2. Chronic Myeloid Leukemia(CML)
• Chronic myeloid leukemia (CML)
was the first human malignancy to
be associated with a specific
genetic lesion, the Philadelphia
chromosome, harboring the BCR-
ABL oncogene.
• Its cytogenetic hallmark is a
reciprocal t (9;22) (q34; q11)
chromosomal translocation that
creates a derivative 9q+ and a small
22q–, known as the Philadelphia
(Ph) chromosome(3)
What is chronic myeloid leukemia(CML)?
3. Epidemiology
Incidence
• The incidence rate of CML is only 10 to 15 cases per 106 inhabitants per year(4). Only 15-20% of all leukemia
patients are diagnosed with CML(5).
• Male: Female =1.3:1
• rate is higher in adults
• The median age for the western patients diagnosis with CML is 55-65 years old, whereas less than 10% cases
are below 20 years of age.
• For the people of Asia, Africa, Eastern/Southern Europe and Latin American region, the median age for CML
in an average is 38-41 years(6).
Prevalence
• After the invention of targeted therapy (TKIs) the prevalence of CML patients has gradually increased(7)
4. Etiology
• Though the molecular pathogenesis of CML is well understood(8) but the mechanism that involves in
the gene translocation in CML is still unknown(9).
• high-dose ionizing radiation (not that much significant)
• There is no such strong evidence of inherited disposition or association with chemical exposure(10),
except a reported borderline increased risk of CML in first-degree relatives of patients with
myeloproliferative diseases(11).
5. Pathogenesis of CML
• Occur through well defined chromosomal abnormalities.
• Caused by a reciprocal translocation of the c-ABL (Abelson) gene on chromosome 9 and the BCR
(breakpoint cluster region) gene on chromosome 22 as t(9;22)(q34;q11).
• this rearrangement is well known as Philadelphia chromosome(Ph).
• This fused gene translates into a membrane-associated constitutively active protein tyrosine kinase
product BCR-ABL1 with an unregulated activity.
• Which leading to abnormal growth and division of the mutated cell and all resulting daughter cells
(3)
7. Sign and symptoms
• About 30-50% of the patients diagnosed with CML are asymptomatic(14).
• during the diagnosis, white blood cell (WBC) count may be found relatively low in these patients the
level of leukocytosis correlates with tumor burden(15).
• The symptoms of CML observed in chronic phase resulting from anemia and splenomegaly(14).
Common symptoms include fatigue, weight loss, malaise, left upper quadrant fullness or pain, and
easy satiety.
Rare symptoms include bleeding (associated with a low platelet count and/or platelet dysfunction),
gouty arthritis due to elevation of uric acid levels, thrombosis (associated with thrombocytosis and/or
marked leukocytosis), priapism (usually with marked leukocytosis or thrombocytosis), retinal
hemorrhages, upper gastrointestinal ulceration and bleeding from elevated histamine levels due to
basophilia.
8. Sign and symptoms
• Uncommon symptoms that observed in the CP are different leukostatic syndromes such
as loss of coordination, drowsiness, dyspnea, confusion due to sludging in the pulmonary
or cerebral vessels even though white blood cell (WBC) counts exceeding 100_109/L(14).
• Most common (detected in 50% to 60% of cases.) physical sign in CML is splenomegaly.
Sign and symptoms of accelerated or blastic phases of CML.
• Lymphadenopathy and infiltration of skin or other tissues.
9. Sign and symptoms
• During the CML transformation following symptoms are occurred frequently:
Headaches, bone pain, arthralgia, pain from splenic infarction, and fever.
• Almost 80% patients progress to acute phase prior to the blastic phase but
rest 20% evolve directly to BP without developing acute phase.
• worsening anemia, splenomegaly, and organ infiltration, fever, night sweat, weight loss, bone pain
are commonly observed symptoms in the acute phase(AP).
• Transformation of AP into BP associated with worsening constitutional symptoms, bleeding, fever,
and infections(14).
10. Diagnosis
ESMO (European Society for Medical Oncology) Clinical Practice Guidelines for diagnosis, treatment,
and follow-up suggested that (17):
RT-PCR: diagnosis must be confirmed by cytogenetics showing t (9; 22) (q3.4; q1.1), and by reverse
transcriptase-polymerase chain reaction (RT-PCR) showing BCR-ABL copies.
