OSH STATE UNIVERSITY

INTERNATIONAL MEDICAL FACULTY

SUBMITTED TO: OMOROVA A.H MAM

. SUBMITTED BY :ABOOBAKKAR SAAHIN BANU
GROUP:2B
SUBJECT: HOSPITAL THERAPY
TOPIC: CHRONIC LEUKEMIA
INTRODUCTION:

• Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma

(SLL) is an indolent malignancy characterized by increased production
of mature but dysfunctional B lymphocytes.
• CLL/SLL is defined as a monoclonal lymphoproliferative disease
characterized by the proliferation and accumulation of
morphologically mature but immunologically dysfunctional B-cell
lymphocytes that are smudge cells, as noted on peripheral smear.
• The primary disease sites include peripheral blood, spleen, lymph
nodes, and bone marrow
• CLL and SLL are identical from a pathologic and immunophenotypic
standpoint.
• Both CLL and SLL originate from B-cell lymphocytes but present with
different manifestations depending on where the abnormal cells are
found.
• Usually, the initial leukemic phase represents CLL, where the cells are
present in the blood.
• This eventually progresses to the lymphoma phase, representing SLL,
where the cells are found in the lymph nodes.
• The term SLL is commonly used to represent the lymphoproliferative
process limited to the lymph nodes.
ETIOLOGY:
• The exact etiology of CLL is unknown. Genetic factors, rather than
environmental factors, are the most likely cause of CLL.
• few known risk factors for CLL include occupational causes by
exposure to certain chemicals, radiation exposure, and tobacco users.

• Reports of farmers working around rubber manufacturing industries

and workers with exposure to benzene and heavy solvent have shown
an increased risk of CLL/SLL.
 In atomic bomb survivors, no known increase in the incidence of
CLL/SLL has been noted. However, there has been an increased risk of
other types of leukemia.
The uranium miner population, who suffer exposure to ionizing and
non-ionizing radiation, has shown increased CLL incidence.
Tobacco users and cigarette smokers show a significantly elevated risk
of CLL compared to non-tobacco users.
The Veterans Affairs recognizes CLL as having a relationship to
exposure to Agent Orange or other herbicides during military service
PATHOGENESIS:
• The pathogenesis of CLL/SLL is a two-step process that leads to the
clonal replication of malignant B lymphocytes.
• The first step is the development of MBL cells secondary to multiple
factors such as antigenic stimulation, genetic mutations, and
cytogenetic abnormalities.
• The second step is the progression of MBL to CLL/SLL by the further
insult to the B-cell clone, either due to additional genetic abnormalities
or changes in the bone marrow microenvironment. B-cell antigen
receptor (BCR) expression induces antigen-independent cell-
autonomous signaling, which is an important step in the pathogenesis
of CL
• In CLL, CD5+ B cells are continuously activated by mutations leading to
MBL.
• The accumulation of genetic abnormalities in more mature B cells causes
a clonal division of the neoplastic B-cell within the lymph nodes.
• In CLL/SLL, the most common abnormal physical examination findings
are lymphadenopathy, which is seen in 50 to 90% of patients. Cervical,
supraclavicular, and axillary lymph nodes are the most commonly
affected sites.
• These increased B-cell lymphocytes eventually spill into the peripheral
blood leading to the detection of lymphocytosis on a CB
• These neoplastic B cells escape apoptosis and continue to divide over
time within the lymph nodes.
• They then infiltrate the spleen and bone marrow, causing
splenomegaly and hypercellular bone marrow (on bone marrow
biopsy).
• The splenomegaly leads to increase sequestration of RBCs and
platelets, leading to anemia and thrombocytopenia by decreasing the
RBCs and platelets.
• Patients are more susceptible to autoimmune hemolytic anemia
(positive Coombs test) and autoimmune thrombocytopenia
• These B cells eventually spread throughout the body, causing systemic
symptoms such as fever, night sweats, unintentional weight loss,
fatigue, and early satiety.

