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Chronic myelogenous leukemia

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Chronic myelogenous leukemia

Classification and external resources

The Philadelphia chromosome as seen by metaphase FISH.

ICD-10 C92.1

ICD-9 205.1

ICD-O: M9875/3

DiseasesDB 2659

MedlinePlus 000570

eMedicine med/371

MeSH D015464

Chronic myelogenous (or myeloid) leukemia (CML), also known as chronic
granulocytic leukemia (CGL), is a form of leukemia characterized by the increased
and unregulated growth of predominantly myeloid cells in the bone marrow and the
accumulation of these cells in the blood. CML is a clonal bone marrow stem cell
disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and
basophils) and their precursors is the main finding. It is a type of myeloproliferative
disease associated with a characteristic chromosomal translocation called the
Philadelphia chromosome. Historically, it has been treated with chemotherapy,
interferon and bone marrow transplantation, although targeted therapies introduced at
the beginning of the 21st century have radically changed the management of CML.

Contents
[hide]

• 1 Signs and symptoms
• 2 Diagnosis
• 3 Pathophysiology
• 4 Classification
o 4.1 Chronic phase
o 4.2 Accelerated phase
o 4.3 Blast crisis
• 5 Treatment
o 5.1 Chronic phase
• 6 Prognosis
• 7 Epidemiology
• 8 References

• 9 External links

[edit] Signs and symptoms
Patients are often asymptomatic at diagnosis, presenting incidentally with an elevated
white blood cell count on a routine laboratory test. In this setting, CML must be
distinguished from a leukemoid reaction, which can have a similar appearance on a
blood smear. Symptoms of CML may include: malaise, low-grade fever, gout,
increased susceptibility to infections, anemia, and thrombocytopenia with easy
bruising (although an increased platelet count (thrombocytosis) may also occur in
CML). Splenomegaly may also be seen.[1][2]

[edit] Diagnosis
CML is often suspected on the basis on the complete blood count, which shows
increased granulocytes of all types, typically including mature myeloid cells.
Basophils and eosinophils are almost universally increased; this feature may help
differentiate CML from a leukemoid reaction. A bone marrow biopsy is often
performed as part of the evaluation for CML, but bone marrow morphology alone is
insufficient to diagnose CML.[2][3]

Ultimately, CML is diagnosed by detecting the Philadelphia chromosome. This
characteristic chromosomal abnormality can be detected by routine cytogenetics, by
fluorescent in situ hybridization, or by PCR for the bcr-abl fusion gene.[2]

Controversy exists over so-called Ph-negative CML, or cases of suspected CML in
which the Philadelphia chromosome cannot be detected. Many such patients in fact
have complex chromosomal abnormalities which mask the (9;22) translocation, or
have evidence of the translocation by FISH or RT-PCR in spite of normal routine
karyotyping.[4] The small subset of patients without detectable molecular evidence of
bcr-abl fusion may be better classified as having an undifferentiated
myelodysplastic/myeloproliferative disorder, as their clinical course tends to be
different from patients with CML.[5]

[edit] Pathophysiology
CML was the first malignancy to be linked to a clear genetic abnormality, the
chromosomal translocation known as the Philadelphia chromosome. This
chromosomal abnormality is so named because it was first discovered and described
in 1960 by two scientists from Philadelphia, Pennsylvania: Peter Nowell of the
University of Pennsylvania and David Hungerford of the Fox Chase Cancer Center at
Temple University. [6]

In this translocation, parts of two chromosomes (the 9th and 22nd by conventional
karyotypic numbering) switch places. As a result, part of the BCR ("breakpoint
cluster region") gene from chromosome 22 is fused with the ABL gene on
chromosome 9. This abnormal "fusion" gene generates a protein of p210 or
sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because
abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine
kinase), the bcr-abl fusion gene product is also a tyrosine kinase.[1][3]

The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The
bcr-abl transcript is continuously active and does not require activation by other
cellular messaging proteins. In turn, bcr-abl activates a cascade of proteins which
control the cell cycle, speeding up cell division. Moreover, the bcr-abl protein inhibits
DNA repair, causing genomic instability and making the cell more susceptible to
developing further genetic abnormalities. The action of the bcr-abl protein is the
pathophysiologic cause of chronic myelogenous leukemia. With improved
understanding of the nature of the bcr-abl protein and its action as a tyrosine kinase,
targeted therapies have been developed (the first of which was imatinib mesylate)
which specifically inhibit the activity of the bcr-abl protein. These tyrosine kinase
inhibitors can induce complete remissions in CML, confirming the central importance
of bcr-abl as the cause of CML.[3]