CBA : The cytogenetics must be performed by chromosome banding analysis (CBA) of marrow cell metaphases.
I-FISH: If marrow cells cannot be obtained, CBA can be substituted by interphase fluorescence in situ
hybridization (I-FISH) of blood cells.
Chromosome Banding Analysis is required to detect additional chromosome abnormalities but FISH is not required,
although it may require to identify some different translocations(18)
Qualitative RT-PCR (RT-Q-PCR) :To identify the chromosome transcript type, Qualitative RT-PCR (RT-Q-PCR) is
performed on RNA extracted from freshly collected blood cell or bone marrow sample.
11. Diagnosis
ESMO recommended baseline diagnaostic workup for CML are(17):
Name of the examination Baseline (diagnostic
workup)
Blood counts and differential Yes
Bone marrow, cytology Yes
Bone marrow, Karyotype
(CBA)
Yes
Blood, I-FISH No
Blood, RT-PCR (qualitative) Yes
Blood, RT-Q-PCR
(quantitative, BCR-ABL
%)
No
Mutational analysis Only in AP or BP
12. Staging
There are three stage of CML:
1. Chronic Phase (CP)
2. Accelerated Phase (AP)
3. and Blast Crisis (BC)
• Blood counts and differential are very important for the calculation of a prognostic risk and
for the distinction between chronic, accelerated and blast phases.
13. Staging
• Clinical and hematologic criteria for the definition of AP and BP according to WHO (21)and to ELN(22):
Accelerated phase
WHO(21) ELN (22)
Blast phase
WHO(21) ELN (22)
Spleen Persisting or increasing splenomegaly unresponsive to therapy / / /
WBC Persisting or increasing WBC (>10 × 109/l) unresponsive to therapy / / /
Blast cells 10%–19% 15%–29% ≥20% ≥30%
Basophils >20% >20% / /
Platelet count >1000 × 109/l uncontrolled by therapy
<100 × 109/l unrelated to therapy
/Yes /
/
/
/
CCA/Ph+ Present Present / /
Extra medullary
involvementb
/ / Present Present
14. Management and Treatment (17)(26)
• Treatment recommendations according to ESMO guideline(17)
Chronic phase
First line Imatinib 400 mg, or nilotinib 300 mg × 2, or dasatinib 100 mg
Second line In case of intolerance, switch to another TKI, taking into
consideration the side effects of the first TKI, and
comorbidities
In case of failure of imatinib, switch to nilotinib, or
dasatinib, taking into consideration the presence and the
type of BCR-ABL KD mutation
In case of failure of nilotinib or dasatinib, switch to
dasatinib or nilotinib, taking into consideration the
presence and the type of BCR-ABL KD mutation. Consider
alloHSCT
15. Management and Treatment (17)(26)
Third line In case of failure of two or three TKI, consider alloHSC
Accelerated/blastic phase
Accelerated/blastic phase
TKI naïve Imatinib 600 or 800 mg, or nilotinib 400 mg × 2 or dasatinib 140 mg,
and consider alloHSCT
TKI pretreated Switch to another TKI, consider chemotherapy and alloHSCT
16. Management and Treatment (17)(26)
• Treatment options based on bcr-abl1 mutation profile(26)
Mutation Treatment Recommendationl
Y253H, E255K/V, or F359V/C/I Dasatinib
F317L/V/I/C, T315A, or V299L Nilotinib
E255K/V, F317L/V/I/C, F359V/C/I,
T315A, or Y253H
Bosutinib
T315I Ponatinib,m Omacetaxine,n allogeneic HCT or clinical
trial
3. Melo J V, Hughes TP, Apperley JF. Chronic myeloid leukemia. Hematol Am Soc Hematol Educ Progr [Internet]. 2003 [cited 2017 Feb 23];2003(1):132–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14633780
4. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol. 2009;22(3):295–302.
