Chronic Myeloid Leukemia: Pharmacologic Management

Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a hematologic malignancy that arises from dysregulation of hematopoietic stem cells in the bone marrow (myeloproliferative neoplasm).^1,2 It is caused by a reciprocal translocation between chromosomes 9 and 22, resulting in the Philadelphia chromosome (Ph).³ This translocation [t(9;22)(q34;q11.2)] results in fusion of the BCR gene and the ABL1 gene, giving rise to the BCR/ABL1 fusion gene.³

The BCR/ABL1 fusion gene encodes a constitutively active tyrosine kinase that leads to activation of multiple cellular processes that contribute to abnormal regulation of myelopoiesis and development of CML.¹ The presence of BCR-ABL1 fusion protein leads to accumulation of additional genomic abnormalities, such as T315I mutation, which are associated with exacerbation of the disease, resistance to treatment, and poor prognosis.¹  

CML is a relatively rare cancer that accounts for approximately 3% of all cancers and 3.9% of cancer deaths.⁴ In 2023, there will be an estimated 8930 new cases and 1310 deaths from CML in the United States.⁵ Although the etiology of CML is unknown, risk factors for the malignancy include⁶:

• Radiation exposure (exposure to high-dose radiation, such as from an atomic bomb or nuclear reactor accident)
• Age (higher risk among individuals of older age)
• Gender (higher incidence among men) 

With the introduction of the first tyrosine kinase inhibitor (TKI) therapy — imatinib — in 2001, the prognosis of patients with CML has improved dramatically, with the 5-year survival rate before 1983 being less than 15%, and increasing to 87%, where it has remained since 2001.⁷  

CML can present in 3 phases: the chronic phase, the accelerated phase, and the blast phase (also called blast crisis).  These phases are defined by the number of blast cells in the peripheral blood or bone marrow.¹ The World Health Organization (WHO) defines blast crisis as greater than 20% blasts in the peripheral blood or bone marrow, and the National Comprehensive Cancer Network (NCCN), as well as major TKI trials, define blast crisis as 30% or greater blasts.³ Progression from the chronic phase to the accelerated and blast phases of CML is accompanied by exacerbation of symptoms, such as bone pain and splenomegaly, cytogenetic changes, and worse prognosis.⁸ 

Chronic Myeloid Leukemia Treatment

NCCN recommendations that treatment of CML consist largely of targeted therapy with TKIs for early-phase and newly diagnosed CML, and allogeneic hematopoietic cell transplantation (HCT) and clinical trials for advanced-phase and TKI-resistant CML.⁸  

TKIs are inhibitors of protein tyrosine kinases that are involved in a wide range of cellular functions, including cell growth, apoptosis, motility, and angiogenesis.^9,10 TKIs block the activity of dysregulated protein tyrosine kinases in cancer cells, targeting them for cell death. In CML, TKIs block activity of the fusion protein BCR-ABL1, leading to a decrease in the number of malignant leukemic cells.¹¹ 

NCCN recommendation for TKI therapy for the treatment of CML consists of 6 TKIs⁸:

• Imatinib, a first-generation TKI
• Dasatinib, a second-generation TKI
• Nilotinib, a second-generation TKI
• Bosutinib, a second-generation TKI
• Ponatinib, a third-generation TKI
• Asciminib, a third-generation TKI

Although they have transformed the approach to treatment of CML and dramatically improved survival of patients with CML, there are limitations associated with TKI therapy in CML. Imatinib treatment results in resistance or intolerance in more than 50% of cases, and serious adverse reactions, including arterial occlusive events and hemorrhage, have been associated with some TKIs, namely nilotinib and ponatinib.¹² Treatment-related toxicity needs to be considered when selecting TKI therapy, especially in patients requiring long-term treatment.¹³     

Diagnosis of CML is made based on pathologic findings, bone marrow cytogenetics, and detection of BCR::ABL1 mRNA transcripts using reverse transcriptase-polymerase chain reaction (RT-PCR).⁸ NCCN recommends assessing baseline BCR-ABL1 transcripts at the initial workup using quantitative RT-PCR (qPCR).⁸ 