• Lack of functional B cells decreases the body’s ability to produce

antibodies for immune responses leading to hypogammaglobinemia,
which eventually leads to an increased risk of infection
• Skin is the most commonly affected nonlymphoid tissue in patients
with CLL.
• Leukemia cutis (skin lesions) mainly involves the face and manifests as
papules, macules, plaques, ulcers, blisters, or nodules. Skin biopsy
can help confirm the diagnosis of CLL. Nonspecific secondary
cutaneous lesions may occur due to bleeding, vasculitis, and infection.
• Exaggerated reactions to insect bites have been reported in patients
as well.
DIAGNOSIS:
• Patients with CLL are often asymptomatic at the initial presentation,
when a routine CBC reveals abnormal lymphocytosis, leading to CLL
diagnosis.
• Approximately 5 to 10% of patients with CLL are symptomatic with B
symptoms such as Fever of > 100.5 degrees F for > 2 weeks with no
evidence of infection; unintentional weight loss >/= 10% of body
weight over the last 6 months; drenching night sweats with no
evidence of infection; extreme fatigue; and early satiety.
• Upon physical examination, 50 to 90% of the patients with CLL present
with localized/generalized lymphadenopathy. The most common sites
include cervical, supraclavicular, and axillary lymph nodes.
• On palpation, the nodes are firm, non-tender, round, and freely mobile.
• Splenomegaly is the second most commonly enlarged lymphoid organ,
seen in 25 to 55% of cases. On palpation, it is painless on non-tender
with a smooth, firm surface.
• Hepatomegaly is seen in 15 to 25% cases. The liver is mildly enlarged
and palpated 2-6 cm below the right costal margin. On palpation, the
liver is firm and non-tender with a smooth surface
• Skin examination is an important part of physical examination
because skin cancers are a relatively frequent CLL complication. Skin is
the most common non-lymphoid tissue involved in patients with CLL.
• Leukemia cutis (skin lesions) mainly involve the face and manifest as
papules, macules, plaques, ulcers, blisters, or nodules. Skin biopsy
can help confirm the diagnosis of CLL. Nonspecific secondary
cutaneous lesions may occur due to bleeding, vasculitis, and infection.

• Exaggerated reactions to insect bites have been reported in for

patients as well
• Infiltration of the spleen and bone marrow with neoplastic B cells causes
splenomegaly and hypercellular bone marrow.
• The splenomegaly leads to increased sequestration of RBCs and
platelets, leading to anemia and thrombocytopenia by decreasing the
RBCs and platelets.
• Patients with anemia are symptomatic with fatigue and shortness of
breath; patients with thrombocytopenia easily bleed/bruises, and
petechiae can be seen on physical examination.
• Lack of functional B cells decreases the body’s ability to produce
antibodies for immune responses leading to hypogammaglobinemia,
which eventually leads to an increased risk of infection
• The first step in the diagnosis of CLL is a peripheral blood smear. The
peripheral blood smear shows an absolute lymphocyte count of
greater than 5000/mcL and smudge cells that confirm CLL.
• Although the diagnostic criteria for CLL are >=5000/mcL B
lymphocytes on peripheral smear, a large proportion of patients
present with an absolute lymphocyte count > 100,000/mcL.
• In patients with SLL, peripheral blood smear shows an absolute
lymphocyte count of less than 5000/mcL along with
lymphadenopathy but without cytopenias. However, lymph node
biopsy is required to confirm the diagnosis of SLL
• Immunophenotypic analysis of the peripheral circulating lymphocytes by peripheral blood flow
cytometry can be performed, which can help confirm the clonality of circulating B cells in CLL patients.
• Flow cytometry can be performed on both peripheral blood and bone marrow aspirate to look for the
classical immunophenotypic markers of CLL. To reiterate, characteristic CLL/SLL lymphocyte
phenotype features include low levels of immunoglobulins (most often IgM immunoglobulin and
sometimes both IgM and IgD); expression of B-cell associated antigens (CD19, CD20, CD21, CD23,
and/or CD24); and expression of CD5 which is a T-cell associated antigen.
• The most common immunophenotype expression of CLL/SLL is the coexpression of CD5, CD19, and
CD23. However, different levels of expression of other immunophenotypic antigens are also seen.
Serum immunoglobulins and free-light chains are measured at baseline to assess the
immunodeficiency and during treatment, to look at immune reconstitution, especially with the newer
generation B-cell receptor signaling drugs.
• As for the light chain immunoglobulins, only one type of light chain suggesting the monoclonality of
the lymphocytes. Rarely, some patients express both kappa and lambda light chains, known as
“Biclonal cll
• Excisional lymph node histology demonstrates diffuse effacement of nodal
architecture along with some scattered residual likely germinal centers.
• These lymph node infiltrates are predominantly composed of small
lymphocytes. However, large lymphoid cells, such as pro-lymphocytes, are
always present in clusters and are known as “ pseudo-follicles”
(proliferation centers), a pathognomic finding, and CLL/SLL patients.
• Spleen histology demonstrates the infiltration of red and white pulp with a
more prominent white pulp involvement compared to red pulp.
• From an imaging standpoint, a CT scan helps in evaluation to see the
degree of lymphadenopathy and organ infiltration in the form of spleen
and liver sizes.
 TREATMENT:
According to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
for “active disease,” indications for treatment include :

