CGL-1

Definition: chronic granulocytic leukemia

(CGL) is a clonal malignant transformation
of the HAEMATOLOGICAL stem cell,
characterized by proliferation of the
granulocytes which retain their capacity to
differentiate.
Characteristics:
-the presence of the Ph-chromosome;
-the very low (or even zero) score of the
leukocytic alkaline phosphatase;
-the presence of the all stages of the
granulocytic precursors in peripheral blood;
-splenomegaly

Synonyms :
-chronic myelogenous leukemia;
-chronic myeloid leukemia;
-chronic myelocytic leukemia.
 CGL-2

Etiology :
1. – Irradiation :
2. –Chemicals and drugs :
3. –Genetic background :

Epidemiology:
1. –incidence in the USA : 1,4/100,000 ;
2. –the higher incidence appears in the fourth and fifth decade ; the
CGL is uncommon in children and accounts for less than 5% of
all childhood leukemias ;
3. –a slightly higher incidence in men has been observed;

Pathogenesis:

A.-at molecular level:

• - CGL appears from the malignant transformation of
a single stem cell.
• -the abnormal clone coexists in the same patient with
normal stem cells;
• -the cytogenetic hallmark of the CGL is the presence
of the Ph-chromosome. The Philadelphia chromosome
consists in a reciprocal translocation t(9,22)(q34;q11). The
break-points appears on the long-arm of the 22-chromosome,
named “break point cluster region” or bcr and in a region of the
long arm of the chromosome 9, where the c-abl gene is located
( c-abl is the cellular homologue of the transforming oncogene
of the Abelson murine leukemia virus). The remaining
sequences of the bcr-region on the 22-chromosome act as an
accepter for the c-abl gene and a chimeric fusion gene ABL-
BCR appears, which is active: it gives rise to a chimeric RNA-
messenger and consequently to a chimeric protein, namely a
new 210 kD tyrosine-kinase, which has the capacity to activate
cells. But the translocation phenomenon is reciprocal, so that a
piece of chromosome 22 is translocated also to the
chromosome 9.

CGL-3
B.-at cellular level :
1. -the transformed hematopoietic stem cell generates an increasingly
expanded pool of committed stem cells for granulocytic and, at
least initially, megakaryocytic and erythroid cell lines;
2. -the leukemic cells retain partially their maturation capacity: in
peripheral blood , a continuously increasing number of neutrophils
appears, as well as eosinophils and basophils; in earlier stages,
because megakaryocytes are increased in bone marrow, a great
number of platelets appears in peripheral blood;
3. -the leukemic cellular pool overwhelms the normal erythropoiesis and
extends to extramedullary sites;
C.-at clinical level :
1.-leukemic cells proliferate:
a.-in bone marrow :
• spontaneous pain of the sternum , accentuated by palpation;
• as the diseases progresses, pain appears in long bones,
especially of the lower extremities;
b.-in extramedullary sites :
• in spleen, they proliferate profusely, growing out from the red
pulp toward the white pulp, where progressively replace the
normal lymphoid population ;
• in liver, the leukemic cells proliferate within the sinusoids;
• as the disease progresses, the leukemic cells proliferate also
in lymph nodes and infiltrate diffusely or nodular other organs
and systems, including the central nervous system (CNS);
2.-as result :
a.-progressively involvement of the bone
marrow
• osseous pain associates with anemia, increased tendency to
infection, spontaneous bruising;
b.-involvement of extramedullary sites:

CGL-4
Clinical features:
 A.-for a variable period, the patient is asymptomatic ;
• no splenic enlargement (or a small and painless splenic
enlargement only), neither liver or other organs or systems
involvement ; the diagnosis could be suggested by fortuitous
laboratory investigation and confirmed by specific tests (see
later);
B.- as the leukemic clone extends, appear :
• a “general malignant impregnation syndrome”: malaise,
decreased tolerance to exercise, loss of appetite, sweating, mild
fever;
• a progressive splenic enlargement, with discomfort, early
satiety and abdominal fullness ;
• a progressive liver enlargement, with local pain ;
C.- Some patients with chronic myelogenous leukemia (CML) progress
to a transitional or accelerated phase, which
may last for several months. The survival of patients diagnosed in this
phase is 1-1.5 years. This phase is characterized by poor control of the
blood counts with myelosuppressive medication and the appearance of
peripheral blast cells (>15%), promyelocytes (>30%), basophils (>20%),
and platelet counts less than 100,000 cells/μL unrelated to therapy.

D.- Acute phase, or blast crisis, is similar to acute

leukemia, and survival is 3-6 months at this stage. Bone marrow and
peripheral blood blasts of 30% or more are characteristic. Skin or tissue
infiltration also defines blast crisis. Cytogenetic evidence of another Ph-
positive clone (double) or clonal evolution (other cytogenetic abnormalities
such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y
chromosome) is usually present.

