This document provides information on chronic myeloid leukemia (CML), including: 1. CML is driven by the BCR-ABL1 fusion gene resulting from the Philadelphia chromosome, and was historically treated with tyrosine kinase inhibitors (TKIs) like imatinib which improved 10-year survival to 85%. 2. CML progresses through chronic, accelerated, and blast phases; TKIs can stabilize the disease in chronic phase and reduce transformation rates. 3. Diagnosis involves detecting the Philadelphia chromosome through cytogenetics of bone marrow samples and monitoring molecular response to TKIs is now standard practice.

1. MYELOPROLIFERATIVE
NEOPLASMS-1
Ajay Kumar Yadav
PGY3,Medicine
IOM-TUTH, Kathmandu

2. LAYOUT
• WHO classification of MPN
• CML
• Introduction
• Diagnosis
• TKIs
• Monitoring of therapy
• Treatment
• Investigational therapies

3. INTRODUCTION OF CML
• MPN characterized by
 Share an origin in a multipotent hematopoietic progenitor cell;
 Overproduction of one or more of the formed elements of the blood without significant
dysplasia;
 Predilection to extramedullary hematopoiesis, myelofibrosis, and
 Transformation at varying rates to acute leukemia.

4. WHO classification of CML

5. CHRONIC MYELOID LEUKEMIA(CML)

6. INTRODUCTION
• CML is a clonal hematopoietic stem cell disorder.
• The salient biologic features of CML cells are as follows: increased proliferation, resistance to
apoptosis, perturbed interaction with bone marrow stromal cells, and genetic instability
• The disease is driven by the BCR-ABL1 chimeric gene product, resulting from a reciprocal
balanced translocation between the long arms of chromosomes 9 and 22, t(9;22) (q34;q11.2),
cytogenetically detected as the Philadelphia chromosome.
• Untreated, the course of CML may be biphasic or triphasic, with an early indolent or chronic
phase, followed often by an accelerated phase and a terminal blastic phase.

7. • Before the era of TKIs, the median survival in CML was 3–7 years, and the 10-year
survival rate was 30% or less.
• Today, the estimated 10-year survival rate with imatinib mesylate is 85%.
• Allogeneic SCT is now offered as second- or third-line therapy after failure of TKIs.

8. EPIDEMIOLOGY
• CML accounts for 15% of all cases of leukemia.
• Sex : Slight male preponderance (M:F ratio 1.6:1).
• Age :
• The median age at diagnosis is 55–65 years. ( < 20 years : 3%)
• CML incidence increases slowly with age, with a steeper increase after the age of 40–50
years.
• The annual incidence of CML is 1.5 cases per 100,000 individuals.
• With TKI therapy, the annual mortality has been reduced from 10-20% to about 2%.

11. PHASES OF CML

12. 2016 revised criteria fot accelerated CML

13. Transformation to Accelerated and Blastic
Phase
• CCA/Ph+ is present in 70% to 80% of cases and includes a number of nonrandom abnormalities,
the most common of which are +8 (34% of cases with CCA/Ph+), +Ph (30%), i(17q) (20%), +19
(13%), -Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%).
• CML-BP : Pre-B-lymphoid (25%), Myeloid (70%), or Indeterminate (5%) phenotype

14. ETIOLOGY
• No familial associations.
• No associations exist with exposures to benzene or other toxins, fertilizers, insecticides, or
viruses.
• Not a frequent secondary leukemia following therapy of other cancers with alkylating agents
and/or radiation.
• Exposure to ionizing radiation
• Dose dependent risk of CML
• Peaks at 5–10 years after exposure
• The median time to development of CML among atomic bomb survivors was 6.3 years.

15. PATHOPHYSIOLOGY
• The t(9;22) (q34;q11.2) is present in more than 90% of classical CML cases.
• It is present in hematopoietic cells (myeloid, erythroid, megakaryocytes, and monocytes; less
often mature B lymphocytes; rarely mature T lymphocytes, but not stromal cells), but not in other
cells in the human body.
• BCR-ABL1 fusion gene product Codes for a novel oncoprotein of MW 210 kDa, referred to as
p210BCR-ABL1 aka Major BCR  Exhibits constitutive kinase activity Excessive proliferation and
reduced apoptosis of CML cells.
• Minor BCR region (mBCR) : p190BCR-ABL1
• Micro-BCR (μ-BCR) : Larger p230BCR-ABL1 , a/w more indolent CML course.