• Constitutional symptoms in patients such as fevers >100.5 degrees F or 38.0 degrees C

for ≥2 weeks without evidence of infection, night sweats for ≥1 month without evidence
of infection, unintentional weight loss of ≥10% within the previous 6 months, extreme
fatigue, and early satiety.
•
• Progressive lymphocytosis with >50% increase in lymphocytes over a 2-month period or
lymphocyte doubling time (LDT) of <6 months. LDT is obtained by linear regression
extrapolation of absolute lymphocyte counts at every 2 weeks interval period over a
time span of 2 to 3 months. Patients with initial blood lymphocyte counts of
<30,000/mcL may need to be observed for a longer time period to help determine the
LDT. Also, other lymphocytosis/lymphadenopathy contributing factors (e.g., infection)
other than CLL should be excluded.
Patients with rapid disease progression such as massive (i.e., ≥6 cm
below the left costal margin)/progressive/symptomatic splenomegaly
or massive nodes (i.e., ≥10 cm in longest
diameter)/progressive/symptomatic lymphadenopathy.
Autoimmune hemolytic anemia and/or autoimmune thrombocytopenia
that is poorly responsive or unresponsive to corticosteroids.
Evidence of progressive bone marrow failure by
developing/worsening/symptomatic anemia and/or thrombocytopenia.
• Patients with recurrent infections.
Targeted Agents
Bruton tyrosine kinase (BTK) inhibitors
Single-agent ibrutinib is an effective treatment for older patients with CLL. It has demonstrated
improvement in both overall survival (OS) and progression-free survival (PFS) when compared to
chlorambucil in older patients and when compared to the combination of bendamustine plus
rituximab (BR). In younger patients, ibrutinib plus rituximab or obinutuzumab has demonstrated
an overall PFS and OS benefit when compared to the combination of fludarabine plus
cyclophosphamide and rituximab. Acalabrutinib is another BTK inhibitor that improves PFS when
compared to chlorambucil plus obinutuzumab.[65][66][67][65]
• A combination of venetoclax plus obinutuzumab is particularly used in patients in whom
ibrutinib is contraindicated, such as patients with multiple comorbidities (example, history of
severe bleeding, hepatic impairment, or atrial fibrillation) or if on any anticoagulation
medications. Studies have shown that the combination of venetoclax plus obinutuzumab
demonstrates higher PFS and OS when compared with chlorambucil plus obinutuzumab
Chemoimmunotherapy

