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Hematology, oncology > CML > Flashcards

CML Flashcards

1
Q

chromosomes involved in philadelphia translocation

A

9 and 22

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2
Q

name 2 other hematologic malignancies that can harbor t(9;22)

A

Ph+ AML
Ph+ ALL

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3
Q

3 phases of CML

A

chronic phase
accelerated phase
blast phase

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4
Q

criteria for accelerated phase per MD Anderson

A
  • Peripheral or marrow blasts greater than 15%
  • Platelets <100K unrelated to therapy, >1 million unresponsive to therapy
  • Increasing spleen size and WBC count unresponsive to therapy
  • Peripheral blood basophils greater than 20%
  • Additional clonal cytogenetic abnormalities in Ph+ cells
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5
Q

Are infections rare or common at presentation in CML + why?

A

Rare (neutrophil function is preserved)

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6
Q

CML lab findings

A
  • absolute eosinophilia (90%)
  • persistent monocytosis
  • leukocytosis (neutrophilia)
  • thrombocytosis or both
  • absolute basophilia (universal finding in peripheral smear. hallmark feature)
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7
Q

poor prognostic factors in CML

A

Age, spleen size, platelet count, blast percentage on peripheral blood

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8
Q

Treatment of intermediate or high risk CML

A

Second-generation TKI

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9
Q

SE profile of imatinib

A

skin rash + muscle cramps + diarrhea + periorbital swelling + edema + LFT abnormalities + hypophosphatemia + QT prolongation

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10
Q

First line second generation TKI’s

A

Nilotinib
dasatinib
bosunitib
*ponatinib not approved in first line due to increased risk of arterial and venous thrombosis

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11
Q

First generation TKI

A

imatinib

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12
Q

Variables incorporated into risk stratification models for CML

A

Age, spleen, platelet count

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13
Q

Various ways in which response is defined in CML

A

1) Hematologic response (cell counts)
2) Cytogenetic response (Ph-positive metaphase chromosomes)
3) Molecular response (BCR-ABL transcripts)

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14
Q

Hematologic response definition

A

Platelet count <450K
WBC <10K
basophils <5%
no palpable spleen

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15
Q

Cytogenetic response in CML refers to

A

percentage of Ph+ cells

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16
Q

Complete molecular response defined as

A

BCR-ABL1 transcripts undetectable (in a lab where PCR sensitivity of at least 4.5 logs below standardized baseline)

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17
Q

Management of patient with TKI intolerance

A

Switch to other TKI approved as first line treatment or switch to bosutinib (second generation TKI FDA approved for patients with TKI intolerance)

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18
Q

Definition of TKI treatment failure

A

no CHR at 3 months

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19
Q

Management of TKI failure

A

monitor for adherence + drug interactions + test for ABL kinase mutations (50% of patients with treatment failure)

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20
Q

ABL kinase mutation that confers resistance to all first and second generation TKIs

A

T3151

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21
Q

Role of ASCT in CML

A

1) 3rd or 4th line treatment after TKI failure in chronic phase CML patients
2) accelerated or blast phase after best response to TKI is achieved (regardless of the depth of response)
3) Young patients with chronic phase CML who have a suitable donor and are not responding to TKI

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22
Q

Success rate of ASCT for CML

A
  • long-term cure rate of 65% for patients transplanted in chronic phase
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23
Q

Labs in CML

A

Absolute eosinophilia (90%) + persistent monocytosis + neutrophilia + absolute basophilia (universal finding in peripheral smear. hallmark feature) + mild normochromic/normocytic anemia (45-60%) (crowding out in bone marrow) + leukocytosis + normal or elevated platelet count (why?)

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24
Q

Backbone of therapy for CML

A

BCR-ABL TKIs

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25
Q

Pathophysiology of CML

A

Clonal myeloproliferative neoplasm of stem cells (this is why you see leukocytosis)

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26
Q

Atypical CML refers to

A

Philadelphia chromosome negative CML

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27
Q

Phase in which most patients are diagnosed

A

Chronic phase

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28
Q

What patients with CML transform to

A
  • from chronic to accelerated phase, NOT AML
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29
Q

How common is transformation to accelerated phase

A
  • Nowadays, in the TKI era, few people transform into accelerated phase and fewer people transform into blast phase
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30
Q

Workup

A
  • BMB with aspirate for cytogenetics
  • FISH or PCR for BCR-ABL (only in Ph negative)
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31
Q

Cytogenetics basically refers to

A

Chromosome analysis

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32
Q

CHR stands for

A

Complete hematologic response

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33
Q

CHR definition (generally speaking)

A

normalization of cell counts + no splenomegaly

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34
Q

Complete cytogenetic response definition

A

0 Ph+ chromosomes identified

35
Q

Partial cytogenetic response definition

A

1-35 Ph+ chromosomes identified

36
Q

Minor cytogenetic response definition

A

36-95 Ph+ chromosomes identified

37
Q

How TKI selection is made

A
  • comorbidities
  • side effect profile
  • cost/insurance coverage
38
Q

Management of leukocytosis greater than 100k

A

hydroxyurea
Allopurinol 300 mg daily until blood count normalizes

39
Q

CML prognosis

A

Very good (most go on to live normal life span)

40
Q

How is response to treatment monitored

A

quantitative PCR for BCR-ABL

41
Q

Treatment of low-risk CML

A

Second generation TKI

42
Q

Initial management of TKI failure

A

monitor for adherence
rule out drug interactions
Mutation analysis for ABL kinase mutation