16. Cont..
• BCR-ABL1 TKIs bind to the BCR-ABL1 kinase domain (KD), preventing the activation of
transformation pathways and inhibiting downstream signaling.
• The cause of the BCR-ABL1 molecular rearrangement is unknown.
• Atypical CML or chronic myelomonocytic leukemia.
• Do not respond to TKI therapy
• Poor prognosis with a median survival of about 2–3 years.
• The transition of CML from chronic to accelerated-blastic phase are poorly understood.

17. Cont..
• BCR-ABL1 itself induces genetic instability that leads to the acquisition of additional mutations
and eventually to blastic transformation.
• This is supported by the effect of TKIs on the ability to stabilize the CML genome, leading to a
much reduced transformation rate.
• Resistance to TKIs :
• Various mechanisms
• The most clinically relevant one is the development of different ABL1 kinase domain
mutations that prevent the binding of TKIs to the catalytic site (ATP binding site) of the
kinase.

18. PROGRESSION OF CP-CML TO BC-CML

19. CLINICAL PRESENTATION
• Depends upon the availability of health care.
• Easy access to health care : 50–60% of pts. diagnosed on routine blood tests and
have minimal symptoms at presentation, s/a fatigue.
• Limited access to health care : Present with high CML burden including
splenomegaly, anemia, and related symptoms (abdominal pain, weight loss,
fatigue).

20. SYMPTOMS
• Most pts. with CML (90%) present in the indolent or chronic phase.
• Asymptomatic
• When symptomatic present with manifestations of anemia and splenomegaly.
• Fatigue, malaise
• LOW (if high leukemia burden)
• Early satiety and left upper quadrant pain or mass(from splenomegaly).
• Less common presenting symptoms include thrombotic or vasoocclusive events (from severe
leukocytosis or thrombocytosis).
• Include Priapism, CV complications, MI , venous thrombosis, visual disturbances, dyspnea
and pulmonary insufficiency, drowsiness, loss of coordination, confusion, or stroke.

21. Cont..
• High basophil counts may be associated with histamine overproduction causing pruritus,
diarrhea, flushing, and even GI ulcers.
• Accelerated or blastic phase
• Unexplained fever
• Significant weight loss
• Severe fatigue
• Bone and joint aches
• Bleeding and thrombotic events
• Infections

23. PHYSICAL FINDINGS
• Pallor (30-50%)
• Splenomegaly (20–70%)
• Hepatomegaly (10–20%)
• Lymphadenopathy (5–10%)
• Extramedullary disease (skin or subcutaneous lesions)
• Pruritus or scratch marks

24. HEMATOLOGIC FINDINGS
• Leukocytosis : ranges from 10–500 × 109/L
• Left-shifted shift with predominance of neutrophils and the presence of bands,
myelocytes, metamyelocytes, promyelocytes, and blasts (usually ≤5%).
• Basophils and/or eosinophils : Frequently increased.
• Thrombocytosis is common.

27. Cont..
• Thrombocytopenia is rare and, when present, suggests a worse prognosis,
disease acceleration, or an unrelated etiology.
• Anemia : 1/3rd of pts.
• Biochemical abnormalities
• Low LAP score
• High levels of vitamin B12, uric acid, LDH, and lysozyme.

28. MARROW FINDINGS
• Hypercellular BM
• Marked myeloid hyperplasia
• High M/E ratio : 15–20:1
• Marrow blasts :
• 5% or less : Chronic phase
• 10-19% : Accelerated phase
• >20 % : Blast phase
• Increased reticulin fibrosis (by Snook’s silver stain) is common

29. • Findings in CML Transformation Progression of CML is usually a/w leukocytosis resistant to
therapy, increasing anemia, fever and constitutional symptoms, and increased blasts and
basophils in the peripheral blood or marrow.

31. CYTOGENETICS and MOLECULAR FINDINGS
• Classical CML (90% cases): t(9;22)(q34;q11.2) ;Philadelphia chromosome
• Variant Ph : involves ≥3 translocations that include chromosomes 9 and 22 and one or more
other chromosomes.
• Masked Ph : involves translocations between chromosome 9 and a chromosome other than 22.
• Monitoring patients on TKI therapy by cytogenetics, FISH, and molecular studies has become an
important standard practice to assess
• Response to therapy
• Compliance
• Treatment resistance
• Change TKI therapy and
• Study mutational studies.

