This document describes a case of a 50-year-old male presenting with abdominal discomfort and fever for several months. Examination revealed splenomegaly. Investigations showed elevated white blood cell count with blasts. Bone marrow biopsy demonstrated features of chronic myeloid leukemia in accelerated phase. The patient was positive for the Philadelphia chromosome translocation. The document then provides details on the definition, epidemiology, pathogenesis, classification, clinical features, diagnosis, treatment and prognosis of chronic myeloid leukemia.

1. CHRONIC MYELOID LEUKEMIA

2. 50 yrs /M
Dharan
office worker
M.opd
-abdominal discomfort-3months
- fever-1 month
Past history
-No h/o TB/DM/HTN/IHD
Personal history
-mixed diet
- alcohol on and off
-non-smoker
Family history
- No h/o TB/DM/HTN
Treatment history
not on any treatment
O/E-conscious,oriented
P-/I-/Cy-/Clu-/ED-/Lym-
B.P.-130/70 mm Hg
pulse-110/min
• GI- spleenomegaly 6 cm
below LCM
• CVS- WNL
• RS- WNL
• CNS-WNL

3. • Imp.- Spleenomegaly-cause under evaluation
D/D- 1.Chronic malaria
2.Kala-azar
3.Haematological malignancy

4. Investigations
• CBC-Hb.-13gm%
• TLC-23,200
• DLC-N80L20
• P.C.-75000
• PS for MP/Optimal for MP-
Negative
• rk39-Negative
• Blood C/S- sterile after 48
hrs
• LFT- T.protein-6.4gm
albumin-3.5gm
SGOT/PT-25/15
• Sr.bilirubin-0.8 (T)
-0.2 (C)
• Blood urea-47
• Sr.creatinine-0.8
• Urine R/E- wnl

5. • USG-abdomen- massive spleenomegaly
• PS for cytology- showed leucocytosis with 15% blasts. Blast
cells are large,2-3 times the size of small lymphocyte with
enlarged nucleus, irregular nuclear membrane, opened up
chromatin, 1-3 prominent nucleoli and scant number of
cytoplasm.
Features suggestive of chronic myeloid leukaemia.

6. • Bone marrow aspiration-
-hypercellular (70% celllularity)
- myeloid-erythroid ratio 10:1.
- myelopoeisis - increased
- predominance - myelocytes
-promyelocytes,
- blasts (18%).
Imp.- CML IN accelerated phase
• Fluorescence in-situ Hybridization
- specimen positive for t(9;22)

7. CHRONIC MYELOID LEUKAEMIA

8. Chronic myeloid leukaemia is also known as
• Chronic myelogenous leukaemia
• Chronic granulocytic leukaemia
• Chronic myelocytic leukaemia

9. Definition
A myeloproliferative stem cell disorder resulting
in proliferation of all haematopoietic lineages but
manifesting predominantly in granulocytic series.(1)
Incidence
-1.5 per 100,000 people per year
- M:F =1.9:1.1
- Age group -30-80yrs
- peak incidence at 55 yrs. (2)

10. Etiology
No clear etiology has been found for CML
Radiation
Cigarette smoking
Chemicals

11. Pathophysiology
• First malignancy to be linked to a clear genetic
abnormality
• chromosomal translocation- Philadelphia
chromosome.
• reciprocal translocation-t(9;22).
• BCR-ABL fusion gene
• chimeric gene
• fusion proteins -p210,p230

13. Classification
1.Chronic phase
2.Accelerated phase
3.Blast crisis

14. The WHO criteria:
Accelerated phase
1.10–19% myeloblasts in the blood or bone marrow
2.>20% basophils in the blood or bone marrow
3.Platelet count <100,000, unrelated to therapy
4.Platelet count >1,000,000, unresponsive to therapy
5.Cytogenetic evolution – development of chromosomal
abnormalities other than philadelphia chromosome.

15. Blast crisis
1.>20% myeloblasts or lymphoblasts in the blood or
bone marrow
2.Large clusters of blasts in the bone marrow on biopsy
3.Presence of extramedullary blastic infiltrates
myeloid sarcoma, also k/a granulocytic sarcoma or
chloroma.

