CML Flashcards
chromosomes involved in philadelphia translocation
9 and 22
name 2 other hematologic malignancies that can harbor t(9;22)
Ph+ AML
Ph+ ALL
3 phases of CML
chronic phase
accelerated phase
blast phase
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
Are infections rare or common at presentation in CML + why?
Rare (neutrophil function is preserved)
CML lab findings
- absolute eosinophilia (90%)
- persistent monocytosis
- leukocytosis (neutrophilia)
- thrombocytosis or both
- absolute basophilia (universal finding in peripheral smear. hallmark feature)
poor prognostic factors in CML
Age, spleen size, platelet count, blast percentage on peripheral blood
Treatment of intermediate or high risk CML
Second-generation TKI
SE profile of imatinib
skin rash + muscle cramps + diarrhea + periorbital swelling + edema + LFT abnormalities + hypophosphatemia + QT prolongation
First line second generation TKI’s
Nilotinib
dasatinib
bosunitib
*ponatinib not approved in first line due to increased risk of arterial and venous thrombosis
First generation TKI
imatinib
Variables incorporated into risk stratification models for CML
Age, spleen, platelet count
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)
Hematologic response definition
Platelet count <450K
WBC <10K
basophils <5%
no palpable spleen
Cytogenetic response in CML refers to
percentage of Ph+ cells
Complete molecular response defined as
BCR-ABL1 transcripts undetectable (in a lab where PCR sensitivity of at least 4.5 logs below standardized baseline)
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)
Definition of TKI treatment failure
no CHR at 3 months
Management of TKI failure
monitor for adherence + drug interactions + test for ABL kinase mutations (50% of patients with treatment failure)
ABL kinase mutation that confers resistance to all first and second generation TKIs
T3151
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
Success rate of ASCT for CML
- long-term cure rate of 65% for patients transplanted in chronic phase
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?)
Backbone of therapy for CML
BCR-ABL TKIs
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)
