Chronic myelogenous leukemia

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**Chronic myelogenous leukemia**
*Classification & external resources*

The Philadelphia chromosome as seen by metaphase FISH.
ICD-10	C 92.1
ICD-9	205.1
ICD-O:	M 9863/3
DiseasesDB	2659
MedlinePlus	000570
eMedicine	med/371

Chronic myelogenous leukemia (CML) is a form of chronic leukemia characterized by increased and unregulated clonal production of predominantly myeloid cells in the bone marrow. CML is a 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.

1 Incidence and epidemiology
2 Signs and symptoms
3 Pathophysiology
4 Diagnosis
5 Phases of CML
6 Treatment
- 6.1 Chronic phase
- 6.2 Blast crisis
7 Prognosis
8 See also
9 References
10 External links

[edit] Incidence and 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.^[2]

[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, 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.

[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.

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.

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.

[edit] Diagnosis

CML is often suspected on the basis on the complete blood count, which shows increased granulocytes of all types, typically including immature 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.

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.

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.^[3] 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.^[4]

[edit] Phases of CML

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.

[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.

[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,^[5] by Sokal et al,^[6] and the World Health Organization.^[7] The WHO criteria are perhaps most widely used, and include:

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.

[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. Blast crisis is diagnosed if any of the following are present in a patient with CML:

>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 US 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. 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 is a high rate of transplant-related mortality.

Another new drug, dasatinib (marketed as Sprycel®; previously known as BMS-354825), which has a similar mechanism of action to imatinib but inhibiting a broader spectrum of tyrosine kinases, was approved by the U.S. FDA in June 2006 for use in patients with CML who are no longer responding to, or who can no longer tolerate, therapy with imatinib. [1] Pre-clinical research indicates that the anti-leukemic effect of dasatinib may be further enhanced by the addition of a small molecular inhibitor known as PD184352 [2]

Various combinations of the different treatment modalities are being explored.

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.^[8]

Two other drugs, ceflatonin (homoharringtonine) and nilotinib (AMN 107) are currently in active clinical trials in patients with CML who have developed resistance to imatinib. [3].

[edit] Blast crisis

Blast crisis carries all the symptoms and characteristics of either acute myelogenous leukemia or acute lymphoblastic leukemia, and has a very high mortality rate. This stage can most effectively be treated by a bone marrow transplant after high-dose chemotherapy. In young patients in the accelerated phase, a transplant may also be an option. However the likelihood of relapse after a bone marrow transplant is higher in patients in blast crisis or in the accelerated phase as compared to patients in the chronic phase.

[edit] Prognosis

The prognosis of CML depends on a number of different parameters. Two different scoring systems are in use: one by Sokal et al (1984) and one by Hasford et al (1998).^[9]^[10]

[edit] See also

[edit] References

^ ^a ^b The biology of chronic myeloid leukemia. Faderl S; Talpaz M; Estrov Z; O'Brien S; Kurzrock R; Kantarjian HM. N Engl J Med 1999 Jul 15;341(3):164-72.
^ Radiogenic leukemia revisited. Moloney WC. Blood 1987 Oct;70(4):905-8.
^ Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. Savage DG; Szydlo RM; Goldman JM. Br J Haematol 1997 Jan;96(1):111-6.
^ The World Health Organization (WHO) classification of the myeloid neoplasms. Vardiman JW; Harris NL; Brunning RD. Blood 2002 Oct 1;100(7):2292-302.
^ 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. PMID 3162181.
^ Sokal J, Baccarani M, Russo D, Tura S (1988). "Staging and prognosis in chronic myelogenous leukemia.". Semin Hematol 25 (1): 49-61. PMID 3279515.
^ Vardiman J, Harris N, Brunning R (2002). "The World Health Organization (WHO) classification of the myeloid neoplasms.". Blood 100 (7): 2292-302. PMID 12239137. Full text
^ Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, Amabile M, Forconi F, Gozzetti A, Raspadori D, Amadori S, Lauria F. 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 2005;365:657-62.
^ Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in good risk chronic granulocytic leukemia. Blood 1984;63:789-799. PMID 6584184.
^ Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998;90:850-858. PMID 9625174.