Fludarabine, cyclophosphamide, and rituximab (FCR) is an initial treatment option

in younger patients who can tolerate chemotherapy without 17p deletion/TP53
mutation but with IGHV mutated CLL. In patients with IGHV unmutated CLL,
targeted therapy with ibrutinib is preferred over FCR due to improved OS and PFS.
FCR is contraindicated in older patients due to the high risk of infections, adverse
events, and high risk of immunosuppression.[62][68][62]
• Bendamustine plus rituximab (BR) as a treatment of choice for older patients (>
65 years of age) without 17p deletion/TP53 mutation but with IGHV mutated CLL.
In patients with IGHV unmutated CLL, targeted therapy with ibrutinib is preferred
over BR due to improved OS and PFS
• Chlorambucil based therapy is usually not used as an initial treatment for CLL as other
targeted therapy (example, ibrutinib, venetoclax plus obinutuzumab) has demonstrated
higher efficacy in patients with 17p deletion, TP53 mutation, or IGHV unmutated CLL.
• Chlorambucil plus obinutuzumab is a combination that could be used in elderly patients
with IGHV mutated CLL, and recently it was found that the combination of chlorambucil
with obinutuzumab is superior to rituximab plus chlorambucil in achieving a complete
response and prolonging progression-free survival.
• This combination has demonstrated similar efficacy to ibrutinib based therapy and
venetoclax plus obinutuzumab combination therapy in patients with IGHV mutated CLL.
• Adverse effects of chlorambucil include significant anemia, neutropenia, and/or
thrombocytopenia. Less common adverse effects include hepatotoxicity, drug
hypersensitivity, seizures, interstitial pneumonia, pulmonary fibrosis, and infertility
Management of complications of CLL and its therapy
CLL/SLL is characterized by hypo/agammaglobulinemia, which increases the risk of
infections, especially Staphylococcus, H. influenza, Pneumococcus, and herpes.
These infections can be managed with antimicrobials for bacterial, fungal, or viral
infections. For refractory infections in patients with hypogammaglobinemia, or for
2 or more severe infections within a timeframe of 6-month, monthly IVIG infusions
are considered.
• CLL/SLL also produces autoantibodies directed against RBCs and platelets,
leading to immune-mediated hemolytic anemia and thrombocytopenia. These
can be acutely managed with packed RBC transfusion for anemia and platelet
transfusion for bleeding secondary to thrombocytopenia. The cytopenias can be
eventually treated with prednisone.
Relapsed/Refractory CLL

It is important to confirm relapsed/refractory CLL histologically prior to restarting

treatment. Recurrent CLL in asymptomatic patients should be monitored for symptoms
requiring treatment. Richter’s transformation should specifically be excluded. The
treatment of choice at relapse depends upon the initial treatment used and the initial
duration of response to that treatment.

• Ibrutinib is the first-line therapy to improve progression-free survival and response to

treatment in relapsed/refractory CLL. Other drugs of choice for relapsed CLL include
idelalisib (a phosphoinositide 3’-kinase [PI3K] delta inhibitor), Alemtuzumab (a
monoclonal antibody directed against CD52, a cellular marker found in CLL) and
venetoclax (Bcl-2 inhibitor)
Venetoclax is actively used in refractory CLL patients with 17p deletion. Venetoclax induces
brisk apoptosis and occasionally induces tumor lysis syndrome. Anti-CD19 chimeric
antigen receptor (CAR) T-cell therapy has also been active in refractory cases. Anti-CD20
monoclonal antibody (rituximab, ofatumumab, obinutuzumab) may briefly alleviate
symptoms in relapsed/refractory CLL patients.