16. Clinical features
Asymptomatic
Fatigue
Malaise
Weight loss
Fever
Left upper quadrant pain and/or mass
Early satiety
Bone pain and joint pain
Infections, thrombosis or bleeding
Signs:
Pallor
Spleenomegaly
Hepatomegaly
Lymphadenopathy

17. Diagnosis
CBC-increased white blood cell counts.
- Platelet count elevated at the time of diagnosis.
PS for cytology -
- <5% circulating blasts
- <10%Circulating blasts and promyelocytes.
-Normocytic normochromic anaemia
Bone marrow aspiration-hypercellular bone marrow
with an increased myeloid to erytheroid ratio.

18. • Acceleration phase-
– blood or marrow blasts between 10-20%,
– blood or marrow basophils between >= 20%
– platelet count <100000/microlitre
• Blast crisis-
– blood or marrow blasts>=20%
– Hyposegmented neutrophils (Pelger –Huet
anomaly)

19. • Chromosomal findings
– Evidence of translocation
– Molecularly or by cytogenetics
– FISH.

21. Treatment
1.Tyrosine kinase inhibitors (TKI’s)
2.Allogenic haematopoeitic cell transplantation
(HCT)
3. Plliative therapy with cytotoxic agents.(3)

22. • Tyrosine kinase inhibitors
• Imatinib- First generation Tyrosine kinase
inhibitor
Dose -400mg/day
Other newer agents:
Nilotinib - 400 mg P.O. BD
Dasatinib - 100 mg P.O. OD
Bosutinib - 500 mg P.O. OD
Ponatinib - 45 mg P.O. OD

23. Allogenic HCT
-Proven curative treatment
Favourable prognostic factors
a) Transplantation in chronic phase
b) Young age (<35 yrs )
c) Early transplantation ( </= 12 months of
diagnosis )
d)CMV seronegative patients
e) Grade 0-II acute GVHD.

24. • Minimal residual disease
• BCR-ABL 1 transcripts denote the burden of
disease.
• Slow reduction – increased chance of
haematological relapse

25. Treatment of relapse after HCT
• Donor leukocyte infusions
• Imatinib

26. • Treatment of CML according to phase
• 1.Chronic phase
• Two main options are:
1.Tyrosine kinase inhibitors.
2.Allogenic haematopoeitic cell
transplantation

27. Accelerated phase
• Transplantation after the best response has
been achieved by TKI
• Initial treatment with a TKI followed by
another TKI at relapse followed by
transplantation.

28. Blast crisis
Two major forms
a)Myeloid (70%)
b)Lymphoid (30 %)

29. • Myeloid form
- doesnot respond to standard AML induction
regimens
-TKI’s alone or in combination with
chemotherapy followed by HCT.
Lmphoid form
- responds to chemotherapy used for ALL
combined with TKI’s.
vincristine, prednisone, and doxorubicin, along
with imatinib(50% remission)

30. Responses
• Haematological response
- WBC,DLC and Platelet count.
Complete haematological response-
WBC-<10000/microL with no immature
granulocytes
DLC-< 5% basophils
P.C.-<<450,000/microL

31. • Cytogenetic response – assesed by bone
marrow biopsy
• Complete cytogenetic response
- no Philadelphia positive chromosomal cells
Partial cytogenetic response
-1-35% Philadelphia positive chromasomal cells
Major cytogenetic response

32. Major cytogenetic response
- includes partial and complete cytogenetic
response
- 0-35% Philadelphia positive chromosomal
cells
Minor cytogenetic response
-36-65% philadelphia positive chromosommal
cells

33. Minor cytogenetic response
- 36-65% Philadelphia positive chromossomal
cells
No cytogenetic response
- > 95% Philadelphia positive chromosomal cells

34. • Molecular response – based on PCR
Major molecular response
- ratio of BCR-ABL transcript to housekeeping genes
=< 0.1% (=> 3 log reduction) on
International Scale (IS)
Complete molecular response
- BCR-ABL transcript not detectable and non
quantifiable in an assay that have 4-5 log range
of detection on two consecutive samples.