Treatment Response Monitoring in Chronic Myeloid Leukemia

NCCN recommends the following for diagnosis and workup of patients with CML⁸:

• Physical examination with history
• Complete blood count (CBC)
• Bone marrow cytogenetics consisting of fluorescence in situ hybridization (FISH) on peripheral blood sample with dual probes for BCR and ABL1 genes an acceptable alternative
• qPCR to measure BCR::ABL1 mRNA transcripts at baseline

Following TKI treatments, molecular response (MR), defined as the ratio of BCR-ABL1 to ABL1 transcripts according to the International Scale (IS)¹, is assessed using qPCR.⁸ 

Response to treatment is categorized in the following manner, according to NCCN guidelines⁸:

• Complete hematologic response
  • Complete normalization of peripheral blood counts with leukocyte count less than 10 x 10⁹/L
  • Platelet count less than 450 x 10⁹/L 
  • No immature cells in peripheral blood
  • No signs and symptoms of disease with resolution of palpable splenomegaly

• Cytogenetic response
  • Complete cytogenetic response (CCyR) — No Ph+ metaphases
  • Major cytogenetic response (MCyR) — 0% to 35% Ph+ metaphases
  • Partial cytogenetic response (PCyR) — 1% to 35% Ph+ metaphases
  • Minor cytogenetic response — more than 35% to 65% Ph+ metaphases

• Molecular response
  • Early molecular response (EMR) — BCR::ABL1 (IS) less than 10% at 3 and 6 months
  • Major molecular response (MMR) — BCR::ABL1 (IS) less than or equal to 0.1%
  • Deep molecular response (DMR) — MR4.0: BCR::ABL1 (IS) less than or equal to 0.01%; MR4.5: BCR::ABL1 (IS) less than or equal to 0.0032%

Pharmacologic Treatment of Chronic Myeloid Leukemia

Tyrosine Kinase Inhibitors

TKIs are the standard of care for patients with newly diagnosed CML in all phases of disease.¹ NCCN recommends TKIs in this setting based on the results of 4 phase 3 clinical trials demonstrating that⁸:

• All TKIs recommended are highly effective in patients with newly diagnosed, chronic phase CML
• Second-generation TKIs achieve cytogenetic and molecular responses faster and result in less disease progression than imatinib 
• Survival rates of patients receiving imatinib were not significantly different than those of patients receiving a second-generation TKI

First-Line Tyrosine Kinase Inhibitor Therapy

The goal of TKI therapy in patients with chronic phase CML is to prevent disease progression to accelerated-phase or blast-phase CML and to achieve  CCyR or MMR within 1 year of starting first-line TKI therapy.⁸ The selection of first-line TKI therapy should be based on the patient’s risk score, age, comorbidities, tolerance to the therapy, and the toxicity associated with the therapy. 

NCCN recommends the following as first-line TKI treatment options for chronic-phase CML across all risk scores⁸:

• Imatinib at 400 mg daily
• Second-generation TKIs bosutinib 400 mg daily, dasatinib 100 mg daily, and nilotinib 300 mg twice daily

NCCN does not recommend high-dose imatinib (800 mg) as an initial treatment. Instead, second-generation TKIs are recommended based on the lower risk of disease progression, shorter time to molecular response, and higher rates of MMR compared with imatinib.⁸

NCCN recommends monitoring the response to TKI therapy with⁸:

• Bone marrow cytogenetics to assess the number of Ph+ metaphases 
• qPCR to measure the amount of BCR::ABL1 transcripts
• BCR::ABL1 kinase domain mutation analysis to detect the presence of new mutations 

Molecular monitoring of the response to TKI therapy should be performed every 3 months for all patients after starting TKI therapy. After CCyR has been achieved, molecular monitoring is recommended every 3 months for 2 years, then every 3 to 6 months thereafter.⁸

NCCN guidelines designated MR less than or equal to 10% at 3 and 6 months after the start of first-line TKI therapy as response milestones. If MR remains greater than 10% at 6 and 12 months after the initiation of TKI therapy, the CML is considered TKI-resistant. NCCN recommends evaluation for allogeneic HCT for patients with TKI-resistant CML.⁸