[edit] Classification
CML is often divided into three phases based on clinical characteristics and laboratory
findings. In the absence of intervention, CML typically begins in the chronic phase,
and over the course of several years progresses to an accelerated phase and ultimately
to a blast crisis. Blast crisis is the terminal phase of CML and clinically behaves like
an acute leukemia. One of the drivers of the progression from chronic phase through
acceleration and blast crisis is the acquisition of new chromosomal abnormalities (in
addition to the Philadelphia chromosome).[1] Some patients may already be in the
accelerated phase or blast crisis by the time they are diagnosed.[2]

[edit] Chronic phase

Approximately 85% of patients with CML are in the chronic phase at the time of
diagnosis. During this phase, patients are usually asymptomatic or have only mild
symptoms of fatigue or abdominal fullness. The duration of chronic phase is variable
and depends on how early the disease was diagnosed as well as the therapies used.
Ultimately, in the absence of curative treatment, the disease progresses to an
accelerated phase.[2]

[edit] Accelerated phase

Criteria for diagnosing transition into the accelerated phase are somewhat variable;
the most widely used criteria are those put forward by investigators at M.D. Anderson
Cancer Center,[7] by Sokal et al.,[8] and the World Health Organization.[5][9] The WHO
criteria are perhaps most widely used, and define the accelerated phase by any of the
following:

• 10–19% myeloblasts in the blood or bone marrow
• >20% basophils in the blood or bone marrow
• Platelet count <100,000, unrelated to therapy
• Platelet count >1,000,000, unresponsive to therapy
• Cytogenetic evolution with new abnormalities in addition to the Philadelphia
chromosome
• Increasing splenomegaly or white blood cell count, unresponsive to therapy

The patient is considered to be in the accelerated phase if any of the above are
present. The accelerated phase is significant because it signals that the disease is
progressing and transformation to blast crisis is imminent.[5]

[edit] Blast crisis

Blast crisis is the final phase in the evolution of CML, and behaves like an acute
leukemia, with rapid progression and short survival.[2] Blast crisis is diagnosed if any
of the following are present in a patient with CML:[10]

• >20% myeloblasts or lymphoblasts in the blood or bone marrow
• Large clusters of blasts in the bone marrow on biopsy
• Development of a chloroma (solid focus of leukemia outside the bone
marrow)

[edit] Treatment
[edit] Chronic phase

Chronic phase CML is treated with inhibitors of tyrosine kinase, the first of which
was imatinib mesylate (marketed as Gleevec or Glivec; previously known as STI-
571). In the past, antimetabolites (e.g. cytarabine, hydroxyurea), alkylating agents,
interferon alfa 2b, and steroids were used, but these drugs have been replaced by
imatinib. Imatinib was approved by the United States FDA in 2001 and specifically
targets BCR/abl, the constitutively activated tyrosine kinase fusion protein caused by
the Philadelphia chromosome translocation. It is better tolerated and more effective
than previous therapies. The IRIS study is an international study that compared
Interferon/Cytarabine combination with imatinib. Long term follow up demonstrating
the superiority of Imatinib regimens is clear cut. However, the data of this study
which allowed cross-over to glivec has never been presented in an intent to treat
analysis. The question remains as to whether glivec treatment following
cytarabine/interferon is better than glivec alone in the long term is left unanswered.
Bone marrow transplantation was also used as initial treatment for CML in younger
patients before the advent of imatinib, and while it can often be curative, there was a
high rate of transplant-related mortality. The transplant-related mortality rate in the
present is less than 5%. [3]

As described below, a number of newer drugs are being used to treat the minority of
patients who develop imatinib resistance. However, trials such as SPIRIT 2 are also
underway to evaluate these newer drugs as 'upfront' therapy for patients with newly
diagnosed chronic phase CML.

To overcome imatinib resistance and to increase responsiveness of TK inhibitors, two
novel agents have been developed. The first, dasatinib, is a TK inhibitor that blocks
several oncogenic proteins and has been approved by the US FDA to treat CML
patients who are either resistant to or intolerant of imatinib in 2007. Another TK
inhibitor, nilotinib, is also approved by the US FDA for the same indication. Nilotinib
is designed to bind more tightly than imatinib to the Bcr-Abl abnormal fusion protein
responsible for chronic myeloid leukemia. Dasatanib is being compared with Imatinib
for first line therapy in the SPIRIT II trial being undertaken in the United Kingdom.
Study on the combination of alpha Interferon with Imatanib is currently recruiting in
higher risk patients in chronic phase CML.

