INTRODUCTION

CML is associated with the fusion of two genes: BCR (on chromosome 22) and
ABL1 (on chromosome 9) resulting in the BCR-ABL1 fusion gene. This
abnormal fusion typically results from a reciprocal translocation between
chromosomes 9 and 22, t(9;22)(q34;q11), that gives rise to an abnormal
chromosome 22 called the Philadelphia (Ph) chromosome. It is this
derivative chromosome 22 which harbors the BCR-ABL1 fusion gene.
The BCR-ABL1 fusion gene results in the formation of a unique gene product,
the BCR-ABL1 fusion protein. This protein product includes an enzymatic
domain from the normal ABL1 with tyrosine kinase catalytic activity, but
relative to ABL1, whose kinase activity is tightly regulated, the kinase activity
of BCR-ABL1 is elevated and constitutive due to fusion with a portion of BCR.
It is this deregulated tyrosine kinase that is implicated in the pathogenesis of
CML.
The clinical hallmark of CML is the uncontrolled production of mature and
maturing granulocytes, predominantly neutrophils, but also basophils and
eosinophils. In the absence of treatment, CML has a triphasic or biphasic
clinical course as it progresses from a chronic phase to an accelerated phase
and on to a terminal blast crisis. Sometimes it goes from chronic phase directly
to blast crisis, particularly when the blast phase is lymphoid.
EPIDEMIOLOGY
The median age at presentation is approximately 50 years for patients enrolled
on clinical studies, but the actual median age from cancer registry data may be
10 years older. Exposure to ionizing radiation is the only known risk factor.
CLINICAL MANIFESTATIONS
CML has a triphasic or biphasic clinical course: a chronic phase, which is
present at the time of diagnosis in approximately 85 percent of patients; an
accelerated phase, in which neutrophil differentiation becomes progressively
impaired and leukocyte counts are more difficult to control with treatment; and
blast crisis, a condition resembling acute leukemia in which myeloid or
lymphoid blasts proliferate in an uncontrolled manner.
Twenty to 50 percent of patients are asymptomatic, with the disease first being
suspected from routine blood tests.
Among symptomatic patients, systemic symptoms such as fatigue (34
percent), malaise (3 percent), weight loss (20 percent), excessive sweating (15
percent), abdominal fullness (15 percent), and bleeding episodes due to
platelet dysfunction (21 percent) are common.

Abdominal pain and discomfort may include left upper quadrant pain
(sometimes referred to the left shoulder) and early satiety, due to the enlarged
spleen with or without perisplenitis and/or splenic infarction. Tenderness over
the lower sternum, due to an expanding bone marrow, is sometimes seen.
Acute gouty arthritis may also present at this time, due to overproduction of
uric acid.
Other frequent findings include splenomegaly (present in 48 and 76 percent in
two series), anemia (45 and 62 percent), white blood cell count above
100,000/microL (52 and 72 percent), and platelet count above 600,000 to
700,000/microL (15 and 34 percent). Involvement of extramedullary tissues
such as the lymph nodes, skin, and soft tissues is generally limited to patients
with blast crisis.
PERIPHERAL BLOOD:
The peripheral smear typically demonstrates a leukocytosis with a median
white count of approximately 100,000/microL (range 12 to 1000/microL). The
white blood cell differential typically shows virtually all cells of the neutrophilic
series, from myeloblasts to mature neutrophils with peaks in the percent
myelocytes and segmented neutrophils. Blasts typically account for less than 2
percent. The presence of a greater percent of myelocytes than the more
mature metamyelocytes is one of the classic findings in CML. The granulocytes
of chronic phase are morphologically normal with no evidence of dysplasia, but
dysplasia can develop in more advanced disease, and particularly in
accelerated phase
Although morphologically normal, the neutrophils in CML are cytochemically
abnormal. The cytochemical reaction called leukocyte (or neutrophil) alkaline
phosphatase (LAP, or NAP) when scored is low. The low LAP score is useful in
excluding a reactive leukocytosis or "leukemoid reaction," typically due to
infection, in which the score is typically elevated or normal. Low LAP activity
was also classically used to exclude polycythemia vera (PV) in the differential
diagnosis of CML, in which LAP activity is also often increased.
The platelet count can be normal or elevated. Platelet counts above
600,000/microL are seen in 15 to 30 percent of patients. Low platelet counts or
thrombocytopenia, if present at diagnosis, should make one reconsider other
diagnostic possibilities, such as one of the myelodysplastic syndromes. A
normochromic, normocytic anemia is seen in 45 to 60 percent of patients.
BONE MARROW BIOPSY
Bone marrow aspiration and biopsy demonstrates granulocytic hyperplasia
with a maturation pattern that reflects that seen in the peripheral smear
(promyelocytes, myelocytes, metamyelocytes, band forms, and mature