• Allogeneic Hematopoietic Stem Cell Transplantation is rarely performed in CLL but has
been used in refractory cases in appropriate patients. Those with a very aggressive form
of the disease, such as patients with 17p deletion, especially in younger patients, HLA-
matched donors, should be recommended to get bone marrow transplant. Those
without a matched donor or older in age can be given a trial of ibrutinib. Palliative
radiation therapy can be given to chemotherapy-resistant areas of lymphadenopathy,
liver, and spleen. Total body irradiation occasionally helps relieve symptoms temporarily.
DIFFERENTIAL DIAGNOSIS:
Acute Lymphoblastic Leukemia (ALL)
Acute promyelocytic leukemia
Diffuse large cell lymphoma
Follicular lymphoma
Hairy cell leukemia
Lymphoblastic lymphoma
Mantle cell lymphoma
Non-Hodgkin lymphoma
Monoclonal B-cell lymphocytosis (MBL)
Prolymphocytic lymphoma (PLL)
Lymphoplasmacytic lymphoma
• Histologic transformation — CLL/SLL can convert to more aggressive histology (Richter transformation), either
diffuse large B cell lymphoma or Hodgkin lymphoma.
RAI CLASSIFICATION:
RAI Classification

Stage 0: Absolute lymphocytosis of > 10,000/mcL in peripheral blood and >/=

30% lymphocytes in bone marrow
Stage I: Stage 0 plus lymphadenopathy (enlarged lymph nodes)
Stage II: Stage 0 plus hepatomegaly or splenomegaly
Stage III: Stage 0 plus anemia with hemoglobin < 11 g/dL (< 110 g/L) due to
bone marrow infiltration of tumor cells.
• Stage IV: Stage 0 plus thrombocytopenia with platelet counts <100,000/mcL
due to bone marrow infiltration of tumor cells.
BINET CLASSIFICATION:
Binet Classification