If the ratio of BCR::ABL1 (IS) is greater than 10% after 3 months of TKI treatment, the CML is considered to be possibly TKI resistant, at which point the dose of imatinib can be increased, or an alternate TKI can be given. If the ratio remains greater than 10% after 6 to 12 months of TKI treatment, the CML is considered to be TKI-resistant. NCCN recommends changing to an alternative TKI and evaluating for allogeneic HCT in those cases.⁸

Second-Line Tyrosine Kinase Inhibitor Therapy

Although effective, imatinib therapy results in resistance in approximately 50% of cases.¹² For patients not achieving MR at 3 months, instead of increasing the dose of imatinib, NCCN recommends switching to the second-generation TKIs nilotinib or dasatinib.⁸

For patients resistant to bosutinib, nilotinib, and dasatinib, NCCN recommends switching to another TKI other than imatinib. However, there is no evidence that switching treatment improves response in this group of patients. NCCN recommends that these patients be evaluated for allogeneic HCT and enrollment in trials for ponatinib and asciminib.⁸

Pharmacologic Agents in Treatment of Chronic Myeloid Leukemia

Imatinib

Imatinib mesylate is a selective inhibitor of BCR-ABL1 kinase, a kinase generated by the translocation found in CML.¹⁴ Imatinib was the first TKI found to be highly effective in the treatment of CML, with an overall survival rate of 85% (93% if only CML-related deaths are considered).¹⁵ The CCyR rate after 1 year of imatinib therapy ranges from 49% to 77%, with the rate of MMR achieved after 1 year of therapy ranging from 18% to 58%.¹⁵ Imatinib has been the gold standard for the treatment of CML since its introduction in 2001. It is indicated for the treatment of¹⁴:

• Adult and pediatric patients with newly diagnosed, chronic state Ph+ CML
• Patients with chronic, accelerated, or blast-phase Ph+ CML after failure of interferon-alfa therapy

Dosing and Administration

Imatinib is taken orally at 400 mg/d for chronic-phase Ph+ CML and at 600 mg/d for accelerated and blast crisis Ph+ CML for adult patients. For pediatric patients with chronic-phase Ph+ CML, 340 mg/m²/d is given orally once daily or split into 2 doses taken once in the morning and once in the evening. The pediatric dose should not exceed 600 mg. The  imatinib dose of 800 mg should be divided into 400 mg taken twice daily. Imatinib doses of 400 mg or 600 mg are taken once daily. Imatinib should be taken with food and water.¹⁴ 

Adverse Reactions

Serious adverse reactions reported with imatinib include¹⁴:

• Edema and severe fluid retention
• Hematologic toxicity (anemia, neutropenia, thrombocytopenia)
• Severe congestive heart failure and left ventricular dysfunction
• Severe hepatotoxicity, including death
• Grade 3/4 hemorrhage
• Gastrointestinal perforations
• Cardiogenic shock
• Bullous dermatologic reactions (erythema multiforme, Stevens-Johnson syndrome)
• Embryo-fetal toxicity
• Growth retardation in children and preadolescents
• Tumor lysis syndrome
• Renal toxicity

Other side effects of imatinib include¹⁴:

• Nausea and vomiting
• Muscle cramps
• Musculoskeletal pain
• Diarrhea
• Rash
• Fatigue
• Abdominal pain

Drug Interactions

Imatinib is metabolized by the cytochrome P450 isoenzyme, CYP3A4. Taking imatinib concurrently or soon before/after taking the following medications should be avoided¹⁴:

• CYP3A inducers (dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital, St John’s wort) 
• CYP3A inhibitors
• Medications metabolized by CYP3A4 (triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, warfarin)
• Medications metabolized by CYP2D6
• Cardiovascular medications (amiodarone, diltiazem, verapamil)
• Anti-infective agents (azole antifungals) 

Special Populations

The pregnancy status of female patients should be verified before starting imatinib treatment. Pregnant patients should be advised of the risk of harm to the fetus. Pregnancy should be avoided during and for 14 days after treatment with imatinib. Breastfeeding should be discontinued during treatment and for 1 month following the last dose of imatinib.¹⁴ 

