CML

Question 1

Preferred option (until the initiation of TKI therapy) to lower very high white blood cell (WBC) counts

Answer 1

Hydroxyurea

Question 2

Rarely indicated for cytoreduction , except for
high-risk indications (eg, persistent priapism, shortness of breath, transient ischemic attack)

Answer 2

Leukapheresis

Question 3

The presence of major route additional chromosomal abnormalities (ACAs) in Ph-positive cells may have a negative prognostic impact on survival in patients with accelerated phase

Answer 3

• trisomy 8
• isochromosome 17q
• second Ph
• trisomy 19
• chromosome 3 abnormalities

Question 4

If treatment is needed during pregnancy, it is preferable to initiate treatment with

Answer 4

Interferon alfa-2a

TKI therapy, particularly during the first trimester, should be avoided because of teratogenic risk.

Question 5

2G TKIs are preferred:

Answer 5

• Intermediate or high-risk score
• Younger patients who are interested in ultimately discontinuing treatment
• Young patients assigned female at birth whose goal is to achieve a deep and rapid molecular response and eventual discontinuation of TKI therapy for family planning purposes

Question 6

TKI preferred for older patients with comorbidities such as cardiovascular disease.

Answer 6

Imatinib

Nilotinib or bosutinib may be preferred for patients with a history of lung disease or deemed to be at risk of developing pleural effusions.

Dasatinib or bosutinib may be preferred in patients with a history of arrhythmias, cardiovascular disease, pancreatitis, or hyperglycemia.

Question 7

TRUE OR FALSE

Disease progression to advanced phase while on TKI therapy has worse prognosis than de novo advanced phase CML.

Answer 7

TRUE

Disease progression to advanced phase while on TKI therapy has worse prognosis than de novo advanced phase CML.

Question 8

TRUE OR FALSE

Lumbar puncture and CNS prophylaxis is recommended for both myeloid and lymphoid BP-CML.

Answer 8

FALSE

Lumbar puncture and CNS prophylaxis is recommended for lymphoid BP-CML.

Question 9

How to differentiate between de novo BP-CML and de novo Ph-positive ALL

Answer 9

Perform interphase FISH for the detection of BCR::ABL1 transcript on blood granulocytes

Question 10

Drug indicated for the treatment of AP-CML that is resistant and/or intolerant to two or more TKIs.

A treatment option for patients with disease progression to AP-CML.

Answer 10

Omacetaxine

Omacetaxine is NOT a treatment option for patients who present with AP-CML

Question 11

Preferred treatment option for patients with a T315I mutation in any phase.

It is also a treatment option for CP-CML with resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated.

Answer 11

Ponatinib

Question 12

Another treatment option for CP-CML patients with the T315I mutation and/or CP-CML with resistance or intolerance to at least two prior TKIs.

Answer 12

Asciminib

Question 13

Preferred over bosutinib in patients with F317L mutation

Answer 13

Nilotinib

Question 14

Contraindicated mutations for Asciminib

Answer 14

A337T, P465S, or F359V/I/C

Question 15

Contraindicated mutations for Bosutinib

Answer 15

T315I, V299L, G250E, or F317Laa

Question 16

Contraindicated mutations for Dasatinib

Answer 16

T315I/A, F317L/V/I/C, or V299L

Question 17

Contraindicated mutations for Nilotinib

Answer 17

T315I, Y253H, E255K/V, or F359V/C/I

Question 18

If CCyR post Allogeneic HCT, frequency of qPCR would be

Answer 18

Every 3 mo for 2 y, then every 3–6 mo thereafter

Question 19

If persistently negative on qPCR post allo HCT, consider TKIi therapy for at least ____ year in patients with prior AP-CML or BP-CML

Answer 19

1 year

Question 20

Modified MDACC Criteria for AP-CML

Answer 20

• Peripheral blood myeloblasts ≥15% and <30%
• Peripheral blood myeloblasts and promyelocytes combined ≥30%
• Peripheral blood basophils ≥20%
• Platelet count ≤100 x 109/L unrelated to therapy
• Additional clonal cytogenetic abnormalities in Ph+ cells

Question 21

IBMTR criteria for BP-CML

Answer 21

• ≥30% blasts in the blood, marrow, or both
• Extramedullary infiltrates of leukemic cells

Question 22

TRUE OR FALSE

TKI therapy appears to affect some male hormones at least transiently, but does not appear to have a deleterious effect on male fertility.

