This document provides an overview of chronic myelogenous leukemia (CML) for primary care physicians. It discusses the epidemiology, clinical manifestations, molecular pathophysiology, natural history, diagnosis, and treatment of CML. Key points include: CML represents 15-20% of adult leukemias, with the median age of onset being 45-55 years. The Philadelphia chromosome, resulting from a translocation, produces a Bcr-abl fusion gene that drives uncontrolled proliferation. CML progresses through chronic, accelerated, and blast phases if left untreated. Tyrosine kinase inhibitors like imatinib revolutionized treatment by targeting the Bcr-abl protein. Imatinib induces high rates of remission but side effects can include

1. Chronic Myelogenous Leukemia
for Primary Care Physicians
Presenter; Elynse Kamugisha
Facilitator; Erius Tebuka

2. Epidemiology
• Chronic myelogenous leukemia (CML) represents approximately 15%
to 20% of the leukemias in adults, with an annual incidence of 1 to 2
cases per 100,000 (approximately 5000 new cases in the USA per
year).
• The median age at presentation is 45 to 55 years, although all age
groups, including children are affected
• The male-to-female ratio is 1.4:1.
• The prevalence of CML is steadily increasing in the Western world
because of the dramatic effect of tyrosine kinase inhibitors (TKI) on
survival.

3. Clinical Manifestations
• Clinical findings at diagnosis vary among reported series and also
depend on the stage at diagnosis.
• Twenty percent to 50% of patients are asymptomatic at the time of
diagnosis after abnormal routine blood.
• For those patients who present with symptoms, the most common
finding include fatigue/lethargy, bleeding episodes because of platelet
dysfunction (ie, purpura, menorrhagia, prolonged bleeding after
dental extraction, and other mucosal bleeding, such as epistaxis),

4. • weight loss, anorexia, excessive sweating, abdominal fullness or pain
because of splenic pathology, and malaise.
• Frequently, patients present with physical findings of splenomegaly,
but hepatomegaly is unusual. Involvement of extramedullary tissues,
such as the lymph nodes, soft tissues, and skin, is generally limited to
patients presenting after progression to acute leukemia.

5. Molecular Pathophysiology
• The Philadelphia (Ph) chromosome, first described in 1960, is the
hallmark of CML. It is a shortened chromosome 22 resulting from a
Reciprocal translocation, t(9;22) (q34; q11), between the long arms of
chromosomes 9 at the Ableson leukemia virus (ABL) gene and 22 at
the breakpoint cluster region (BCR) gene.
• Because of this translocation, a Bcr-abl fusion gene is generated that
translates into a chimeric Bcr-abl protein with deregulated tyrosine
kinase activity.
• The Ph chromosome is found in up to 95% of patients, with the other
5% having a complex or variant translocation involving additional
chromosomes but resulting in the same Bcr-abl fusion gene

7. Natural History
• CML is a clonal neoplasm of hematopoietic progenitor cells and
involves myeloid, monocytic, erythroid, megakaryocytic, B-lymphoid,
and occasionally T-lymphoid lineages.
• This disease has a multiphasic clinical course, including chronic,
accelerated, and blast phases. A median of 3-5 years after onset, CML
progresses to the accelerated and blast phases. The chronic phase is
present at the time of diagnosis in approximately 85% to 90% of
patients

8. Chronic-phase CML
• Chronic-phase CML resembles a benign expansion of myelopoiesis
where myeloid progenitor cells expand at various stages of
maturation and are released prematurely into the peripheral blood
and relocate to extramedullary locations. The chronic phase is a
genetically unstable state, and the high proliferative rate allows for
the accumulation of additional molecular and chromosomal
abnormalities, which leads to impairment of hematopoietic
differentiation and disease transformation.

9. accelerated phase
• During the accelerated phase, neutrophil differentiation becomes
progressively impaired. The phase is characterized by leukocytosis
with an increase in the number of blasts in the periphery and bone
marrow (generally between 10% and 19%), basophilia, increase or
decrease in platelet count unrelated to treatment, and clinical
manifestations, such as fever, splenomegaly, extramedullary disease,
weight loss, and bone and joint pain. During this phase, leukocyte
counts are more difficult to control with treatment.