Stage A:
Absolute lymphocytosis of > 10,000/mcL in blood and ≥ 30% lymphocytes in bone marrow
Hemoglobin ≥ 10 g/dL ( ≥ 100 g/L)
Platelets ≥100,000/mcL
≤ 2 involved sites*
Stage B: As for stage A, but 3–5 involved sites
• Stage C : As for stage A or B, but hemoglobin < 10 g/dL (< 100 g/L) or platelets <
100,000/mcL.
CHRONIC MYELOID LEUKEMIA:
• Chronic myeloid leukemia (CML), BCR-ABL1-positive, is classified as a
myeloproliferative neoplasm predominantly composed of
proliferating granulocytes and determined to have the Philadelphia
chromosome/translocation t(9;22)(q34;q11.2). CML affects both the
peripheral blood and the bone marrow.
• There is an increased incidence of CML among atomic bomb
survivors; however, the predisposing risk factors are unknown. This
activity reviews the pathophysiology, evaluation, and management of
chronic myeloid leukemia (CML) and explains the role of the
interprofessional team in caring for patients with this condition
ETIOLOGY AND EPIDEMIOLOGY:
Etiology
• There is an increased incidence of CML among atomic bomb survivors;
however, the predisposing risk factors are unknown
• Epidemiology
• CML has a worldwide annual incidence rate of 0.87 people per 100,000,
increasing with age up to 1.52 in patients older than 70 years. There is a slight
male predominance. The median age of diagnosis is 56 years old.
• In the United States, the annual incidence rate between 2009 and 2013 was
1.4 and 2.2 per 100,000 for females and males, respectively.
• Estimates for 2018 were 8490 new cases of CML and 1090 estimated deaths
PATHOGENESIS :
• The fusion oncoprotein BCR-ABL1 defines CML. 90% to 95% of patients with
CML have a shortened chromosome 22 because of a reciprocal translocation
t(9;22) (q34;q11.2) called the Philadelphia chromosome.
• The ABL1 gene encodes a non-receptor tyrosine kinase on chromosome 9,
and BCR is a breakpoint cluster region on chromosome 22. The translated
oncoprotein, in most cases, is 210-kd and called p210 BCR-ABL1. Alternative
splicing results in p190 and p230 BCR-ABL1, which may show different
presentations.
• This oncoprotein acts as a constitutively expressed defective tyrosine kinase.
The downstream pathways affected include JAK/STAT, PI3K/AKT, and
RAS/MEK; they involve cell growth, cell survival, inhibition of apoptosis, and
activation of transcription factors
• Remainder of patients has variant or complex translocations involving
additional chromosomes detected by routine cytogenetics or a cryptic
BCR-ABL1 translocation detected with fluorescent in situ hybridization
(FISH) or reverse transcriptase-polymerase chain reaction (PCR)
HISTOPATHOLOGY:
Chronic Phase
• The peripheral blood smear will show a leukocytosis due to granulocytes in
various stages of maturation. There will be a bimodal distribution with
higher proportions of mature segmented neutrophils and myelocytes.
• Blast cells will account for less than 2% of the white blood cells. Increased
basophils and eosinophils are common. Significant dysplasia affecting
greater than 10% of the granulocyte population is absent. Monocytosis may
be present;
• however, it is usually less than 3% of the white blood cells. Platelets usually
range from the normal range to a significant increase. Thrombocytopenia is
an uncommon finding.
• Bone marrow aspirate and biopsy will show hypercellularity with marked
granulocytic proliferation and significantly increased myelocytes, although
significant dysplasia should be absent.
• Blasts are usually less than 5%. Erythroid precursors are decreased considerably,
and there is an increased myeloid to erythroid ratio. Megakaryocytes may be
reduced, normal, or increased.
• About half of the cases show a megakaryocytic proliferation. The megakaryocytes
in CML show a small, hypo-lobate “dwarf” morphology. The biopsy will show
immature granulocytes in a thickened band of 5 to 10 cells along bone trabeculae.
• Adjacent to bone trabeculae is the normal distribution site of immature
granulocytes; however, it is usually 2 to 3 cells thick. The bone marrow may also
show increased reticulin fibrosis
Accelerated Phase:
The peripheral smear may or may not show increased blasts (10% to 19%). The
bone marrow aspirate and biopsy will show similar changes to chronic phase CML
with increased blasts (10% to 19%), possibly dysplastic changes in granulocytes,
and increased reticulin and collagen fibrosis.
Blast Phase:
• The peripheral smear and/or bone marrow aspirate will show greater than 20%
blasts, or there will be an extramedullary proliferation of blasts. Most cases will
show blasts with myeloid differentiation; however, other lineages or
combinations may be present, including lymphoblasts. Extramedullary
proliferation is most commonly seen in the skin, lymph nodes, bone, and the
central nervous system (CNS).
DIAGNOSIS:
Initially, if CML is suspected, cytogenetic testing, fluorescent in situ hybridization
(FISH), and/or reverse transcriptase-polymerase chain reaction (PCR) to determine the
Philadelphia chromosome, or BCR-ABL1 oncoprotein presence can be performed on
peripheral blood.

• At the time of diagnosis, laboratory blood testing should include a complete blood
count with differential, chemistry panel, hepatitis panel, and a quantitative PCR for
BCR-ABL1.
• A baseline bone marrow aspirate and biopsy should be performed with cytogenetics.
Quantitative PCR should be repeated every three months after initiation of therapy.
After BCR-ABL1 is less than or equal to 1% by international scale, quantitative PCR
should continue for two years and then every 3 to 6 months after two years
Chronic phase CML is established, additional evaluation includes determining the risk score
using Sokal et al. or Hasford et al. risk calculations before determining first-line therapy.

