CML

Question 1

Name the second generation TKI that is associated with the side effect (can only use each one)
Hyperglycemia -
Pleural effusions and pulm HTN -
Voluminous Diarrhea  -
Cardiac infarct-

Answer 1

Hyperglycemia - Nilotinib
Pleural effusions - Dasatinib
Voluminous Diarrhea - Bosutinib (also causes thrombocytopenia, elevated LFTs)
Cardiac infarct Nilotinib, (3rd gen: Ponatinib)

Question 2

In clinical trials of Imatinib stoppage (STIM, TWISTER) what TWO patient features were inclusion criteria for entering the study?

Answer 2

1. Patients treated with imatinib x 3 + years ( 5 data points for BCR-ABL transcript)
2. Undetectable MRD (MMR log 5 in stim, 4.5 twister) x 2 years
   (STIM: CP and AP, TWISTER: CP only)

What percentage of individuals will have durable remission upon stoppage of Imatinib?
▪ 40-50%

o What clinical feature was most predictive of patients who could successfully come off therapy?
▪ Low sokal (Sokal- blast age plt spleen size)
▪ Longer duration of imatinib therapy (>50 mo)
▪ Males

Question 3

What is different about the activity of ponatinib compared to other TKI

Answer 3

Ponatinib has activity in pts with T315I mutation which causes a structural change of the ATP binding pocket on BCR-ABL. This mutation causes resistance to all of the other TKIs.

Question 4

For each log reduction (1-5), list % the BCR-ABL transcript that is detectable. What is MMR, DMR and CMR?

Answer 4

Log 1=10% EMR
Log 2=1%
Log 3=0.1% MMR 
Log 4=0.01% DMR
Log 4.5=0.0032%
Log 5 = 0.001% CMR

Question 5

In which CML patients would you consider transplant?

Answer 5

1. Intolerant to all TKIs
2. Blast phase (ideally get into CR with TKI or chemo)
3. Patients relapsing with a T315I mutation because response to ponatinib is usually short.
4. Accelerated phase with poor response to TKI

Question 6

What is omacetaxine?

Answer 6

Protein synthesis inhibitor that has demonstrated activity in CML in chronic phase with a T315I mutation, or failure of 2 previous TKIs.

SC BID x 14days q28 days

SE: adverse events included hematological toxicity (thrombocytopenia, anemia, neutropenia, lymphopenia), gastrointestinal (diarrhea, nausea) toxicity, weakness and fatigue, as well as reaction at the injection site.

Question 7

What are the 3 major break point mutations seen in CML?

Answer 7

1. p190BCR-ABL1 (resulting from fusion at the minor breakpoint or m-BCR site)
2. p210BCR-ABL1 gene product (resulting from fusion at the major breakpoint or M-BCR site)
3. p230BCR-ABL1 (resulting from fusion at the micro breakpoint or mu-BCR site)

*p210 is most common.

Question 8

What is the median survival for blast phase CML? (in the TKI era)

Answer 8

bad! 7-11 months

Question 9

What is the criteria for complete hematological response (CHR) in CML?

Answer 9

1. resolution of symptoms/signs of the disease, including palpable splenomegaly
2. leukocytes <10 × 109/
3. Normal differential (absence of immaturity (myelocytes, pro-myelocytes, blasts, etc.)
4. platelets <450 × 109/L

Question 10

How many Ph-positive metaphases are seen in: minor, minimal, major and complete cytogenetic response?

Answer 10

Based on marrow cyto:
complete (no Ph+ cells).
major (1 to 35 percent)
minor (36 to 65 percent)
minimal (66 to 95 percent) 
no response (>95 percent)

Question 11

5 unique toxicities of Nilotinib

Answer 11

1. Hyperglycemia
2. Hyperlipidemia
3. Qtc prolongation
4. Increased lipase
5. Increased stroke risk
6. increased CAD
7. Increased PVD

*extreme caution in individuals with diabetes mellitus, cardiovascular disease, or metabolic syndrome

Question 12

ENESTnd compared nilotinib (either 300mg or 400mg PO BID to Imantinib 400mg PO daily). What were the significant end points

Answer 12

Nilotinib was superior in terms of:

1. EMR at 3 mos, CCyR at 12 months
2. Time to progression to AP or blast phase
3. MMR, MR
4. Comparable PFS and OS (approximately 95 percent OS after two years) (300mg PO BID)

*Nilotinib 400 mg twice daily was superior to imatinib with regard to OS, PFS, EFS, and progression, but this dose was associated with unacceptable levels of CV toxicity.

Question 13

Other that T315I, name 3 other markers of TKI resistance in CML.

Answer 13

1. F317L
2. F359V/C/I
3. E255K/V
4. V299L
5. M244V

Question 14

Major side effects of potnatinib (BB warnings):

Answer 14

1. Vascular events: MI, stroke, stenosis of large arterial vessels of the brain, severe PVD
2. VTE
3. Heart failure
4. Hepatoxicity
   Others: HTN, rash, thrombocytopenia, abdominal pain.

Question 15

What are the arguments for choosing 2nd generation TKI upfront for CP CML instead of imatinib?