Dasatanib and nilotinib failed to overcome the Imatinib resistance caused by the
T315I mutation. All current treatments for this mutation are experimental. Recently
Chemgenex released results of their open label Phase 2/3 study (CGX-635-CML-202)
which investigated the use of omacetaxine, administered subcutaneously in CML
patients who had failed imatinib and who have the highly drug resistant T315I kinase
domain mutation.

Dr. Jorge Cortes, MD, Professor of Medicine and Deputy Chair in the Department of
Leukemia at The University of Texas, MD Anderson Cancer Center, a lead
investigator in the study, presented the data. Dr. Cortes said, “It appears that
omacetaxine was well tolerated in this study and durable hematological and
cytogenetic responses were observed in some CML patients with the T315I
mutation.” He added that “Several novel drugs have already been investigated in this
difficult-to-treat population, but they have not had a reasonable risk:benefit ratio.
These results suggest that omacetaxine may represent the first viable treatment option
for this population of patients who currently have no established treatment options.”

Stem cell transplantation is an option for those patients developed T315I mutation.[11]
[12]

In 2005 favourable results of vaccination were reported with the BCR/abl p210 fusion
protein in patients with stable disease, with GM-CSF as an adjuvant.[13]

[edit] Prognosis
In one analysis of several clinical studies, three different risk groups were identified
based on a prognostic scoring system that includes several variables: age, spleen size,
blast count, platelet count, eosinophil count and basophil count. In the lowest risk
group, the median survival time was 98 months. In the middle group, the median was
65 months, and in the highest risk group, the median was about 42 months. Of all
patients analyzed, the longest survival time was 117 months.[14] However, this study
pre-dates the advent of treatments using targeted therapy. A follow-up on patients
using imatinib published in the New England Journal of Medicine shows an overall
survival rate of 89% after five years.[15]

[edit] Epidemiology
CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its
annual incidence is 1–2 per 100,000 people, and slightly more men than women are
affected. CML represents about 15–20% of all cases of adult leukemia in Western
populations.[1] The only well-described risk factor for CML is exposure to ionizing
radiation; for example, increased rates of CML were seen in people exposed to the
atomic bombings of Hiroshima and Nagasaki[16] Long-term exposure to benzene may
also contribute.[citation needed]

