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

CML Flashcards by Ned Jones

chromosomes involved in philadelphia translocation

9 and 22

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

Ph+ AML
Ph+ ALL

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3 phases of CML

chronic phase
accelerated phase
blast phase

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criteria for accelerated phase per MD Anderson

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

Rare (neutrophil function is preserved)

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CML lab findings

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

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poor prognostic factors in CML

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

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Treatment of intermediate or high risk CML

Second-generation TKI

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SE profile of imatinib

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

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First line second generation TKI’s

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

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First generation TKI

imatinib

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Variables incorporated into risk stratification models for CML

Age, spleen, platelet count

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Various ways in which response is defined in CML

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

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Hematologic response definition

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

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Cytogenetic response in CML refers to

percentage of Ph+ cells

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Complete molecular response defined as

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

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Management of patient with TKI intolerance

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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Definition of TKI treatment failure

no CHR at 3 months

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Management of TKI failure

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

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

T3151

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Role of ASCT in CML

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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Success rate of ASCT for CML

long-term cure rate of 65% for patients transplanted in chronic phase

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Labs in CML

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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Backbone of therapy for CML

BCR-ABL TKIs

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Pathophysiology of CML

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

Atypical CML refers to

Philadelphia chromosome negative CML

Phase in which most patients are diagnosed

Chronic phase

What patients with CML transform to

- from chronic to accelerated phase, NOT AML

How common is transformation to accelerated phase

- Nowadays, in the TKI era, few people transform into accelerated phase and fewer people transform into blast phase

Workup

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

Cytogenetics basically refers to

Chromosome analysis

CHR stands for

Complete hematologic response

CHR definition (generally speaking)

normalization of cell counts + no splenomegaly

Complete cytogenetic response definition

0 Ph+ chromosomes identified

Partial cytogenetic response definition

1-35 Ph+ chromosomes identified

Minor cytogenetic response definition

36-95 Ph+ chromosomes identified

How TKI selection is made

- comorbidities - side effect profile - cost/insurance coverage

Management of leukocytosis greater than 100k

hydroxyurea Allopurinol 300 mg daily until blood count normalizes

CML prognosis

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

How is response to treatment monitored

quantitative PCR for BCR-ABL

Treatment of low-risk CML

Second generation TKI

Initial management of TKI failure

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

Management of TKI failure

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

Management of TKI induced myelosuppression

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

Class effects of TKI's

- myelosuppression - QT prolongation - fluid retention - hepatoxicity

To watch out with TKI discontinuation

TKI withdrawal syndrome

TKI outcomes in blast phase in general

Dismal

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

Complete cytogenetic response

Variable most important in predicting response

Early Response (at 3 months)

Distinct features of myeloproliferative disorders

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

Acute leukemia refers to

AML at diagnosis OR CML in blast crisis

Other features that will classify CML as in blastic phase

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

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

- second generation TKIs produce faster and deeper responses that imatinib - improved overall survival hasn't been shown

prognosis generally speaking

- 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)

Standard response assessment in CML

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

Complete hematologic response (CHR) criteria

- white count less than 10K - less than 5% basophils - platelet count less than 450K - spleen not palpable

First steps with increasing PCR signal while on TKI

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

Definition of treatment failure

No CHR at 3 months

TKI duration

Continued indefinitely as long as tolerated and treatment milestones are met

When you can consider TKI discontinuation + caveat

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

Management of accelerated phase CML + why

*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

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

Omacetaxine mepesuccinate

What connotes TKI resistance at 3 month mark in CML?

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

what is MMR in CML?

Major molecular remission

Threshold of blasts for blast crises

greater than 20%

Threshold of blasts defining accelerated phase CML

10-19%

Management of blast phase

- upfront second generation TKI/steroids followed by evaluation for HSCT

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

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

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

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

management of priapism in CML

leukopheresis

Imatinib clinical use

Only FDA approved for low risk disease

Criteria for TKI discontinuation

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

Mutations associated with TKI resistance in CML

T315 F317

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

Patient has lymphoid rather than myeloid blast crisis

BCR-ABL TKI with CNS penetration

dasatinib

Response assessment in CML

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

Drug interaction to know with BCR-ABL TKI's

CYP3A4 or CYP3A5 induces or inhibitors

Definition of loss of a major molecular response (MMR)

BCR-ABL greater than or equal to 0.1%

Definition of TKI resistance

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

Lab that is low in CML patients

Leukocyte alkaline phosphatase (LAP)

Most common mutation in atypical CML

SETBP1

Asciminib mechanism

STAMP inhibitor

Criteria for TKI discontinuation

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