10. • The accumulation of chromosomal abnormalities and uncontrolled
differentiation ultimately results in acute leukemia, or blast-phase
CML. This phase is usually marked by similar symptoms as in the
accelerated phase with an even higher number of blasts in the blood
and bone marrow (generally >20%). One-third of acute leukemias
resemble B-lineage acute leukemia, and two-thirds are similar to
acute myeloid leukemia.
• Median survival in the blast phase is less than 6 months, with
infection and hemorrhage being the most common causes of death

11. DIAGNOSIS
• The diagnosis of CML is first suspected by clinical findings described earlier
and typical findings on peripheral blood and bone marrow specimens. The
peripheral smear demonstrates a leukocytosis with a median white count
of 100/L (usually greater than 25/L). The differential can show all cell types
included in the granulocyte spectrum of maturation. Absolute basophilia is
a universal finding and absolute eosinophilia is seen in 90% of cases.
Absolute monocytosis is not uncommon.
• Platelet count can be normal or elevated; platelet counts >600/L are seen
in 15% to 30% of patients. The median hemoglobin for patients <40years
old is 10.4 g/dL, and 11.4 g/dL for patients >40 years old.
•

12. • Bone marrow biopsy shows hypercellularity, increased
myeloid:erythroid cell ratio, increased megakaryocytes, and
granulocytic hyperplasia with a maturation pattern reflecting what is
seen on the peripheral blood smear. The aspirate differential with
blast percentage helps to determine the disease phase.
• The final diagnosis of CML, however, is based on the detection of the
Ph translocation. This is detected using conventional cytogenetic
analysis (karyotype) or fluorescence in situ hybridization (FISH)
analysis or by reverse transcription-polymerase chain reaction (RT-
PCR). FISH and RT-PCR analysis can be performed on peripheral
blood. All patients with CML have positive results by at least one of
these tests.

13. Tyrosine Kinase Inhibitors
• Imatinib mesylate, a potent oral TKI, has revolutionized the treatment of
CML in the last decade. Inhibiting the tyrosine kinase activity of Bcr-abl
blocks proliferation and induces apoptosis in the cells expressing Bcr-abl.
• Before imatinib, stem cell transplant (SCT) and interferon alpha-based
treatment were the treatments of choice in newly diagnosed patients
• A randomized phase III trial of imatinib as first-line therapy in chronic
phase CML compared to interferon plus cytarabine, known as the IRIS trial
demonstrated the benefit of imatinib in 2003. The estimated rates of
complete cytogenetic response (CCyR), or absence of Ph-positive cells in
the bone marrow, at 18 months were 76.2% with imatinib vs 14.5% with
interferon and cytarabine (P < 0.001)

14. • Freedom from progression to the accelerated phase or blast phase
was 96.7% with imatinib and 91.5% in the combination-therapy
group; 89% of patients on the interferon arm.
• The IRIS 5-year follow-up analysis reported that the rate of CCyR was
87%; progression-free survival was 83%, and overall survival was 89%
in the patients randomized to imatinib.
• 93% of the patients had not progressed to the accelerated phase or
blast crisis

15. • Several mechanisms have been suggested as the cause for resistance
to imatinib. Of those, acquiring point mutations in the kinase domain
of Bcr-abl has been identified in 30% to 50% of patients who become
resistant to imatinib.
• The second-generation TKIs, including nilotinib and dasatinib, were
developed with the intention of creating more potent agents.
• Studies have confirmed that 50% to 70% of patients with imatinib
resistance or imatinib intolerance have durable responses with these
agents

16. • Nilotinib and dasatinib have since been approved for first-line
therapy based on these studies; however, longer follow-up will be
needed to confirm a sustained response with these agents.
• Other current treatment CML is a a third-generation TKI ponatinib.
• The TKI should be initiated immediately at the time of diagnosis with
the goal being to reduce the number of cells containing the Ph
chromosome and decrease the probability of the development of
new mutations that could lead to blast crisis.