35. • Monitoring response to therapy
• NCCN
TIME MONTHS Expected Failure
3 Complete haematologic
remission
No complete haematologic
remission
6 Any cytogenetic remission No cytogenetic remission
12 Complete or partial
cytogenetic remission
Minor or no cytogenetic
remission
18 Complete cytogenetic
remission
Partial minor or no
cytogenetic remission

36. • ELN
TIME MONTHS SUBOPTIMAL FAILURE
3 Minor cytogenetic
remission
No cytogenetic remission
6 Partial cytogenetic
remission
Minimal cytogenetic
remission
12 Less than major
molecular response
Less than partial
cytogenetic
remission;new mutations

37. PROGNOSTIC FACTORS
• SOKAL INDEX-
• based on patients treated with chemotherapy
• Includes - % of circulating blasts
- spleen size
- platelet count
- age
- cytogenetic clonal evaluation

38. • Hasford Index
• based on patients treated with Interferon
alpha
• Includes - % of circulating blasts
- spleen size
- platelet count
- age
- % of basophils and eosinophils

39. RELATIVE RISK
SOKAL
EXPONENTIAL OF TOTAL
PARAMETRS
HASFORD
EXPONENTIAL OF TOTAL
PARAMETERS X 100
LOW RISK < 0.8 </= 780
INTERMEDIATE RISK 0.8-1.2 781-1480
HIGH RISK >1.2 >1480

40. MEDIAN SURVIVAL(10 yrs) SOKAL HASFORD
LOW RISK 34% 37%
INTERMEDIATE RISK 28% 16%
HIGH RISK 8% 0%

41. • Interferon alfa
• In the past, interferon alfa was the treatment
of choice for most patients with CML who
were too old for bone marrow transplantation
(BMT) or who did not have a matched bone
marrow donor.

42. • Chemotherapy
formerly the mainstay of treatment to convert a
patient with CML from an uncontrolled initial
presentation to one with hematologic remission
Agents-
1.Hydroxyurea -0.5-2 gm/day
2.Busalfan – 4 mg/day
• Autologus HCT
No longer recommended

43. • Leukapheresis
Leukapheresis using a cell separator can lower
WBC counts rapidly and safely in patients with WBC
counts greater than 300,000 cells/µL, and it can
alleviate acute symptoms of leukostasis,
hyperviscosity, and tissue infiltration.
• Leukapheresis usually reduces the WBC count
only temporarily. Thus, it is often combined with
cytoreductive chemotherapy for more lasting
effects

44. T3151 MUTATION
• patients have several point mutations at and around
the ATP binding pocket of the ABL kinase domain in
BCR-ABL
In order to address the resistance of mutated BCR-ABL
to imatinib, 2(nd) generation inhibitors such as
dasatinib, and nilotinib were developed. These
compounds were approved for the treatment of CML
patients who are resistant to imatinib. All of the BCR-
ABL mutants are inhibited by the 2(nd) generation
inhibitors with the exception of the T315I mutant

45. • Treatment of T3151 mutant and who failed
All currently available Tyrosine kinase inhibitors:
1.Omacetaxine
2.XL228
3.FTY720
4.AP24534
5.DCC -2036
6.PH-739358
7.Sorafenib.

46. • Splenectomy and splenic irradiation have
been used in patients with large and painful
spleens, usually in the late phase of CML.

47. RECENT advances:
• can treatment be stopped?
complete molecular response (CMR) for at least 2 years
while taking imatinib could safely stop drug treatment .
Results showed that a little less than half of the
patients who stopped were still without any signs of
disease (and still in CMR) 12 months later. But, imatinib
worked again for the patients whose CML came back.
This approach is being studied with other TKIs, as well.
• More research is needed to see if which CML patients
can safely stop taking TKI.(4)

48. New drugs for CML
• Farnesyl transferase inhibitors
-lonafarnib and tipifarnib.
• Histone deacetylase inhibitor
-panobinostat
• Proteasome inhibitor-
-bortezomib (Velcade).(4)

49. CANCER VACCINE
• In one small study, a vaccine
called CMLVAX100 was given along with imatinib
and seemed to increase its effectiveness.
• Research into this and other vaccines
iscontinuing.(5)

50. • REFERENCES
1.DAVIDSON’s PRINCIPLE AND PRACTICE OF MEDICINE
2.HARISONS PRINCIPLES OF INTERNAL MEDICINE
18 th Edition(chapter 109, Meir Wetzler, Guido
Marcucci, Clara D. Bloomfield)
3.UP TO DATE – OVERVIEW OF TREATMENT OF CML
4. AMERICAN CANCER SOCIETY ,www. Cancer.org
5. www.cancerworld.com, fda news