Answer 22

TRUE

TKI therapy appears to affect some male hormones at least transiently, but does not appear to have a deleterious effect on male fertility.

Miscarriage or fetal abnormality rate is not elevated in female partners of male patients on TKI therapy

Question 23

TRUE OR FALSE

In patients assigned male at birth, TKI therapy must be discontinued if a pregnancy is planned.

Answer 23

FALSE

In patients assigned male at birth, TKI therapy need not be discontinued if a pregnancy is planned.

In patients assigned female at birth, TKI therapy should be stopped prior to natural conception, and patients should remain off therapy during pregnancy

But the optimal timing of discontinuation is unknown.

Question 24

The panel recommends against the use of hydroxyurea during pregnancy, especially in the ________ trimester.

Answer 24

First trimester

Leukapheresis can be used for a rising white blood cell (WBC) count and/ or platelet count, although there are no data that recommend at what levels leukapheresis and/or platelet pheresis should be initiated.

Low-dose aspirin or low-molecular-weight heparin can be considered for patients with thrombocytosis.

Question 25

Recommended qPCR monitoring among pregnant

Answer 25

**Monthly** monitoring of **CBC** with differential and frequent monitoring with q**PCR (every 1–3 mo)** would be helpful to guide the timing for initiation of TKI therapy.

Question 26

TKI therapy can be restarted after ______

Answer 26

After delivery ## Footnote Patients should be advised **not to breastfeed while on TKI** therapy, as TKIs pass into human breast milk.

Question 27

# CRITERIA FOR RESPONSE Complete hematologic response (CHR)

Answer 27

* Complete normalization of peripheral blood counts with leukocyte count <10 x 109/L * Platelet count <450 x 109/L * No immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood * No signs and symptoms of disease with resolution of palpable splenomegaly

Question 28

# CRITERIA FOR RESPONSE Cytogenetic response

Answer 28

* **Complete cytogenetic response (CCyR):** No Ph-positive metaphases * **Major cytogenetic response (MCyR)**: 0%–35% Ph-positive metaphases * **Partial cytogenetic response (PCyR):** 1%–35% Ph-positive metaphases * **Minor cytogenetic response:** >35%–65% Ph-positive metaphases

Question 29

# CRITERIA FOR RESPONSE Molecular response

Answer 29

* **Early molecular response (EMR):** BCR::ABL1 (IS) ≤10% at 3 and 6 months * **Major molecular response (MMR):** BCR::ABL1 (IS) ≤0.1% or ≥3-log reduction in BCR::ABL1 transcripts from the standardized baseline, if qPCR (IS) is not available * **Deep molecular response (DMR):** MR4.0: BCR::ABL1 (IS) ≤0.01% or MR4.5: BCR::ABL1 (IS) ≤0.0032%

Question 30

# CRITERIA FOR RESPONSE Relapse

Answer 30

* Any sign of loss of hematologic response * Any sign of loss of CCyR or its molecular response orrelate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as an increase in BCR::ABL1 transcript to >1% * 1-log increase in BCR::ABL1 transcript levels with loss of MMR ## Footnote **The loss of MMR in the presence of a CCyR does not necessarily indicate inadequate response to treatment.**

Question 31

# MONITORING RESPONSE TO TKI THERAPY Bone marrow cytogenetics

Answer 31

* At diagnosis * Response milestones not reached * Any sign of loss of hematologic response * Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as an increase in BCR::ABL1 transcript to >1%

Question 32

# MONITORING RESPONSE TO TKI THERAPY qPCR using IS

Answer 32

* At diagnosis * Every **3 months** after initiating treatment. After BCR::ABL1 (IS) ≤1% (MR2.0)2 has been achieved, **every 3 months for 2 years** and **every 3–6 months** thereafter * If there is a *1-log increase* in BCR::ABL1 transcript levels with MMR, qPCR should be repeated **in 1–3 months**

Question 33

When to perform BCR::ABL1 kinase domain mutation analysis

Answer 33

* CP-CML * Response milestones not reached * Disease progression to AP-CML or BP-CML