granulocytes). Other non-specific bone marrow findings include an increase in

reticulin fibrosis and vascularity.
The vast majority of patients (90 to 95 percent) demonstrate the t(9;22)
(q34;q11.2) reciprocal translocation that results in the Ph chromosome. Some
of the remaining minority have variant translocations such as complex
translocations involving other chromosome (eg, t(9;14;22)). The rest have
cryptic translocations of 9q34 and 22q11.2 that cannot be identified by routine
cytogenetics. These are referred to as "Ph-negative" and require FISH analysis
to identify the BCR-ABL1 fusion gene, or RT-PCR to identify the BCR-ABL1 fusion
mRNA.
Although the Philadelphia chromosome (Ph) translocation is the initiating event
in CML, progression to accelerated phase or blast crisis appears to require the
acquisition of other chromosomal or molecular changes [7]. Additional
cytogenetic abnormalities develop in over 80 percent of patients in the
accelerated and blast crisis phases, most commonly trisomy 8, trisomy 19,
duplication of the Ph chromosome, and isochromosome 17q (leading to the loss
of the P53 gene on 17p).
The evolution of any of these additional karyotypic findings confers a worse
prognosis
DIAGNOSIS
The diagnosis of CML is first suspected by identifying the typical findings in the
blood and bone marrow, and then confirmed by the demonstration of the
Philadelphia chromosome
DIFERENTIAL DIAGNOSIS

Leukemoid reaction A leukemoid reaction describes a high leukocyte

count with neutrophilia and prominent left shift, usually in response to
infection. The peripheral blood count may be as high as 50,000/microL and
can easily mimic CML. However, the following features are more commonly
found in a leukemoid reaction and help to distinguish it from CML: toxic
granulation in the neutrophils, a high LAP score, lack of a "myelocyte
bulge", and most importantly, the presence of an obvious cause for the
neutrophilia. Bone marrow examination is often not helpful. Cytogenetic or
molecular testing is definitive for CML if the distinction cannot be made
clinically.
Juvenile myelomonocytic leukemia Juvenile myelomonocytic leukemia
(JMML, formerly called "juvenile CML") is a rare fatal disorder of infancy and
early childhood characterized by the combination of hepatosplenomegaly,
lymphadenopathy, pallor, fever, and skin rash

Patients with JMML demonstrate clonal overproduction of maturing myeloid

cells, usually with an excess of monocytic lineage cells that are hyperresponsive to granulocyte macrophage colony-stimulating factor (GM-CSF),
leading to organ infiltration with relatively normal appearing monocytes and
macrophages and death from organ failure or infection. In contrast to CML,
the karyotype in JMML is normal or sometimes shows monosomy 7, and
progression to acute leukemia is rare. Many patients with JMML have
mutations in genes that encode elements of the GM-CSF signal transduction
pathway, including PTPN11, NRAS and KRAS2, CBL, and NF1

Chronic myelomonocytic leukemia Chronic myelomonocytic leukemia

(CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by
the overproduction of maturing monocytic cells and sometimes dysplastic
neutrophils, often accompanied by anemia and/or thrombocytopenia. Unlike
CML, the bone marrow morphology in CMML demonstrates prominent
dysplastic changes in at least two of the three myeloid lineages. In
addition, genetic testing does not demonstrate evidence of BCR-ABL1, the
Ph chromosome or their products

PROGNOSIS
The prognosis of patients with CML has improved dramatically since the
incorporation of tyrosine kinase inhibitors (TKIs) into the initial treatment.
Attempts have been made to identify patients at diagnosis who have an
unfavorable prognosis.
Patients with chronic phase at the time of diagnosis can have years of disease
control with treatment while those in accelerated phase or blast crisis have a
much poorer prognosis.
TREATMENT
Treatment decisions for patients with chronic myeloid leukemia (CML) are
complex, due to the variety of available options, many of which are conflicting.
Available treatment options include:
Potential cure with allogeneic hematopoietic cell transplantation (HCT)
Disease control without cure using tyrosine kinase inhibitors (TKIs)
Palliative therapy with cytotoxic agents
Factors influencing the choice of therapy include: the phase of CML; availability
of a donor for HCT; patient age; the presence of medical co-morbidities
affecting patient suitability for HCT; and, for patients in earlier phases of CML,
the response to treatment with TKIs.

RESPONSE CRITERIA
The following categories define hematologic, cytogenetic, and molecular
treatment response in CML
Hematologic response Hematologic response is assessed by the white blood
cell count, differential, and platelet count. Complete hematologic response
(CHR) is defined by a white blood cell count <10,000/microL with no immature
granulocytes and <5 percent basophils on differential; platelet count
<450,000/microL; and spleen not palpable.
Cytogenetic response is classified according to the percent Philadelphia
chromosome positive cells into none (>95 percent), minimal (66 to 95 percent),
minor (36 to 65 percent), major (1 to 35 percent), and complete (no
Philadelphia chromosome positive cells).