5. Jordanides NE, Jorgensen HG, Holyoake TL, Mountford JC. Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate. Blood [Internet]. 2006 Aug 15 [cited 2017 Feb 16];108(4):1370–3. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2006-02-003145
6. Hegedus T, Orfi L, Seprodi A, Váradi A, Sarkadi B, Kéri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta [Internet]. 2002 Jul 18 [cited 2017 Feb 17];1587(2–3):318–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12084474
7. Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1–positive chronic myeloid leukemia. Blood. 2009;113(8).
9. Hehlmann R. Chronic myeloid leukemia [Internet]. 2016 [cited 2017 Feb 23]. Available from: https://books.google.com.bd/books?id=O8PeDAAAQBAJ&printsec=frontcover&dq=Chronic+myeloid+leukemia+Hehlmann,+Rüdiger.&hl=en&sa=X&ved=0ahUKEwjmicvzgqbSAhUQ4GMKHdVRCf4Q6AEIGjAA#v=onepage&q=Chronic myeloid leukemia Hehlmann%2C Rüdiger.&f=false
3. Melo J V, Hughes TP, Apperley JF. Chronic myeloid leukemia. Hematol Am Soc Hematol Educ Progr [Internet]. 2003 [cited 2017 Feb 23];2003(1):132–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14633780
14. Susan O’Brien, Julie M. Vose HMK, editor. Management of Hematologic Malignancies - Google Books [Internet]. Cambridge: Cambridge University Press,2010; 2010 [cited 2017 Feb 25]. 69 p. Available from: https://books.google.com.bd/books?id=kIZxSXRSSyIC&dq=sign+and+symptoms+of+CML&source=gbs_navlinks_s
17. Baccarani M, Pileri S, Steegmann J-L, Muller M, Soverini S, Dreyling M. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol [Internet]. 2012 Oct 1 [cited 2017 Feb 27];23(suppl 7):vii72-vii77. Available from: https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mds228
17. Baccarani M, Pileri S, Steegmann J-L, Muller M, Soverini S, Dreyling M. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol [Internet]. 2012 Oct 1 [cited 2017 Feb 27];23(suppl 7):vii72-vii77. Available from: https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mds228
21. Vardiman JW, PJ M, V N, SH S, E C, NL H. Chronic Myelogenous Leukemia, BCR - ABL1 +. Am J Clin Pathol [Internet]. 2009 Aug 1 [cited 2017 May 4];132(2):250–60. Available from: https://academic.oup.com/ajcp/article-lookup/doi/10.1309/AJCPUN89CXERVOVH
22. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic Myeloid Leukemia: An Update of Concepts and Management Recommendations of European LeukemiaNet. J Clin Oncol [Internet]. 2009 Dec 10 [cited 2017 May 4];27(35):6041–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19884523
17. Baccarani M, Pileri S, Steegmann J-L, Muller M, Soverini S, Dreyling M. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol [Internet]. 2012 Oct 1 [cited 2017 Feb 27];23(suppl 7):vii72-vii77. Available from: https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mds228
26. Chen Y, Li D, Li S. Chronic Myeloid Leukemia. Cell Cycle. 2009;8(21):3488–92.
17. Baccarani M, Pileri S, Steegmann J-L, Muller M, Soverini S, Dreyling M. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol [Internet]. 2012 Oct 1 [cited 2017 Feb 27];23(suppl 7):vii72-vii77. Available from: https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mds228
26. Chen Y, Li D, Li S. Chronic Myeloid Leukemia. Cell Cycle. 2009;8(21):3488–92.
lPatients with disease that is resistant to primary treatment with imatinib should be treated with nilotinib, dasatinib, or bosutinib in the second-line setting. Patients with disease that is resistant to primary treatment with nilotinib or dasatinib could be treated with an alternate TKI (other than imatinib) in the second-line setting.
mPonatinib is a treatment option for patients with a T315I mutation or for patients for whom no other TKI is indicated
nOmacetaxine is a treatment option for patients with disease that is resistant and/or intolerant to 2 or more TKIs.
17. Baccarani M, Pileri S, Steegmann J-L, Muller M, Soverini S, Dreyling M. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol [Internet]. 2012 Oct 1 [cited 2017 Feb 27];23(suppl 7):vii72-vii77. Available from: https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mds228
26. Chen Y, Li D, Li S. Chronic Myeloid Leukemia. Cell Cycle. 2009;8(21):3488–92.