18. Response to TKI therapy typically proceeds in an orderly manner:
• first, restoration of spleen size and normalization of the blood count
(hematologic remission);
• then, reversion of the bone marrow to Ph negativity (cytogenetic
remission or CCyR);
• and eventually with reduction in the number of Bcr-abl transcripts in
the blood and marrow to very low or undetectable levels (molecular
remission )

19. • The level of the Ph chromosome and Bcr-abl can be monitored by the
same tests used to make the diagnosis of CML, including standard
cytogenetics,FISH and RT-PCR

20. • Patients responding to TKI therapy should be continued on the drug
indefinitely. Patients who are not achieving a cytogenetic or
molecular remission or who are losing their response to therapy must
be recognized early so that alternative therapy, such as a different TKI,
can be initiated as soon as possible to prevent the potential for
acceleration of disease.

21. • Patients who present with acute leukemia or develop acute leukemia
despite TKI therapy should be evaluated for SCT with or without
induction chemotherapy, depending on the case.
• Young patients with certain mutations that render their leukemic
cells resistant to TKI therapy should also be considered for early SCT.
With SCT, long-term survival ranges from 50% to 80%. Treatment-
related mortality and morbidity is 10% to 20%

22. Side Effects of TKIs
Overall, imatinib is well tolerated. Although adverse events may be observed
in up to 50% of patients, these are usually mild and manageable.
The most common hematological adverse event is myelosuppression. Severe
neutropenia occurs in 20% to 45% of patients, and thrombocytopenia occurs
in 9% to 25% of patients. Severe anemia occurs in only 5% to 10%
Neutropenia can often be managed with growth-colony stimulating factor,
and anemia usually responds to erythropoietin. Therapy is typically
interrupted in the event of severe neutropenia or thrombocytopenia until
the cytopenias recover and then dose reduction is considered

23. • Nonhematological toxicities include nausea, edema (peripheral and
periorbital), diarrhea, liver toxicity, skin rash, muscle cramps, bone or
joint pain, and fatigue.
• Nonhematologic toxicities typically are low grade, diminish over time,
and can be well managed with conservative supportive care without
needing to change dose or interrupt therapy. For example, nausea is
markedly reduced when the drug is taken with food.

24. • As for the second-generation TKI, they have a different side-effect
profile. Pleural and pericardial effusions may occur in a small number
of patients treated with dasatinib.
• The effusions usually improve with cessation of the drug with or
without the addition of steroids.
• Nilotinib causes more liver function abnormalities compared to
imatinib and also is associated with higher rates of rash, headache,
pruritis, and alopecia.

25. • Given the excellent results seen with the TKI, the prevalence of
patients with CML treated with a TKI is expected to increase
markedly.
• This raises two critical concerns that are important for primary care
physicians. The first is compliance. Patients on the TKIs feel good and
often are not compliant with taking their medications. In one study
26% of patients had an adherence rate <90% and this correlated with
poor long-term outcome

26. • Several drugs or herbal medications may increase the toxicity or
decrease the efficacy of the TKI. Reviewing the drug interactions
before prescribing new medications for patients on TKI is prudent to
prevent any unexpected outcomes. For example, as previously
mentioned, the interaction of nilotinib with other medications may
cause a prolonged QT interval.
• By contrast, the TKI may affect the drug levels of different
medications. For example, imatinib can inhibit cytochrome P-450
pathways, and therefore, careful monitoring of the international
normalized ratio with warfarin therapy is advisable

27. Pregnancy
• There is limited information regarding the successful management of CML
during pregnancy. The effects of imatinib on fertility, pregnancy, and
lactation are known mostly from animal studies.
• The current recommendation, for both male and female patients, is to
practice adequate contraception while on therapy and to abstain from
breastfeeding. Patients who become pregnant while on therapy should be
made aware of the potential hazards to the fetus.
• In addition, the risk of relapse/disease progression if imatinib is
discontinued during pregnancy should also be considered. There are only
anecdotal case reports of patients who continued therapy throughout
pregnancy, and they have resulted in the birth of normal babies, although
sometimes with a low birth weight

28. • For patients diagnosed at the time of pregnancy, it is recommended
to avoid medical intervention in the first trimester. Leukapharesis may
be considered if the mother is symptomatic with leukostasis.
Following the first trimester, either hydroxyurea or interferon may be
used with relative safety

29. • Potential targets in signaling pathways downstream of Bcr-abl are
being investigated. Combining TKIs with additional signal transduction
inhibitors may yield increased benefit in patients with CML.
• Agents targeted against leukemia cells expressing Bcr-abl with
particular mutations that confer resistance to existing TKIs are being
studied currently in patient trials .

30. • THANK YOU.