Imatinib has been demonstrated to be safe and effective for the treatment of Ph+ chronic-phase CML in pediatric patients. Edema was reported at an increased rate in patients aged 65 years and older undergoing treatment with imatinib. Exposure to imatinib is increased in patients with severe hepatic impairment and mild to moderate renal impairment; dose reduction may be necessary in these patients.¹⁴

Dasatinib

Dasatinib is a second-generation multitarget inhibitor of BCR-ABL.¹⁶ Dasatinib has 325-fold higher in vitro activity against BCR-ABL1 and is effective in inducing responses in patients with chronic-phase CML resistant to imatinib.^17,18 Dasatinib was approved by the US Food and Drug Administration (FDA) for the treatment of adults with chronic-phase CML. Dasatinib is indicated for the treatment of¹⁶:

• Adult patients with newly diagnosed, chronic-phase Ph+ CML
• Adult patients with chronic, accelerated, or myeloid or lymphoid blast-phase Ph+ CML with resistance or intolerance to prior therapy, including imatinib

Dosing and Administration

The dosage of dasatinib for adults with chronic-phase CML is 100 mg orally once daily. The recommended dosage for adults with accelerated-phase CML and myeloid or lymphoid blast-phase CML is 140 mg once daily. For pediatric patients with chronic-phase CML, the starting dose is determined based on body weight, according to the prescribing information.¹⁶ 

Adverse Reactions

Serious adverse reactions reported with dasatinib include¹⁶:

• Bone marrow suppression
• Hemorrhage
• Fluid retention
• Cardiac dysfunction
• Pulmonary arterial hypertension
• Severe dermatologic reactions (erythema multiforme, Stevens-Johnson syndrome) 
• Tumor lysis syndrome
• Embryo-fetal toxicity
• Growth retardation in pediatric patients

Other side effects of dasatinib include¹⁶:

• Diarrhea
• Headache
• Rash
• Dyspnea
• Fatigue
• Nausea
• Musculoskeletal pain

Drug Interactions

Dasatinib is metabolized by CYP3A4. Concurrent use of dasatinib and medications affecting CYP3A4 activity can alter dasatinib exposure and efficacy and should be avoided. If concurrent administration cannot be avoided, the dose of dasatinib may need to be adjusted and the patient monitored closely. Concomitant use of dasatinib with gastric-reducing medications can decrease dasatinib efficacy and should be avoided. The timing of administration should be spaced at least 2 hours apart if concurrent use cannot be avoided.¹⁶  

The concomitant use of dasatinib and the following medications should be avoided¹⁶:

• CYP3A inducers and St John’s wort 
• CYP3A inhibitors and grapefruit juice 

• H2 antagonists
• Proton pump inhibitors 

Special Populations

Pregnant patients should be warned of the risk of harm to the fetus with dasatinib treatment. Pregnancy should be avoided during treatment and for 30 days following the last dose of dasatinib. Breastfeeding should be discontinued during and for 2 weeks after the final dose of dasatinib.¹⁶

Pediatric use of dasatinib has been shown to be safe and effective for newly diagnosed chronic-phase CML and Ph+ acute lymphoblastic leukemia (ALL) in children aged 1 year and older. As bone growth and developmental adverse reactions were reported in pediatric patients undergoing treatment with dasatinib, monitoring is advised.¹⁶ 

Nilotinib

Nilotinib is a second-generation TKI that inactivates BCR-ABL1 by binding to and inactivating the kinase domain of the ABL protein.¹⁹ It is 30-fold more potent than imatinib and is active against multiple mutations.²⁰ Nilotinib was effective in achieving responses in patients with imatinib-resistant or intolerant CML.²¹ As first-line treatment for patients with newly diagnosed, chronic-phase CML, nilotinib elicited a long-lasting response superior to that of imatinib.²² Nilotinib is indicated for the treatment of²³:

• Adult patients with newly diagnosed, chronic-phase Ph+ CML 
• Adult patients with chronic or accelerated-phase Ph+ CML resistant to or intolerant to prior therapy with imatinib 

