This document summarizes information about chronic myeloid leukemia (CML), including its history, clinical presentation, diagnosis, treatment and case study. It notes that CML is characterized by the Philadelphia chromosome, which was first observed in 1960. Most patients present with fatigue and splenomegaly and are diagnosed via blood tests showing leukocytosis. Treatment of chronic phase CML initially involves tyrosine kinase inhibitors like imatinib or nilotinib, with the goals of achieving complete hematological and cytogenetic responses and major molecular response. A case study described a 35-year-old female patient who achieved MR4 status after 6 months of nilotinib treatment with no side effects.

1. Chronic myeloid leukaemia

2. Rudolf Virchow (1821-1902)

3. Chronic myeloid leukaemia
In 1960, two physicians
studying chromosomes in
cancer cells noticed that a
chromosome in CML
patients was shorter in
length than that of the
same chromosome in
normal cells. They named
this shortened chromosome
the Philadelphia
chromosome, because the
observation was made at
the University of
Pennsylvania School of
Medicine in that city.
Janet Rowley
Peter Nowell

4. Philadelphia

5. Clinical Presentation of CML
Most patients are diagnosed via routine blood tests1,2
Up to half (50%) of patients are asymptomatic at presentation2
5

6. CML – clinical presentation

7. Chronic myeloid leukaemia
CAT scan
Very large spleen

8. Natural History :
Biphasic or triphasic disease –chronic phase, accelerated phase
and blast crisis;
Accelerated phase characterised by blood counts and
organomegaly becoming increasingly refractory to therapy;
Blast crisis resembles acute leukaemia with > 20% blasts and
promielocytes in blood or marrow; rapidly fatal.

9. Clinical Course: Disease Progression
(untreated)1,2
1. Faderl S, Talpaz M, Estrov Z, et al. N Engl J Med. 1999;341:164-172.
2. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Ann Intern Med. 1999;131:207-219.
9

10. Chronic myeloid leukaemia
Clinical features:
Wt loss, lassitude anorexia night sweats
Splenomegaly
Anaemia pallor dyspnea tachycardia
Bruising epistaxis menorrhagia
Gout renal impairment
Incidental finding (CBC)

11. Clinical symptoms and signs :
30% asymtomatic at diagnosis;
Fatigue, lethargy, weight loss, sweats;
Splenomegaly in > 75% - may cause hipocondrial pain, satiety,
sensation of abdominal fullness;
Gout, bruising / bleeding, sometimes splenic infarction;
Signs include moderate to large splenomegaly , hepatomegaly,
lymphadenophaty unusual;

12. Chronic myeloid leukaemia
Laboratory findings:
Leukocytosis >50 x 109
/L-500
Spectrum of myeloid cells
Neutrophils myelocytes exceed blasts and
promyelocytes
Increased basophils
Anaemia
Hypercellular marrow
Ph chromosome

13. Diagnosis and investigation :
Bone marrow shows marked hypercellularity due to myeloid
hyperplasia ( blasts < 10% in chronic phase; > 10% in accelerated
phase; > 20% blasts + promyelocytes = blast crisis)
Cytogenetic examination of blood or marrow for confirmatory
Cr.Ph ( t 9;22 )
Molecular analysis by real time quantitative reverse transcription
polymerase chain reaction (RT-PCR) for BCR-ABL transcripts
to obtain baseline for subsequent monitoring;
FISH analysis of blood or marrow will confirm presence of BCR-
ABL.

14. Chronic myeloid leukaemia
Hypercellular marrow
Myeloid cells
All stages
Shift to early forms
Less than 20% blasts

15. he Philadelphia Chromosome Chronic myeloid leukaemia

16. Tablou hematologic caracteristic FISH
Real-Time PCR Determinarea locurilor de rupere
e1 b2 a2
b2a2 p210
e1 b2 b3 a2
b3a2 p210
a2
a2
e1
e1a2 p190
e19a2 p230
e1 e19
Citogenetica convenţională
Secvenţierea

17. Differential diagnosis :
Differentiate chronic phase in CML from :
1. Leukaemoid reaction due to infection, inflammation or
carcinoma:
are usually transitory,
have a temporal cause (severe infection, steroids, stress),
have modest increases in the leukocyte count of up to 50 x 109
/L with
toxic granulocytic vacuolation and Döhle bodies in granulocytes,
normal or elevated ALP.
absent Ph chromosome ;
2. CMML ( chronic myelomonocytic leukaemia ) :
- absolute monocytosis;
- trilineage myelodisplasia;
- absent Ph chromosome .
3. Corticosteroid drugs may rarely produce left-shifted
extreme neutrophilia.