GALACTOSEMIA
Galactose is a sugar found primarily in human and bovine milk and milk
products as part of the disaccharide lactose. Lactose is hydrolyzed to glucose
and galactose by the intestinal enzyme lactase. The galactose then is
converted to glucose for use as an energy source.
Altered metabolism of galactose caused by deficient enzyme activity or
impaired liver function results in elevated blood galactose concentration and
the condition known as galactosemia.

PATOGHENESIS
Galactosemia can result from deficiencies of three different enzymes, each with
a distinct phenotype. Impairment of galactose metabolism caused by abnormal
liver function also may result in increased galactose concentrations.
Galactose-1-phosphate uridyl transferase (GALT) deficiency The most common
and severe form of galactosemia is caused by deficiency of GALT, the enzyme
that converts galactose-1-phosphate (galactose-1-P) to uridine diphosphate
galactose (UDPgalactose)

Complete deficiency of GALT activity is known as classic galactosemia

Untreated patients typically have failure to thrive, liver and renal dysfunction,
and sepsis. Both treated and untreated patients may have cataracts, abnormal
neurodevelopment, and premature ovarian failure.
Partial GALT activity occurs in numerous variants. The most common of these is
the Duarte variant, in which patients have one Duarte allele and one classic
allele (D/G), resulting in GALT activity that is approximately 5 to 25 percent of
normal. Patients with two Duarte alleles (D/D) have approximately 25 percent
normal GALT activity. Patients with GALT activity 50 percent of normal appear
to have little to no evidence of neonatal or long-term morbidity if untreated.
Galactokinase (GALK) deficiency GALK is the first enzyme in the pathway of
galactose metabolism, converting galactose to galactose-1-P. The only
consequence of GALK deficiency is the development of cataracts.
Uridine diphosphate (UDP) galactose 4-epimerase (GALE) deficiency UDP
GALE converts UDPgalactose to UDPglucose. In most patients with GALE (or
epimerase) deficiency, the defect is localized to red blood cells (RBCs). These
individuals typically have normal growth and development, whereas patients
with generalized GALE deficiency in both RBCs and all other tissues present
with symptoms similar to classic galactosemia.

GENETICS
Galactosemia is an autosomal recessive disorder, GALt is located in the
chromosome 9p13.
Individuals with classic galactosemia have two classic alleles (G/G). Individuals
with the Duarte variant are compound heterozygotes, with one Duarte allele
and one classic allele (D/G).
CLINICAL FEATURES
Classic galactosemia Classic galactosemia caused by complete deficiency of
galactose-1-phosphate uridyl transferase (GALT) is the most common and
severe type. Early diagnosis and treatment usually prevents or resolves the
early signs and symptoms, such as liver dysfunction, susceptibility to
infections, failure to thrive, and cataracts. However, despite dietary
management, neuropsychological and ovarian problems occur in most
adolescents and adults with this disorder.

Infants with classic galactosemia usually present in the first few days after birth
and initiation of breast milk or cow's milk-based formula feedings. Specific
signs and symptoms occur with different frequencies. The most common
findings are [14]:
Jaundice
Vomiting
Hepatomegaly
Failure to thrive
Poor feeding
Lethargy
Diarrhea
Sepsis
Among infants with sepsis, the most common organism is Escherichia coli
sepsis. Less frequent findings are coagulopathy, ascites, and seizures.
On physical examination, infants typically appear jaundiced, with
hepatomegaly, lethargy, and hypotonia. They may have edema and ascites, a
full fontanelle, encephalopathy, and excessive bruising or bleeding.
Lenticular cataracts may be present at birth, but generally appear after two
weeks as a result of galactitol deposition in the lens. In untreated classic
galactosemia and galactokinase deficiency, typically there is initial clouding of
the embryonic nucleus in the central lens followed by spreading to the cortex.
Occasionally, when children are not caught early, as they grow, they develop a
nuclear cataract, similar to nucleus pulverulentus (derived from the Latin
"pulver" = dust) where the nucleus of the lens looks like a cloud of dust.
Laboratory findings Laboratory findings of classic galactosemia include the
following [16]:

Abnormal carbohydrate metabolism Increased plasma galactose and red

blood cell (RBC) galactose-1-P concentration, increased blood and urine
galactitol levels.

Liver dysfunction Conjugated or unconjugated hyperbilirubinemia, abnormal

liver function tests, coagulopathy, increased levels of plasma amino acids
(especially phenylalanine, tyrosine, and methionine).