32. • Other Philadelphia chromosome-positive malignancies
 Acute precursor B cell lymphoblastic leukemia (ALL): 20-30 pc
 Childhood ALL : 5-10%
 Adult AML : 1%

33. Cont..
• FISH and PCR
• Advantage
 Diagnosis of CML
 Estimate the CML burden in patients on TKI therapy.
 Can be done on peripheral blood samples  Less painful and more convenient.
• Disadvantage
 May not detect additional chromosomal abnormalities (clonal evolution)
 Can be falsely positive at low levels or falsely negative because of technical issues
• A diagnosis of CML must always rely on a marrow analysis with routine cytogenetics.
• Presence of the Ph chromosome.
• Detects clonal evolution, i.e., chromosomal abnormalities in the Ph-positive cells (which may be
prognostic)
• Quantifies the percentage of marrow blasts and basophils.

35. PROGNOSIS AND COURSE
• Before the imatinib era, the annual mortality in CML was 10% in the first 2 years and 15–20%
thereafter. The median survival time in CML was 3–7 years.
• The estimated 8- to 10-year survival rate with TKI is now 85%, or 93% if only CML-related deaths
are considered.
• Use of 2nd generation TKIs as frontline therapy have reduced the incidence of transformation in
the first 2–3 years from 6–8% with imatinib to 2–4% with nilotinib or dasatinib.
• Pts usually develop resistance in the form of cytogenetic relapse, followed by hematologic relapse
and subsequent transformation.

36. • CML Prognostic models
• Sokal
• Hasford
• European Treatment and Outcome Study [EUTOS].
• Achievement of complete cytogenetic response has become the major therapeutic
endpoint and is the only endpoint associated with improvement in survival.
• The lack of achievement of major or complete molecular responses should not be
considered as “failure” of a particular TKI therapy and/or an indication to change the
TKI or to consider allogeneic SCT.

37. SOKAL SCORE

39. TREATMENT

40. Tyrosine Kinase Inhibitors(TKIs): Drug
revolution
• Imatinib mesylate introduced in 2001
• 1st generation TKI : Imatinib
• 2nd -generation TKIs : Dasatinib, Nilotinib, and Bosutinib
• 3rd -generation TKI : Ponatinib
• Imatinib, dasatinib , bosutinib, and ponatinib are approved for the treatment of CML transformation
(accelerated and blastic phase) along with chronic phase, whereas nilotinib is only approved for chronic and
accelerated phase.

41. Cont..
• The sixth approved agent is OMACETAXINE
• A protein synthesis inhibitor with presumed more selective inhibition of the synthesis of the
BCR-ABL1 oncoprotein.
• It is approved for the treatment of chronic- and accelerated-phase CML after failure of two or
more TKIs, at 1.25 mg/m2 subcutaneously twice a day for 14 days for induction and for 7 days
for consolidation-maintenance.
• Potency of newer generation TKI as compared to imatinib : Nilotinib - 30 times ; Dasatinib : 300
times ; Bosutinib : 30–50 times
• PONATINIB is effective against wild-type and mutant BCRABL1 clones.
• It is unique in being the only currently available BCRABL1 TKI that is active against T315I, a
gatekeeper mutant resistant to other 4 TKIs

42. AGENT APPROVED INDICATIONS DOSE SCHEDULE NOTABLE TOXICITIES
 IMATINIB MESYLATE  All phases  400 mg OD  See A/E in next slide
 DASATINIB  All phases  First-line: 100 mg OD
 Salvage: 140 mg OD
 Myelosuppression;
pleural and pericardial
effusions; pulmonary
HTN
 NILOTINIB  All phases except blastic
phase
 First-line: 300 mg BD
 Salvage: 400 mg BD
 Diabetes; VOD ;
pancreatitis
 BOSUTINIB  All phases except
frontline
 500 mg OD  Diarrhea
 PONATINIB  All phases except
frontline
 45 mg daily  Skin rashes, pancreatitis;
VOD (10–20%)
 OMACETAXINE
MEPESUCCINATE
 Failure ≥2 tyrosine
kinase
 inhibitors
 1.25 mg/m2 S/C BD for
 14 days for induction; 7
days of maintenance
 every month
 Myelosuppression

43. A/E OF TKIs

44. TRIALS ON TKIs
• In two RCTs, one comparing nilotinib 300 mg twice daily or 400 mg twice daily with imatinib
(ENEST-nd) and the other comparing dasatinib 100 mg daily with imatinib (DASISION);the
second-generation TKIs were associated with better outcomes
• Higher rates of complete cytogenetic responses (85–87% vs 77–82%),
• Major molecular responses (65–76% vs 46–63%),
• Undetectable BCR-ABL1 transcripts (IS) (32–37% vs 15–30%), and
• Lower rates of transformation to accelerated-blastic phase (2–4% vs 6%).
• Neither study showed a survival benefit with second-generation TKIs