CGL-5
Laboratory:
-Peripheral blood findings in patients with chronic myelogenous leukemia (CML) show a typical

leukoerythroblastic blood picture, with circulating

immature cells from the bone marrow;
WBC=variable, generally at diagnosis : 20,000->90,000?cmm, with myeloblasts,
promyelocytes, myelocytes, metamyelocytes, Band neutrophils, PMN, basophils;
-mild anemia;
-mild / severe trombocytosis

The bone marrow is characteristically

hypercellular, with expansion of the myeloid cell line (eg, neutrophils,
eosinophils, basophils) and its progenitor cells. Megakaryocytes are prominent and may be
increased. Mild fibrosis is often seen in the reticulin stain.

Cytogenetic studies of the bone marrow

cells:
typical Ph1 chromosome, which is a reciprocal translocation of
chromosomal material between chromosomes 9 and 22. This is the hallmark of chronic
myelogenous leukemia (CML), found in almost all patients with the disease, and is present in
CML throughout its entire clinical course.

Chronic myelogenous leukemia (CML) should be differentiated from

Ph-negative diseases with negative PCR results for BCR/ABL m-RNA. These diseases include
other myeloproliferative disorders and chronic myelomonocytic leukemia, which is now
classified with the myelodysplastic syndromes

Imaging investigation :
-hepatomegaly;
-splenic enlargement;
-in acute (blastic crisis) : sometimes, l;ymph nodes enlargement

CGL-6
TREATMENT:
-demonstrates the victory of the molecular therapy (“magic bullet”)

The 3-fold goals of treatment of chronic myelogenous leukemia (CML) are:

 (1) to achieve a hematologic remission (normal
complete blood cell [CBC] count and physical examination [ie, no organomegaly]),

(2) to achieve cytogenetic remission (normal

chromosome returns with 0% Ph-positive cells), and, most recently,

(3) to achieve molecular remission (negative PCR result

for the mutational BCR/ABL m-RNA). The last is an attempt for cure and prolongation of patient
survival.

How ?
= to directly inhibit the molecular cause of the disease, that is, using a protein-tyrosine kinase inhibitor
that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Ph
chromosome translocation abnormality:

• STI571, or imatinib mesylate (Gleevec),

inhibits proliferation and induces apoptosis by inhibiting tyrosine kinase activity in cells
positive for BCR/ABL and fresh leukemic cells in chronic myelogenous leukemia (CML) that is
positive for the Ph chromosome.
 were that imatinib is superior to interferon alfa plus low-dose
cytarabine as first-line therapy in newly diagnosed, chronic-phase
chronic myelogenous leukemia (CML).
○ Treatment of patients with CML in the accelerated phase or in blast crisis has been
dismal:
 -higher doses of Imatinib;
 Other drug, inhibitory of throsin-kinase, non-cross-resistant drugs :

 DASATINIB;
 TASIGNA

Myelosuppressive therapy, which was formerly the mainstay of

treatment to convert a patient with chronic myelogenous leukemia (CML) from an uncontrolled initial
presentation to one with hematologic remission and normalization of the physical examination and
laboratory findings, may soon fall out of favor as the new agents prove to be more effective with fewer
adverse events and longer survival.

• Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis,

is the most common myelosuppressive agent used to achieve hematologic remission. The
initial blood cell count is monitored every 2-4 weeks, and the dose is adjusted depending on
 the WBC and platelet counts. Most patients achieve hematologic remission within 1-2 months.
This medication causes only a short duration of myelosuppression; thus, even if the counts go
lower than intended, stopping or decreasing doses usually controls the blood counts.
Maintenance with hydroxyurea rarely results in cytogenetic or molecular remissions.

• Busulfan (Myleran) is an alkylating agent that has traditionally been

used to keep the WBC counts less than 15,000 cells/µL. However, the myelosuppressive
effects may occur much later and persist longer, making maintaining the numbers within
normal limits more difficult. Long-term use can cause pulmonary fibrosis, hyperpigmentation,
and prolonged marrow suppression lasting for months.

• 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 and is often combined with cytoreductive
chemotherapy for more lasting effects.

• Interferon alfa was the treatment of choice for most patients with chronic
myelogenous leukemia (CML) who are too old for bone marrow transplantation (BMT) or who
do not have a matched bone marrow donor. Interferon alfa is given at an average of 3-5
million IU/d subcutaneously after hematologic remission with hydroxyurea.

BMT should be considered early in young patients (<55 y) who have a matched sibling
donor.The mortality rate associated with BMT is 10-20% or less with a matched sibling and 30-40%
with an unrelated donor. The bone marrow registry approximates the cure rate for patients with chronic
myelogenous leukemia (CML) at 50%.
○ Transplantation is recommended within 1 year of diagnosis or after a 1-year trial of
interferon therapy without a complete or significant cytogenetic remission.
○ Most patients with MRD after transplantation require interferon maintenance therapy
anyway, or they may require a reinfusion of T cells collected from the donor.
• Transplantation has been relegated to patients who do not achieve molecular
remissions or show resistance to imatinib and failure to second-generation bcr-abl
kinase inhibitors such as dasatinib.

Surgical Care