Answer 15

1. Quicker MMR and MR4.5
2. Less mutation/resistance development
3. Decreased rates of progression to AP, BP

But no change in PFS or OS

Question 16

What is the single most important marker of OS and PFS for pts treated with TKI for CP CML?

Answer 16

Early molecular response, BCR-ABL transcripts =10%

*but failure to meet milestone is only a warning, as may be able to “catch up” if reach <1% @ 6 month milestone.

Question 17

When are 4 clinical situations where you might send mutational analysis for a pt with CML?

Answer 17

1. BCR-ABL1 transcripts are >10% at 3 or 6 months or there is failure to meet other response milestones
2. loss of cytogenetic or hematologic response occurs
3. A 1-log or greater increase in BCR-ABL1 transcript levels together with a loss of MMR occurs
4. Disease progression occurs.

Question 18

What are 3 factors with may lead to non-adherence to TKIs and 2 factors associated with good compliance?

Answer 18

1. Male
2. Older age
3. Living alone
4. High dose of TKi
5. Longer length of TKI

Improved compliance:

1. More education about CML
2. Other comorbidites
3. Taking other chronic meds

Question 19

A patient is eligible for TKI discontinuation. ~4 weeks after stopping their TKI they complain of arthralgias. What is this condition and what is the treatment?

Answer 19

“TKI withdrawal syndrome”
Occurs in 25% of pts who d/c TKIs within 1-6 weeks of stopping.
Looks like PMR- arthralgias of hips, shoulders, hands, and feet + pruritus
-Usually resolves spontaneously, but can persist for weeks to months.

Question 20

What was the DES-TINY study design for TKI discontinuation?

Answer 20

Looked at the benefit of an initial 12-month period of a 50% dose reduction from standard doses of imatinib, nilotinib, or dasatinib.

Eligibility: TKI x 3yrs, MMR (or MR 4.0 or deeper) x 12months

-After 1 year of dose reduction, recurrence was significantly lower in the MR4.0 cohort than in the MMR cohort.

Question 21

What is Omacetaxine mepesuccinate?

Answer 21

NOT a TKI (protein synthesis inhibitor) and therefore works through BCR-ABL-independent mechanism
– Approved for chronic or accelerated phase CML resistant and/or intolerant to 2+ TKIs
– AEs: myelosuppression, hyperglycemia

Question 22

Pt develops pleural effusion on Dasatinib 100mg PO daily, how will you manage?

Answer 22

1. Hold Dasatanib
2. CXR to confirm +/- Thora
3. Supportive care such as diuretics
4. If not improved x 7 days, add steroids
5. Once resolved, can restart dasatanib at 80mg PO daily

Question 23

What is asciminib?

Answer 23

Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant.

NJEM 2019, worked in heavily pretreated pts including those that had failed ponatinib.

Does not bind the ATP binding domain as other TKis do.
s
SE: Pancreatitis, HA, fatigue, arthralgia

Question 24

What are 3 risk scores for CML?

Answer 24

1. Sokal
2. EUTOS
3. Hasford
4. ELTS

Question 25

What are the components of the Sokal score?

Answer 25

1. Age
2. Spleen size (below costal margin)
3. Plt count
4. Blast percentage

Question 26

How do you treat accelerated CML de-novo and progression?

Answer 26

1. De novo- Start 2nd Gen TKI, if responding–>continue. If not responding, perform mutation analysis–>If T315I then switch to Ponatinib (or asciminib or omacetaxine)–> if still no response, refer for Tx.
2. If progressed from chronic phase
   - perform T315i mutation analysis and switch TKI as above if present–>refer to Tx (even if responding).
   - If not Tx eligible, con’t on 2nd gen TKI or ponatinib until progression and then palliate.

Question 27

What is the defn of accelerated CML according to the WHO?

Taken out of WHO5
Now only chronic or blast
But RFs in CP matter like ACAs

Answer 27

1. PB or BM blasts 10-19%
2. PB basophils >/= 20%
3. Plt<100, or >1000 (unrelated or unresponsive to therapy)
4. Progressive splenomegaly or inc WBC, not responsive to therapy.
5. Cytogenetic evolution or additional clonal chromosomal abnormalities in Ph+ cells @ diagnosis (trisomy 8 or 19, isochromosome 17q, 2nd Ph), complex karyotype or abnormalities of 3q26.2

Question 28

What are 4 common cytogenetic abnormalities found in CML (mostly in accelerated and blast phase) which confer poor prognosis?

Answer 28

1. trisomy 8
2. isochromosome 17q (leading to the loss of the P53 gene on 17p).
3. trisomy 19
4. duplication of the Ph chromosome

Question 29

How do you treat blast phase CML, initial diagnosis? (transplant eligible and transplant ineligible)

How do you treat blast phase CML, when pt previously on TKI?

Answer 29

All patients with blast crisis should undergo BCR-ABL1 kinase mutational analysis to aid in TKI selection

Diagnosed in blast phase

1. Tx eligible- 2nd gen TKI–> transplant
2. Tx ineligible–> TKI

Progression to blast phase from accelerated phase or chronic phase?
1. Administer AML-type induction chemotherapy combined with a more potent TKI for remission induction.

Patients with CML in LYMPHOID blast crisis are treated with combination chemotherapy in addition to a BCR-ABL1 TK