43
Q

Management of TKI failure

A
  • monitor for adherence
  • rule out drug interactions
  • Mutation analysis for ABL kinase mutation
44
Q

Management of TKI induced myelosuppression

A

Hold therapy if..
- platelets less than 50K or
- ANC less than 1000
- Never hold for anemia
Weekly CBC
Restart when above those thresholds

45
Q

Class effects of TKI’s

A
  • myelosuppression
  • QT prolongation
  • fluid retention
  • hepatoxicity
46
Q

To watch out with TKI discontinuation

A

TKI withdrawal syndrome

47
Q

TKI outcomes in blast phase in general

A

Dismal

48
Q

Gold standard for response assesment (correlated with improved OS) in CML

A

Complete cytogenetic response

49
Q

Variable most important in predicting response

A

Early Response (at 3 months)

50
Q

Distinct features of myeloproliferative disorders

A

1) clonal disorder of hematopoiesis that arises in a hematopoietic stem or early progenitor cell
2) characterized by dysregulated production of a particular lineage of mature myeloid cells with fairly normal differentiation

51
Q

Acute leukemia refers to

A

AML at diagnosis OR CML in blast crisis

52
Q

Other features that will classify CML as in blastic phase

A

1) Large foci or clusters of blasts on bone marrow biopsy
2) Extramedullary blastic infiltrates

53
Q

Second generation vs first generation TKIs in terms of response and OS

A
  • second generation TKIs produce faster and deeper responses that imatinib
  • improved overall survival hasn’t been shown
54
Q

prognosis generally speaking

A
  • chronic phase = people have very durable respones
  • accelerated phase = much less satisfactory
  • blast phase = dismal (often refractory to treatment and there is a significant relapse rate)
55
Q

Standard response assessment in CML

A

Measurement in peripheral blood of BCR-ABL1 transcripts by quantitative polymerase chain reaction (Q-PCR) measurement.
*you don’t need to do serial marrows because peripheral blood BCR-ABL transcripts correlates well

56
Q

Complete hematologic response (CHR) criteria

A
  • white count less than 10K
  • less than 5% basophils
  • platelet count less than 450K
  • spleen not palpable
57
Q

First steps with increasing PCR signal while on TKI

A

1) monitor for adherence
2) rule out drug interactions
3) Mutational analysis for ABL kinase mutations (50% of patients with treatment failure)

58
Q

Definition of treatment failure

A

No CHR at 3 months

59
Q

TKI duration

A

Continued indefinitely as long as tolerated and treatment milestones are met

60
Q

When you can consider TKI discontinuation + caveat

A
  • patients with a sustained deep molecular response
  • but half will relapse (tumor cells remain in a quiescent state during therapy)
61
Q

Management of accelerated phase CML + why

A

*same second generation TKIs but at higher doses, followed by evaluation for ALLO-HSCT
- Initial treatment with TKI. One reason being outcomes are much better if patient is transplanted in chronic phase vs. accelerated phase

62
Q

FDA approved drug for accelerated phase CML in adults with resistance or intolerance to two or more TKIs

A

Omacetaxine mepesuccinate

63
Q

What connotes TKI resistance at 3 month mark in CML?

A

BCR-ABL transcript greater than 10% at 3 month mark

64
Q

what is MMR in CML?

A

Major molecular remission

65
Q

Threshold of blasts for blast crises

A

greater than 20%

66
Q

Threshold of blasts defining accelerated phase CML

A

10-19%

67
Q

Management of blast phase

A
  • upfront second generation TKI/steroids followed by evaluation for HSCT
68
Q

expected response to BCR-ABL TKI’s at 3 months

A
  • You should see BCR-ABL transcripts below 10%, not a good sign to see above 10%
69
Q

Management of patient with BCR-ABL transcript level above 10% at 3 months

A

Continue TKI, but increase the dose.
- consider mutation analysis
- confirm adherence
- evaluate for drug interactions

70
Q

management of priapism in CML

A

leukopheresis

71
Q

Imatinib clinical use

A

Only FDA approved for low risk disease

72
Q

Criteria for TKI discontinuation

A

1) chronic phase
2) ***on TKI for at least 3 years
3) stable molecular response for at least 2 years

73
Q

Mutations associated with TKI resistance in CML

A

T315
F317

74
Q

What does TDT+ suggest in CML patient in setting of high blast count?

A

Patient has lymphoid rather than myeloid blast crisis

75
Q

BCR-ABL TKI with CNS penetration

A

dasatinib

76
Q

Response assessment in CML

A

Just PCR for BCR-ABL oncoprotein. *Don’t need BMB.

77
Q

Drug interaction to know with BCR-ABL TKI’s

A

CYP3A4 or CYP3A5 induces or inhibitors

78
Q

Definition of loss of a major molecular response (MMR)

A

BCR-ABL greater than or equal to 0.1%

79
Q

Definition of TKI resistance

A

BCR-ABL transcript greater than 10% after 3 months of being on a TKI

80
Q

Lab that is low in CML patients

A

Leukocyte alkaline phosphatase (LAP)

81
Q

Most common mutation in atypical CML

A

SETBP1

82
Q

Asciminib mechanism

A

STAMP inhibitor

83
Q

Criteria for TKI discontinuation

A

1) On TKI consistently for more than 3 years
2) Major molecular response (for at least 2 years)

Hematology, oncology (218 decks)

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