Question 34

Criteria for TKI Discontinuation

Answer 34

* Age ≥18 years. * CP-CML. No prior history of AP-CML or BP-CML. * On approved TKI therapy for at least **3 years**. * Prior evidence of quantifiable BCR::ABL1 transcript. * Stable molecular response (MR4; BCR::ABL1 ≤0.01% IS) for **≥2 years**, as documented on at least **4 tests**, performed at least **3 months apart**. * Access to a reliable qPCR test with a sensitivity of detection of at least MR4.5 (BCR::ABL1 ≤0.0032% IS) and that provides results **within 2 weeks**. * Molecular monitoring **every 1–2 months for the first 6 months** following discontinuation, **bimonthly during months 7–12**, and **quarterly** thereafter (indefinitely) for patients who remain in MMR (MR3; BCR::ABL1 ≤0.1% IS). * Prompt resumption of TKI **within 4 weeks** of a loss of MMR with monthly molecular monitoring until MMR is re-established, then every 3 months thereafter is recommended indefinitely for patients who have reinitiated TKI therapy after a loss of MMR. If MMR is not achieved after 3 months of TKI resumption, BCR::ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months.

Question 35

TKIs with studies for TFR

Answer 35

Dasatinib, imatinib, or nilotinib

Question 36

Dosing of Asciminib CP-CML (previously treated with ≥2 TKIs): CP-CML with T315I mutation:

Answer 36

CP-CML (previously treated with ≥2 TKIs): **80 mg orally once daily or 40 mg twice daily** CP-CML with T315I mutation:**200 mg orally twice daily**

Question 37

Dosing of Bosutinib Newly diagnosed CP-CML: CP-CML, AP-CML, or BP-CML with resistance or intolerance to prior therapy:

Answer 37

Newly diagnosed CP-CML: **400 mg once daily** CP-CML, AP-CML, or BP-CML with resistance or intolerance to prior therapy: **500 mg once daily** ## Footnote Doses <300 mg/day have not been evaluated. In patients with **pre-existing mild, moderate, and severe hepatic impairment**, the recommended dose of bosutinib is **200 mg daily**.

Question 38

Dosing of Dasatinib CP-CML: AP-CML and BP-CML:

Answer 38

CP-CML: **100 mg once daily** AP-CML and BP-CML: **140 mg once daily**

Question 39

Rare But Serious Toxicity with Dasatinib

Answer 39

Pulmonary arterial hypertension (PAH) ## Footnote Also associated with reversible **inhibition of platelet aggregation** that may contribute to bleeding

Question 40

Dosing of Imatinib CP-CML: AP-CML and BP-CML:

Answer 40

CP-CML: **400 mg once daily** AP-CML and BP-CML: **600 mg once daily** ## Footnote * Patients with moderate renal impairment **(creatinine clearance [CrCl] = 20–39 mL/min) should receive a 50% decrease** in the recommended starting dose and future doses can be increased as tolerated. * Doses **>600 mg are not recommended** in patients with mild renal impairment (CrCl = 40–59 mL/min)

Question 41

Side effect of Imatinib that is a major factor reducing quality of life

Answer 41

Chronic fatigue (often correlated with musculoskeletal pain and muscular cramps) ## Footnote Other side effects: Skin hypopigmentation

Question 42

Cardiac toxicity/ black box warning with use Nilotinib

Answer 42

Prolongs the QT interval ## Footnote * Prior to administration of nilotinib and periodically, monitor for **hypokalemia or hypomagnesemia** and correct deficiencies. * **Electrocardiograms (ECGs)** should be obtained to monitor the QT interval at **baseline, 7 days after initiation, and periodically** thereafter, as well as following any **dose adjustments**.

Question 43

Dosing of Nilotinib Newly diagnosed CP-CML: Resistant or intolerant CP-CML and AP-CML: BP-CML:

Answer 43

Newly diagnosed CP-CML: **300 mg twice daily** Resistant or intolerant CP-CML and AP-CML: **400 mg twice daily** BP-CML: **400 mg twice daily**

Question 44

Rare But Serious Toxicity with **Nilotinib**

Answer 44

Peripheral arterial occlusive disease (PAOD)

Question 45

Dosing of Omacetaxine Resistant or intolerant CP-CML and AP-CML: Induction dose: Maintenance dose:

Answer 45

Induction dose: **1.25 mg/m2 twice daily for 14 consecutive days of a 28-day cycle** Maintenance dose: **1.25 mg/m2 twice daily for 7 consecutive days of a 28-day cycle**

Question 46

Dosing of Ponatinib CP-CML: AP-CML and BP-CML:

Answer 46

CP-CML: **45 mg once daily with a reduction to 15 mg once daily upon achievement of BCR::ABL1 (IS) ≤1%.** AP-CML and BP-CML: **45 mg once daily**

Question 47

Toxicities with Ponatinib:

Answer 47

* Arterial occlusive events (AOEs; including fatal myocardial infarction and stroke) and venous thromboembolic events (VTEs) * Heart failure * Hepatotoxicity * Grade ≥3 skin rash and pancreatitis **Rare But Serious Toxicities** * Hemorrhage * Cardiac arrhythmias * Tumor lysis syndrome ## Footnote Consider use of low-dose aspirin if there is no contraindication

Question 48

BCR::ABL1 transcripts

Answer 48

* e13a2 and e14a2: p210: M-BCR- CML * e1a2: p190: m-BCR- Ph+ ALL * e19a2: p230: μ-BCR- enhanced neutrophil differentiation ## Footnote * **e13a2** was more frequent in males and the proportion decreased with age in both sexes * **e14a2** at baseline was associated with higher molecular response rates to imatinib * **e1a2** associated with higher risk of disease progression and inferior cytogenetic and molecular responses to TKI therapy * **e19a2** associated with lower rates of cytogenetic and molecular response to TKIs and inferior survival outcomes

Question 49

Most common clonal cytogenetic evolution in Ph-negative cells on patients treated with TKI therapy

Answer 49

Trisomy 8 and loss of Y chromosome

Question 50

Prognostic score based on the patient’s **age, spleen size on clinical examination, platelet count, and percentage of blasts** in the peripheral blood.

Answer 50

Sokal score

Question 51

Prognostic score that includes **eosinophils and basophils** in the peripheral blood in addition to the same clinical variables used in the Sokal score.

Answer 51

Euro score

Question 52

Prognostic score that is based on the same variables as the Sokol score and provides the **most useful predictor of CML-related death** in patients treated with first-line imatinib. Focused on **CML-specific overall survival (OS)**. ## Footnote This is important, as many patients with CML die from non-CML causes, reflecting the efficacy of TKI therapy.

Answer 52

European Treatment and Outcome Study long-term survival (ELTS) score

Question 53

The only tool capable of monitoring responses after the patient has achieved CCyR, since BCR::ABL1 transcripts typically remain detectable after CCyR is achieved.

Answer 53

qPCR ## Footnote A major advantage of qPCR is the strong correlation between the results obtained from the peripheral blood and the bone marrow, allowing for **molecular monitoring without bone marrow aspirations.**

Question 54

The most important goals of TKI therapy are:

Answer 54

* To prevent disease progression to AP-CML or BP-CML * To achieve either MR2.0 (≤1% BCR::ABL1 IS, which corresponds to CCyR) or MMR (≤0.1% BCR::ABL1 IS) within 12 months after first-line TKI therapy

Question 55

Clinical trial on Ponatinib that evaluated the safety and efficacy of response-adjusted dosing regimen ## Footnote Patients were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg, with dose reduction to 15 mg with achievement of ≤1% BCR::ABL1 (IS) in the 45 mg and 30 mg cohorts.

Answer 55

OPTIC trial ## Footnote the FDA has approved a response-adjusted dosing regimen for ponatinib [starting dose of 45 mg once daily with a **reduction to 15 mg upon achievement of BCR::ABL1 (IS) ≤1%]** for patients with CP-CML with resistance or intolerance to at least two prior kinase inhibitors.

Question 56

TKI with literature supporting Initiation at Lower Dose

Answer 56

* Bosutinib * Dasatinib

Question 57

This is an ongoing study that is evaluating the **progressing de-escalation** of all TKIs after **achieving a stable DMR**. ## Footnote Dasatinib or nilotinib

Answer 57

OPTkIMA ## Footnote The **DESTINY trial** showed the feasibility de-escalation of TKI (imatinib, dasatinib or nilotinib) to half the standard dose for 12 months (imatinib 200 mg once daily; dasatinib 50 mg once daily, or nilotinib 200 mg twice daily) in patients achieving MMR or MR4 followed by discontinuation for 24 months (with frequent monitoring). **NILO-RED study** (published only an abstract) demonstrated the feasibility of maintenance therapy with reduced dose nilotinib (once daily) in patients achieving MMR on standard-dose nilotinib (twice daily).

Question 58

TKIs that are currently approved for treatment of CML in children

Answer 58

Imatinib, dasatinib, and nilotinib