18. Differential diagnosis :
4. Essential thrombocythaemia :
- 5% of CML present with predominant of
thrombocytosis and must be differentiated from ET
( NAP increase or normal absent Ph chromosome ).
5. Myelodysplastic or myeloproliferative syndromes:
myelodysplastic syndrome,
agnogenic myeloid metaplasia (MMM),
policitemia vera,

19. Treatment of chronic phase :
Allogeneic SCT is the only curative treatment but carries
significant morbidity and mortality.
Important that each patient is aware of treatment options, risks and
benefits
Imatinib 400mg PO once daily –first line treatment of choice in
newly diagnosed patients in chronic phase, continue to intolerance,
failure or sub optimal response;
Commonest side effects: myelosuppresion, oedema, rash, cramps,
fatigue, diarrhoea, headache, arthralgia.

20. Treatment of chronic phase :
Other agents:
- Dasatinib for patients with CML no longer responding to or
intolerant of Imatinib. Dose : 70mg twice daily.
- Nilotinib orally active (400mg twice daily);highly selective
inhibitor of BCR-ABL tyrosine kinase, 20-50 more potent than
Imatinib.
Hydroxycarbamide may be used to control leucocytosis or
thrombocytosis and reduce spleen size in chronic phase.
Interferon α at dose of 3 million IU SC 3 times weekly corrects
haematological abnormalities in 75% and produce 10-15%CCyR
and 15-30%MCyR.

21. Taken from Michael Mauro presentation, ASCO 2010
Melo JV, Goldman JM. Myeloproliferative Disorders: Hematologic Malignancies. 7th ed.Springer, PA: Springer, 2007;
Nowell & Hungerford, Science 1960;132:1497; Rowley JD. Nature 1973;243:290–93.

22. Definition of response to treatment :
Goals of therapy in order are :
- Complete haematological response,
- Complete cytogenetic response,
- Major molecular response and
- Complete molecular response.

23. Chronic myeloid leukaemia
Death caused by:
Acute transformation
Haemorrhage
Infection

24. CML
Case report

25. B.M. , Female, 35 years old.
Urban area.
Without professional exposure to toxics.
Symptoms and signs: fatigue, night sweats ,
hipocondrial pain, weight loss 5kg in 4 months.
HCA : insignificant.
PPA : insignificant.
Clinical examination: - pallor
- Splenomegaly .

26. Laboratory investigations
CBC : -L=55.000/mmc
Left-shifted leukocytosis
-RBC=3.960.000/mmc, HB=10,7 g/dl
MCV=93,2 fl, MCH=29,3pg, MCHC=31,5 g/dl,
Reticulocite=8 ‰
-Tr = 370.000/mmc
Coagulation tests: D-Dimer =320ng/ml
Biochemical tests : Normal
Urinary infection – Proteus Mirabilis

28. Positive diagnosis
Chronic myeloid leukaemia, chronic phase,
chromosome Philadelphia (Ph1) positive.
Differential diagnosis
 Other Mieloproliferative Syndromes
 Acute Leukaemia/ Leukaemoid reaction
 Myelodysplastic Syndrome

29.  It was administrated treatment with Hydreea,
cps 500mg, 3cps/day(1.5g)
 Stopped after the appearance of
myelosuppresion .
 After three months it was initiated Tasigna
(Nilotinib) cp 150mg, 2x2cp/day.
Treatment

30. Nilotinib 1st
line
EVALUATION HR RCy MR
3 MONTHS L=4.250/mmc,
LF- normal,
HB=10.6g/dl,
Tr=162.000/mmc
complete
-
6 MONTHS Complete complete Bcr-Abl major
=0,00516 % IS , MR4
12 MONTHS Complete
complete
Bcr-Abl major
=0,004% IS, MR4

31. Conclusions
The response to treatment was positive
After 6 months of treatment, MR4 results were
obtained, without any secondary effects.
The tolerability and compliance is very important
in order to obtain a positive result.