Sokal risk calculation uses age, spleen size, platelet count, and percentage of myeloblasts in
peripheral blood to determine the risk group.[11]
Hasford risk calculation uses age, spleen size, platelet count, and percentage of blasts,
eosinophils, and basophils in the peripheral blood to determine the risk group.[12]
• If accelerated or blast phase CML is diagnosed or progresses from chronic phase CML,
additional testing should include flow cytometry to determine lineage, mutational analysis,
and HLA testing if allogeneic hematopoietic stem cell transplant (HCT) is being considered.
Additional bone marrow cytogenetics and mutational analysis should be considered when
there is a failure to reach response milestones or any sign of hematologic or cytogenetic
relapse
TREATMENT:
There are 4 FDA-approved, first-line treatments for chronic phase CML that are commercially available
tyrosine kinase inhibitors, including first-generation imatinib and second-generation dasatinib, nilotinib,
and bosutinib.
Dosing
Imatinib: 400 mg daily
Bosutinib: 500 mg daily
Dasatinib: 100 mg daily
Nilotinib: 300 mg twice a day
For chronic phase, CML with intermediate- or high-risk score, second-generation tyrosine kinase inhibitors
(bosutinib, dasatinib, nilotinib) as first-line therapy may have an additional benefit over imatinib.
• Ponatinib, a third-generation tyrosine kinase inhibitor, dosed at 45 mg daily, is a third-line treatment
option in chronic phase CML for patients who have failed to respond to multiple tyrosine kinase
inhibitors and for individuals who have the T315I mutation.
Advanced CML (accelerated or blast phase) has additional therapeutic
considerations. Second- or third-generation tyrosine kinase inhibitor therapy
should be initiated to reduce the CML burden and be considered for early
allogeneic hematopoietic stem cell transplant (HSCT).[6] Omacetaxine is a
chemotherapeutic agent that is an additional treatment option in cases
refractory to tyrosine kinase inhibitor therapy that advanced from chronic
phase CML.

Allogenic HSCT should be considered in patients resistant to tyrosine kinase

inhibitor therapy in chronic phase CML and cases of advanced CML.
• Clinical trial participation should be considered for all patients
DIFFERENTIAL DIAGNOSIS:
Differentiating CML from other causes of granulocytic leukocytoses, such
as infections or drugs, is necessary. Most causes of reactive leukocytosis
have a white blood cell count less than 50 x 10/L and show toxic changes
such as toxic granulation and Dohle bodies. There will also be an absence
of basophilia.

• Other myeloproliferative disorders such as chronic neutrophilic

leukemia (CNL) and polycythemia vera (PV) may present with
leukocytosis and thrombocytosis. Both CNL and PV will lack the BCR-
ABL1 fusion gene. CNL is rare and presents with mature segmented
neutrophilia and lacks a bimodal leukocytosis with myelocytes
STAGING:
Staging is determined by the phase of the disease, which includes a chronic phase,
accelerated phase, and blast phase.
The chronic phase has less than 10% blasts, asymptomatic to mild symptoms, and
responds to tyrosine kinase inhibitor therapy.
• The World Health Organization (WHO) defines accelerated phase CML as having one or
more of the following criteria:
• Persistent or increasing high white blood cell count (greater than 10 x 10^9/L)
unresponsive to therapy
• Persistent or increasing splenomegaly unresponsive to therapy
• Persistent thrombocytosis (greater than 1000 x 10^9/L) unresponsive to therapy
• Persistent thrombocytopenia (less than 100 x 10^9/L)
• Greater than or equal to 20% basophils in peripheral blood
10-19% blasts in peripheral blood or bone marrow (without extramedullary blast
proliferation)
Additional chromosomal abnormalities in Philadelphia chromosome-positive cells
at diagnosis
Any new clonal chromosomal abnormality in Philadelphia chromosome-positive
cells during therapy
The WHO also considers resistance to tyrosine kinase inhibitors as provisional
criteria for determining accelerated phase CML.

• Blast phase CML is defined by greater than or equal to 20% blasts in the
peripheral blood and/or bone marrow or extramedullary blast proliferation
COMPLICATIONS:
Complications
Complications of CML can include:

Hepatomegaly and/or splenomegaly

Worsening anemia
Changes in platelet count changes resulting in clotting or bleeding complications
Recurrent infections
Bone pain
• Fever