Renal tubular dysfunction Metabolic acidosis, galactosuria (which may be

indicated by the presence of reducing substances in the urine), glycosuria,
aminoaciduria, albuminuria.

Hemolytic anemia.

Galactokinase (GALK) deficiency The consistent phenotypic feature of GALK

deficiency is lenticular cataracts, identical to those seen in classic galactosemia
[17]. The cataracts usually are bilateral and resolve with dietary therapy. (See
"Cataract in children".)

A rare presentation of GALK deficiency is pseudotumor cerebri [18]. The

mechanism is thought to be increased cerebrospinal fluid (CSF) oncotic
pressure resulting from elevated CSF galactitol concentration. Clinical features
of classic galactosemia typically are not present in GALK deficiency.

Uridine diphosphate galactose 4-epimerase (GALE) deficiency Deficiency of

GALE is classically thought to be confined to erythrocytes. Affected individuals
typically are asymptomatic, although erythrocyte levels of galactose-1-P are
elevated. Generalized deficiency is rarely described. In one report, five children
from two families with generalized epimerase deficiency had dysmorphic facial
features, sensorineural deafness, poor growth, and global developmental delay,
but not ovarian failure [19]. However, another review of 10 patients found a
spectrum of GALE activity ranging from 15 to 64 percent of control levels,
suggesting that the metabolic defect is a continuum from mild (ie, red cell) to
severe (ie, both red cells and lymphoblasts) impairment of galactose
metabolism in vitro [20]. Patients with GALE deficiency may be detected by
newborn screening when states screen by measuring total galactose. (See
'Bacterial inhibition assay to measure total galactose' below.)

DIAGNOSIS

GALT deficiency Classic galactosemia should be considered in any newborn

who presents with the findings noted above (jaundice, vomiting, hepatomegaly,
poor feeding, failure to thrive, lethargy, diarrhea, or sepsis). The diagnosis
should be considered even in areas with neonatal screening programs because
affected infants may become symptomatic before the screening results are
available [15].

RBC GALT activity The demonstration of nearly complete absence of

galactose-1-phosphate uridyl transferase (GALT) activity red blood cells (RBCs)
is the gold standard for diagnosis [13]. Quantitative assay of RBC GALT activity
is necessary to confirm the diagnosis. This assay also identifies variants with
partial enzyme activity [16].

Quantitative assay of RBC GALT activity may be affected for as long as three
months by the transfusion of RBC from a normal donor. In such cases, DNA
testing for the Q188R mutation is helpful if the patient is homozygous, but does
not exclude classic galactosemia caused by other mutations. Other tests that
may be helpful in transfused infants include measurement of GALT activity in
the RBCs of both parents to determine whether they are carriers and
measurement of RBC galactose-1-P [16].
Prenatal diagnosis Prenatal counseling should be provided before conception
to parents with a family history of galactosemia or a previously affected child.
Prenatal diagnosis can be made by GALT assay in fibroblasts cultured from
amniotic fluid or chorionic villus biopsy or mutation analysis of DNA extracted
from chorionic villus biopsy if the genotype of the index case is known [21].
When two mutations are found in a proband with classic galactosemia, carrier
screening for GALT mutations is highly effective in determining risk [13].
Clinicians and families should also be aware that this method of testing can
uncover mistaken paternity.

GALK deficiency Galactokinase (GALK) deficiency should be considered in

infants with lenticular cataracts. In addition, GALK deficiency should be
considered in neonates who have positive bacterial inhibition newborn screens
because this screen detects elevated blood galactose without distinguishing
between the three potentially causative enzymes. GALK deficiency is confirmed
by assay of GALK activity in RBC. The results of this assay may be affected by
the transfusion of RBC from a normal donor.

GALE deficiency Galactose-4-epimerase (GALE) deficiency should be

considered in neonates who have positive bacterial inhibition newborn screens
because this screen detects elevated blood galactose without distinguishing
between the three potentially causative enzymes. GALE deficiency is confirmed
by assay of GALE activity in RBCs and/or lymphoblasts. The results of this assay
may be affected by the transfusion of RBC from a normal donor.

DIFFERENTIAL DIAGNOSIS Galactose often is mildly elevated in normal

newborns (6 to 10 mg/dL), resulting in false-positive results. Other causes of
elevated galactose include liver dysfunction from conditions that include
portosystemic vascular shunts, biliary atresia, and Fanconi-Bickel syndrome
[22-24].

NEWBORN SCREENING The newborn screening programs of all states in the

United States test for galactosemia. A newborn with a positive screening test
for galactosemia should be changed immediately to a soy-based infant formula
and the screening test should be repeated. If the second screen is positive,
further testing is performed. A quantitative assay of red blood cell (RBC)
galactose-1-phosphate uridyl transferase (GALT) confirms the diagnosis and
measures the specific level of enzyme activity.