CHRONIC GRANULOCYTIC LEUKEMIA

Definition: chronic granulocytic leukemia (CGL) is a clonal

malignant transformation of the stem cell, characterized by
proliferation of the granulocytes which retain their capacity to
differentiate.
The hallmark of the CGL is :

• 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.
Etiology :
1. - Irradiation : CGL appears with a higher incidence in professional ,
therapeutical or accidental irradiated people(the median latent period
seems to be 4 years in ankylosing spondylitis, 9 years in uterine
cervical cancer and 11 years in Japanese atomic bombs survivors);
2. -Chemicals and drugs : the role played by certain organic solvents
(as benzene) or drugs ( cytostatics, DNA topoisomerase II inhibitors) is
controversial;
3. -Genetic background : a higher incidence of the HLA antigens CW3
and CW4 has been found, suggesting thus a greater susceptibility to
CGL. The disease is acquired, not inherited: children born from
mothers with CGL are not affected, neither the identical twin of a
patient with CGL ;
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:
1. - CGL appears from the malignant transformation of a single stem cell.
Arguments for this :
• the involvement of erythropoiesis, thrombopoiesis and of all of
the granulocytic lineages during the chronic phase of the CGL;
 •the presence of the Ph-chromosome in the precursors of the
erythropoietic, granulocytic and thrombocytic precursors, in
the mono-macrophagic precursors well as (sometimes) in the
lymphocytic ones;
• studies on isoenzymes of the glucose-6-P-dehydrogenase and on
the presence of Ph-chromosome in patients who are a mosaic
for sex chromosomes, as in Turner or Klinefelter syndrome;
2. -the abnormal clone coexists in the same patient with
normal stem cells;

3. -the cytogenetic hallmark of the CGL is the presence of the Ph-

chromosome. It was recognized first as a small 22 chromosome and
has been denominated thus after the city where it has been discovered.
Later studies demonstrated that that 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.

4. -the Ph-chromosome plays (with the greatest probability) the key

pathogenic role.Some arguments :
• -is found in 95 % of the patients ;
• -even in those patients where the Ph-chromosome could not
been revealed by classical methods, the chimeric new gene bcr-
abl can be detected by polymerase chain reaction
• - the Ph-chromosome can be detected in the very early phase of
the CGL;
• -it persists in all stages of the disease, but during the blast crisis,
other chromosomal abnormalities associate (duble Ph, deletion
of Y, trisomy 9, 19 or 21)
• -the affected clone coexists with normal stem cells;
• -in cell culture, the loss of Ph-chromosome associated with loss
of proliferative advantage;
• -the effects of bcr-abl on cell adhesion reveal the loss of blocking
mitosis in clones Ph-positive chromosome, which is the
hallmark of a proliferative advantage;
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:
• splenic and liver enlargement;
• mild lymph nodes enlargement (especially in blast
crisis);
• nodular proliferation (“granulocytoma” ) in organs
and systems, as the disease progresses;
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.

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, and even peripheral

blood, should reveal the 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

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.
o With imatinib at 400 mg/d orally in patients with newly diagnosed
Ph-positive CML in the chronic phase, the complete cytogenetic
response rate is 70% and the estimated 3-year survival rate is 94%.
With higher doses of 800 mg/d, the complete cytogenetic response
rate increases to 98%, the major molecular response rate is 70%,
and the complete molecular response rate is 40-50%.
o For patients with chronic-phase chronic myelogenous leukemia
(CML), imatinib at 400 mg/d is the best candidate for primary
therapy, because it induces a complete hematologic response in
almost all patients and causes a high cytogenetic response rate
  The conclusions of this study in terms of hematologic and
cytogenetic responses, tolerability, and the likelihood of
progression to accelerated-phase or blast-crisis CML, 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).
o 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.13,14
o All siblings should be typed for human leukocyte antigen (HLA)-A,
HLA-B, and HLA-DR. If no match is available, the HLA type can be
entered into a bone marrow registry for a completely matched
unrelated donor.
o 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%.
o Transplantation is recommended within 1 year of diagnosis or after
a 1-year trial of interferon therapy without a complete or significant
cytogenetic remission.
o 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. Mechanisms for resistance to imatinib are: (1) BCR-ABL
amplification, and (2) BCR-ABL– independent mechanisms such as: (A)
Src family of kinase activation and (B) additional molecular events.
• Previous exposure to imatinib before transplantation does not adversely
effect posttransplant outcomes such as overall survival and progression-
free survival with 90% engraftment, higher relapsed mortality (24%) and
lower graft versus host disease (GVHD) (acute, 42%; chronic, 17%)

Surgical Care

• Splenectomy and splenic irradiation have been used in patients with large
and painful spleens, usually in the late phase of chronic myelogenous
leukemia (CML).
o This is rarely needed in patients whose disease is well controlled.
o Some authors believe that splenectomy accelerates the onset of
myeloid metaplasia in the liver. Splenectomy is associated with high
perioperative morbidity and mortality rates because of bleeding or
thrombotic complications.