal blood flowcytometry

3. Bone marrow flowcytometry

4. All the above

FLOW CYTOMETRY

FLOW CYTOMETRY

QUESTION

FURTHER EVALUATION-

1. B.M. CYTOGENETICS - FISH

2. MOLECULAR DIAGNOSTICS-RT PCR

3. L.P.

4. 1&2

5. ALL THE ABOVE

AML ClassificationFAB 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

AML ALOGORITHM

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

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.

Heterogeneity within Cytogenetically

Normal AML Category

Gene Mutation Prognostic ImpactNPM1 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

Impact of Gene Expression in

Cytogenetically Normal AML Category

Gene Impact of

Overexpression

BAALC Unfavorable

ERG Unfavorable

MN1 Unfavorable

Mir181 Favorable

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

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

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

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.

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

Current Role of Allografts for

AML Patients <60 years in CR1

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

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

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.

What recommendations should

be made for Flt3 ITD group?

• Should all of these patients be referred for

allograft? On what basis?

Lestaurtinib Midostaurin Tandutinib

QuizartinibSunitinib Sorafenib

Prescott H, et al. Expert Opin Emerg Drugs. 2011;16:407-423.

FLT3 Kinase Inhibitors

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)

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

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