[edit] References
1. ^ a b c d Faderl S, Talpaz M, Estrov Z, Kantarjian HM (1999). "Chronic
myelogenous leukemia: biology and therapy". Annals of Internal Medicine
131 (3): 207–219. PMID 10428738.
2. ^ a b c d e f Tefferi A (2006). "Classification, diagnosis and management of
myeloproliferative disorders in the JAK2V617F era". Hematology Am Soc
Hematol Educ Program: 240–245. PMID 17124067.
3. ^ a b c d Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet
(2007). "Chronic myeloid leukaemia". Lancet 370 (9584): 342–50.
doi:10.1016/S0140-6736(07)61165-9. PMID 17662883.
4. ^ Savage DG; Szydlo RM; Goldman JM (1997). "Clinical features at
diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral
centre over a 16-year period". Br J Haematol 96 (1): 111–116.
doi:10.1046/j.1365-2141.1997.d01-1982.x. PMID 9012696.
5. ^ a b c Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA,
Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H,
Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG,
Bloomfield CD, Vardiman JW (2007). "Proposals and rationale for revision of
the World Health Organization diagnostic criteria for polycythemia vera,
essential thrombocythemia, and primary myelofibrosis: recommendations
from an ad hoc international expert pane". Blood 110 (4): 1092–1097.
doi:10.1182/blood-2007-04-083501. PMID 17488875.
6. ^ Nowell PC (2007). "Discovery of the Philadelphia chromosome: a personal
perspective". Journal of Clinical Investigation 117 (8): 2033–2035.
doi:10.1172/JCI31771. PMID 17671636.
7. ^ Kantarjian H, Dixon D, Keating M, Talpaz M, Walters R, McCredie K,
Freireich E (1988). "Characteristics of accelerated disease in chronic
myelogenous leukemia". Cancer 61 (7): 1441–6. doi:10.1002/1097-
0142(19880401)61:7<1441::AID-CNCR2820610727>3.0.CO;2-C. PMID
3162181.
8. ^ Sokal J, Baccarani M, Russo D, Tura S (1988). "Staging and prognosis in
chronic myelogenous leukemia". Semin Hematol 25 (1): 49–61. PMID
3279515.
9. ^ Vardiman J, Harris N, Brunning R (2002). "The World Health Organization
(WHO) classification of the myeloid neoplasms". Blood 100 (7): 2292–302.
doi:10.1182/blood-2002-04-1199. PMID 12239137.
http://www.bloodjournal.org/cgi/content/full/100/7/2292. Retrieved 2007-09-
22.
10. ^ Karbasian Esfahani M, Morris EL, Dutcher JP, Wiernik PH (2006). "Blastic
phase of chronic myelogenous leukemia". Current Treatment Options in
Oncology 7 (3): 189–199. doi:10.1007/s11864-006-0012-y. PMID 16615875.
11. ^ Jabbour E, Cortes JE, Giles FJ, O'Brien S, Kantarjian HM (2007). "Current
and emerging treatment options in chronic myeloid leukemia". Cancer 109
(11): 2171–2181. doi:10.1002/cncr.22661. PMID 17431887.
12. ^ Kimura S, Ashihara E, Maekawa T (2006). "New tyrosine kinase inhibitors
in the treatment of chronic myeloid leukemia". Current Pharmaceutical
Biotechnology 7 (5): 371–379. doi:10.2174/138920106778521532. PMID
17076652.
13. ^ Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, Amabile
M, Forconi F, Gozzetti A, Raspadori D, Amadori S, Lauria F (2005). "Effect
of a p210 multipeptide vaccine associated with imatinib or interferon in
patients with chronic myeloid leukaemia and persistent residual disease: a
multicentre observational trial". Lancet 365 (9460): 657–62. PMID 15721470.
14. ^ Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-
Nelemans JC, Alimena G, Steegmann JL, Ansari H (1998). "A new prognostic
score for survival of patients with chronic myeloid leukemia treated with
interferon alfa. Writing Committee for the Collaborative CML Prognostic
Factors Project Group". Journal of the National Cancer Institute 90 (11): 850–
858. doi:10.1093/jnci/90.11.850. PMID 9625174.
15. ^ Druker BJ, Guilhot F, O'Brien SG et al. (2006). "Five-Year Follow-up of
Patients Receiving Imatinib for Chronic Myeloid Leukemia". New England
Journal of Medicine 355 (20): 2408–2417. doi:10.1056/NEJMoa062867.
PMID 17151364. http://content.nejm.org/cgi/content/full/355/23/2408.
16. ^ Moloney WC (1987). "Radiogenic leukemia revisited". Blood 70 (4): 905–
908. PMID 3477299.

[edit] External links
• Chronic Myeloid Leukemia at American Cancer Society
• CML information from The Leukemia & Lymphoma Society
• Merck Manual:Chronic Myelocytic Leukemia (CML)

[hide]

v•d•e

Myeloid Hematological malignancy/leukemia histology (ICD-O 9590-9989,
C81-C96, 200-208)
AML: Acute myeloblastic leukemia
Myelocyte(M0, M1, M2), APL/M3
MP (Chronic neutrophilic leukemia)

AML (AMoL/M5, Myeloid dendritic
cell leukemia)
MonocyteCML (Philadelphia chromosome,
Accelerated phase chronic
CFU-GM myelogenous leukemia)

CFU-GM/ AML (M4)
and other granulocytes MD-MP (Juvenile myelomonocytic
Myelomonocyte
leukemia, Chronic myelomonocytic
leukemia)

OtherHistiocytosis

CFU-BasoAML (Acute basophilic)

AML (Acute eosinophilic)
CFU-EosMP (Chronic eosinophilic leukemia/Hypereosinophilic
syndrome)

AML (AMKL/M7)
CFU-Meg
MP (Essential thrombocytosis)

AML (Erythroleukemia/M6)

MEP MP (Polycythemia vera)

CFU-EMD (Refractory anemia, Refractory anemia with excess
of blasts, Chromosome 5q deletion syndrome,
Sideroblastic anemia, Paroxysmal nocturnal
hemoglobinuria, Refractory cytopenia with multilineage
dysplasia)

Mastocytoma (Mast cell leukemia, Mast cell sarcoma, Systemic
CFU-Mast
mastocytosis)

AML (Acute panmyelosis with myelofibrosis, Myeloid sarcoma) ·
Multiple/unknown
MP (Myelofibrosis) · Acute biphenotypic leukaemia

myeloid navs: cells/physio, disease of
RBCs+megakaryocytes/monocytes+granulocytes/neoplasia, symptoms+signs/eponymous
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