46. Choice and Timing of Allogeneic SCT
• Allogeneic SCT was considered first-line CML therapy before 2000.
• Now SCT is considered 2nd or 3rd line therapy.
• Among pts. who present with or evolve to blastic phase, combinations of chemotherapy and TKIs
should be used to induce remission, f/b allogeneic SCT as soon as possible.
• Pts with T315I mutations at relapse should be offered ponatinib and considered for allogeneic SCT
(because of the short F/U with ponatinib).

47. • Pts with mutations involving Y253H, E255K/V, and F359V/C/I respond better to dasatinib or
bosutinib.
• Patients with mutations involving V299L, T315A, and F317L /F/I/C respond better to nilotinib.
• Pts with clonal evolution, unfavorable mutations, or lack of major/complete cytogenetic
response within 1 year of salvage TKI therapy have short remission durations and should
consider allogeneic SCT as more urgent in the setting of salvage.

48. MONITORING RESPONSE TO THERAPY

49. Cont..
• COMPLETE HEMATOLOGIC RESPONSE
• CHR requires the normalization of WBC and platelet counts as well as the WBC differential.
Normalization of HB is not part of the definition.
• CYTOGENETIC RESPONSE
• At least 20 metaphases must be karyotyped to assess cytogenetic response.
• A partial cytogenetic response (PCyR) is present if 35% or less of these metaphases are Ph+,
and a CCyR if all are Ph-.
• MOLECULAR RESPONSE
• Major molecular response (MMR) : level of 0.1% IS, corresponding to a 3-log reduction
compared with the baseline
• Complete molecular response (CMR) : If BCR-ABL1 mRNA is undetectable by qPCR.

50. WHEN TO CONSIDER TREATMENT FAILURE?
WHEN TO CHANGE THERAPY ??

51. CML PHASE USE OF TKI CONSIDERATION FOR USE OF SCT
 Accelerated or Blastic  Interim therapy to achieve minimal
CML burden
 As soon as possible (exception: de
novo accelerated phase)
 Imatinib failure in chronic
phase; T315I mutation
 Ponatinib to achieve minimal CML
burden
 Depends on longer term follow-up
results of ponatinib efficacy
 Imatinib failure in chronic
phase; no clonal evolution, no
mutations, good initial
response
 Second-line kinase inhibitors long-
term
 Third-line after second line TKI
failure
 Imatinib failure in chronic
phase; clonal evolution or
mutations, or no cytogenetic
response to second-line KI
 Interim therapy to achieve minimal
CML burden
 Second-line
 Older patients (≥65–70 years)
after imatinib failure in
chronic phase
 Salvage TKIs as longer term
 therapy
 May forgo allogeneic SCT in favor of
good quality of life and survival
 in chronic phase

52. TREATMENT OF ACCELERATED AND BLASTIC
PHASES
• Pts. in accelerated or blastic phase may receive therapy with TKIs, preferably second- or third-
generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib), alone or in combination with
chemotherapy, to reduce the CML burden, before undergoing allogeneic SCT.
• Response rates with single-agent TKIs range from 30 to 50% in accelerated phase and from 20 to
30% in blastic phase.
• CML lymphoid blastic phase, the combination of anti-ALL chemotherapy with TKIs results in
complete response rates of 60–70% and median survival times of 2–3 years (compared with
historical response rates of 40–50% and median survival times of 12–18 months).

53. • In CML nonlymphoid blastic phase, anti-AML chemotherapy combined with TKIs results in CR
rates of 30–50% and median survival times of 9–12 months (compared with historical response
rates of 20–30% and median survival times of 3–5 months).
• In accelerated phase, combination usually include TKIs with low-intensity chemotherapy such as
low-dose cytarabine, low-dose idarubicin, decitabine, INF-α, hydroxyurea, or others.

54. MANAGEMENT OF BLAST CRISIS

55. INVESTIGATIONAL THERAPIES

56. REFERENCE
• Harrison 19th Edition
• Wintrobe’s Clinical hematology 13th Edition
• UpToDate 2018
• How I treat CML Blast Crisis Blood Journal 2018
• How I treat newly diagnosed CML Blood Journal 2018

57. THANK YOU