CML Flashcards
Preferred option (until the initiation of TKI therapy) to lower very high white blood cell (WBC) counts
Hydroxyurea
Rarely indicated for cytoreduction , except for
high-risk indications (eg, persistent priapism, shortness of breath, transient ischemic attack)
Leukapheresis
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
- trisomy 8
- isochromosome 17q
- second Ph
- trisomy 19
- chromosome 3 abnormalities
If treatment is needed during pregnancy, it is preferable to initiate treatment with
Interferon alfa-2a
TKI therapy, particularly during the first trimester, should be avoided because of teratogenic risk.
2G TKIs are preferred:
- 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
TKI preferred for older patients with comorbidities such as cardiovascular disease.
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.
TRUE OR FALSE
Disease progression to advanced phase while on TKI therapy has worse prognosis than de novo advanced phase CML.
TRUE
Disease progression to advanced phase while on TKI therapy has worse prognosis than de novo advanced phase CML.
TRUE OR FALSE
Lumbar puncture and CNS prophylaxis is recommended for both myeloid and lymphoid BP-CML.
FALSE
Lumbar puncture and CNS prophylaxis is recommended for lymphoid BP-CML.
How to differentiate between de novo BP-CML and de novo Ph-positive ALL
Perform interphase FISH for the detection of BCR::ABL1 transcript on blood granulocytes
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.
Omacetaxine
Omacetaxine is NOT a treatment option for patients who present with AP-CML
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.
Ponatinib
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.
Asciminib
Preferred over bosutinib in patients with F317L mutation
Nilotinib
Contraindicated mutations for Asciminib
A337T, P465S, or F359V/I/C
Contraindicated mutations for Bosutinib
T315I, V299L, G250E, or F317Laa
Contraindicated mutations for Dasatinib
T315I/A, F317L/V/I/C, or V299L
Contraindicated mutations for Nilotinib
T315I, Y253H, E255K/V, or F359V/C/I
If CCyR post Allogeneic HCT, frequency of qPCR would be
Every 3 mo for 2 y, then every 3–6 mo thereafter
If persistently negative on qPCR post allo HCT, consider TKIi therapy for at least ____ year in patients with prior AP-CML or BP-CML
1 year
Modified MDACC Criteria for AP-CML
- 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
IBMTR criteria for BP-CML
- ≥30% blasts in the blood, marrow, or both
- Extramedullary infiltrates of leukemic cells
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.
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
TRUE OR FALSE
In patients assigned male at birth, TKI therapy must be discontinued if a pregnancy is planned.
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.
The panel recommends against the use of hydroxyurea during pregnancy, especially in the ________ trimester.
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.
Recommended qPCR monitoring among pregnant
Monthly monitoring of CBC with differential and frequent monitoring with qPCR (every 1–3 mo) would be helpful to guide the timing for initiation of TKI therapy.
TKI therapy can be restarted after ______
After delivery
Patients should be advised not to breastfeed while on TKI therapy, as TKIs pass into human breast milk.
CRITERIA FOR RESPONSE
Complete hematologic response (CHR)
- 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
CRITERIA FOR RESPONSE
Cytogenetic response
- 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
CRITERIA FOR RESPONSE
Molecular response
- 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%
CRITERIA FOR RESPONSE
Relapse
- 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
The loss of MMR in the presence of a CCyR does not necessarily indicate inadequate response to treatment.
MONITORING RESPONSE TO TKI THERAPY
Bone marrow cytogenetics
- 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%
MONITORING RESPONSE TO TKI THERAPY
qPCR using IS
- 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
When to perform BCR::ABL1 kinase domain mutation analysis
- CP-CML
- Response milestones not reached
- Disease progression to AP-CML or BP-CML
Criteria for TKI Discontinuation
- 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.
TKIs with studies for TFR
Dasatinib, imatinib, or nilotinib
Dosing of Asciminib
CP-CML (previously treated with ≥2 TKIs):
CP-CML with T315I mutation:
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
Dosing of Bosutinib
Newly diagnosed CP-CML:
CP-CML, AP-CML, or BP-CML with resistance or intolerance to prior therapy:
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
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.
Dosing of Dasatinib
CP-CML:
AP-CML and BP-CML:
CP-CML: 100 mg once daily
AP-CML and BP-CML: 140 mg once daily
Rare But Serious Toxicity with Dasatinib
Pulmonary arterial hypertension (PAH)
Also associated with reversible inhibition of platelet aggregation that may contribute to bleeding
Dosing of Imatinib
CP-CML:
AP-CML and BP-CML:
CP-CML: 400 mg once daily
AP-CML and BP-CML: 600 mg once daily
- 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)
Side effect of Imatinib that is a major factor reducing quality of life
Chronic fatigue (often correlated with musculoskeletal pain and muscular cramps)
Other side effects: Skin hypopigmentation
Cardiac toxicity/ black box warning with use Nilotinib
Prolongs the QT interval
- 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.
Dosing of Nilotinib
Newly diagnosed CP-CML:
Resistant or intolerant CP-CML and AP-CML:
BP-CML:
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
Rare But Serious Toxicity with Nilotinib
Peripheral arterial occlusive disease (PAOD)
Dosing of Omacetaxine
Resistant or intolerant CP-CML and AP-CML:
Induction dose:
Maintenance dose:
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
Dosing of Ponatinib
CP-CML:
AP-CML and BP-CML:
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
Toxicities with Ponatinib:
- 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
Consider use of low-dose aspirin if there is no contraindication
BCR::ABL1 transcripts
- e13a2 and e14a2: p210: M-BCR- CML
- e1a2: p190: m-BCR- Ph+ ALL
- e19a2: p230: μ-BCR- enhanced neutrophil differentiation
- 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
Most common clonal cytogenetic evolution in Ph-negative cells on patients treated with TKI therapy
Trisomy 8 and loss of Y chromosome
Prognostic score based on the patient’s age, spleen size on clinical examination, platelet count, and percentage of blasts in the peripheral blood.
Sokal score
Prognostic score that includes eosinophils and basophils in the peripheral blood in addition to the same clinical variables used in the Sokal score.
Euro score
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).
This is important, as many patients with CML die from non-CML causes, reflecting the efficacy of TKI therapy.
European Treatment and Outcome Study long-term survival (ELTS) score
The only tool capable of monitoring responses after the patient has achieved CCyR, since BCR::ABL1 transcripts typically remain detectable after CCyR is achieved.
qPCR
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.
The most important goals of TKI therapy are:
- 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
Clinical trial on Ponatinib that evaluated the safety and efficacy of response-adjusted dosing regimen
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.
OPTIC trial
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.
TKI with literature supporting Initiation at Lower Dose
- Bosutinib
- Dasatinib
This is an ongoing study that is evaluating the progressing de-escalation of all TKIs after achieving a stable DMR.
Dasatinib or nilotinib
OPTkIMA
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).
TKIs that are currently approved for treatment of CML in children
Imatinib, dasatinib, and nilotinib
