CML

Question 1

Epidemiology

Answer 1

Median age of diagnosis: 66

More common in men

5-year relative survival: 70%

Question 2

Pathophysiology

Answer 2

Unregulated myeloid proliferation–>excess mature neutrophil production

Oncogenic protein resulting in the pathogenesis of CML=Philadelphia chromosome

Present in 95% of patients with CML

Constitutively active tyrosine kinase
Decreased apoptosis

Question 3

Philadelphia chromosome

Answer 3

Breaks in chromosome 9 and 22–>translocate to form BCR-ABL fusion gene

Constitutively active oncogene

Question 4

Risk factors

Answer 4

No genetic component identified

Ionizing radiation

Atomic bomb survivors

Question 5

Presentation

Answer 5

Incidental finding during routine examination or CBC

Fatigue, sweating, bone pain, weight loss, abdominal pain, enlarged spleen

Leukocytosis: MEDICAL EMERGENCY
-As high as 1,000,000 cells/mm3
-Risk of leukostasis
-Acute abdominal pain
-Priapism
-Retinal hemorrhage
-Confusion
-Hyperuricemia

Question 6

Diagnosis

Answer 6

CBC with differential and CMP with uric acid

Bone marrow biopsy

FISH to assess Ph chromosome

PCR to assess BCR-ABL transcript baseline levels

Question 7

Chronic phase

Answer 7

90% of patients at diagnosis

< 10% blasts

Question 8

Accelerated phase

Answer 8

Progressive myeloid maturation

10-19% blasts

Increasing spleen size and WBC count despite drug therapy

Question 9

Blast crisis

Answer 9

Terminal stage

> 20% blasts

1/3 to lymphoid lineage and 2/3 myeloid lineage

Question 10

Treatment

Answer 10

No treatment, fatal within 5 years

Goals: eradicate leukemic clone with minimal toxicity

Only way to cure is allogenic hematopoietic stem cell transplant

TKI: control disease for many years

Question 11

Hematologic Response

Answer 11

Complete: normal peripheral blood count and no immature cells

Question 12

Cytogenic Response

Answer 12

Complete: 0% Ph+ cells

Partial: 1-35% Ph+ cells

Question 13

Molecular Response

Answer 13

Early: BCR-ABL < 10% at 3 and 6 months

Major (MMR): BCR-ABL < 0.1% or > 3 log decrease

Deep: BCR-ABL < 0.01%

Question 14

2nd generation TKI

Answer 14

Dasatnib, Imatinib, Nilotinib

All are approved 1st line setting

No overall survival advantage when compare to imatinib

Faster and deeper response

Question 15

Dasatinib

Answer 15

avoid acid reducers

Fluid retention (pleural effusion)

Question 16

Imatinib

Answer 16

Fluid retention

nausea

rash

Question 17

Nilotinib

Answer 17

Empty stomach

QTc interval prolongation

Metabolic syndrome

Question 18

Resistance

Answer 18

BCR-ABL gene amplification/over expression

Mutations in the kinase domain

Secondary genetic alterations

T315I

Question 19

Asciminib

Answer 19

Second line

Can be used in T315I resistant CML, but study yet to be published on outcomes

Question 20

TKI d/c criteria

Answer 20

No history of AP or BP

On TKI therapy for at least 3 years

Quantifiable BCR-ABL–>BCR-ABL < 0.01% (deep molecular response)

Stable deep molecular response for > 2 years

Question 21

Monitoring after d/c

Answer 21

PCR: monthly for 1-6 months
Every other month for months 7-12
Every 3 months

Patient must remain in major molecular response

Loss of MMR–>restart TKI within 4 weeks