Dosing and Administration

The dosage of nilotinib for newly diagnosed, chronic-phase Ph+ CML is 300 mg orally twice daily. The recommended dosage for resistant or intolerant chronic-phase and accelerated-phase Ph+ CML is 400 mg twice daily. Nilotinib doses should be taken approximately 12 hours apart on an empty stomach. Food should be avoided for at least 2 hours before and at least 1 hour after taking nilotinib.²³

Contraindication

Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome.²³

Adverse Reactions

Serious adverse reactions reported with nilotinib include²³:

• Bone marrow suppression
• QT prolongation (cardiac ventricular repolarization)
• Cardiovascular events (arterial vascular occlusive events)
• Sudden death
• Pancreatitis and elevated serum lipase
• Hepatotoxicity
• Electrolyte abnormalities
• Tumor lysis syndrome
• Hemorrhage
• Fluid retention
• Embryo-fetal toxicity

Other common side effects associated with nilotinib include²³:

• Nausea
• Rash
• Headache
• Fatigue
• Pruritus
• Vomiting
• Diarrhea
• Cough
• Constipation
• Arthralgia
• Nasopharyngitis
• Pyrexia
• Night sweats

Drug Interactions

Concomitant use of nilotinib with CYP3A4 inducers and CYP3A4 inhibitors should be avoided, if possible. The dose of nilotinib should be adjusted and the patient should be closely monitored if CYP3A4 inducers or CYP3A4 inhibitors must be used concurrently with nilotinib.²³  

The concomitant use of nilotinib and the following medications should be avoided²³:

• Strong CYP3A4 inducers (dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, rifampicin, St John’s wort)
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice)
• CYP3A4 substrates (alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, tacrolimus)

The concomitant use of nilotinib with the following additional medications should be avoided²³:

• P-glycoprotein (P-gp) substrates
• Gastric acid drugs (proton pump inhibitors, H2 blockers)
• Antiarrhythmic drugs (amiodarone, disopyramide, procainamide, quinidine, sotalol)
• Drugs that may prolong the QT interval (chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, pimozide)

Special Populations

The pregnancy status of female patients should be verified before starting nilotinib therapy. Pregnant patients should be warned of the risk of fetal harm with nilotinib treatment. Pregnancy should be avoided during and for at least 14 days after nilotinib treatment. Breastfeeding should be discontinued during and for at least 14 days after nilotinib treatment.²³ 

The safe and effective use of nilotinib has not been established in pediatric patients. A reduced starting dose of nilotinib is advised in patients with hepatic impairment.²³

Bosutinib 

Bosutinib is a TKI that inhibits BCR-ABL kinase as well as Src-family kinases.²⁴ In murine myeloid cell lines, bosutinib inhibited a majority of imatinib-resistant forms of BCR-ABL kinase.²⁴ In a phase 3 trial (BFORE), bosutinib demonstrated an MMR rate at 12 months of treatment that was superior to that of imatinib and was granted approval by the FDA as a first-line treatment for patients with chronic phase CML.^25,3 Bosutinib is also effective in the treatment of patients with chronic-phase CML that is resistant to multiple TKIs, including imatinib, dasatinib, and nilotinib.²⁶ 

Bosutinib is used in the treatment of²⁴:

• Adult patients with newly diagnosed, chronic-phase Ph+ CML (accelerated approval) 
• Adult patients with chronic, accelerated, or blast-phase Ph+ CML with resistance or intolerance to prior therapy 

Dosing and Administration

The dosage of bosutinib for the treatment of newly diagnosed, chronic-phase Ph+ CML is 400 mg orally once daily taken with food. The recommended dosage for patients with any phase of Ph+ CML with resistance or intolerance to prior therapy is 500 mg once daily taken with food. If complete hematologic, cytogenetic, or molecular response is not achieved, the dosage of bosutinib can be increased by 100 mg once daily to a maximum of 600 mg in the absence of adverse reactions of grade 3 or higher.²⁴

Adverse Reactions

Serious adverse reactions reported with bosutinib include²⁴:

• Gastrointestinal toxicity
• Bone marrow suppression
• Hepatic toxicity
• Fluid retention
• Renal toxicity
• Embryo-fetal toxicity

Other common side effects of bosutinib include²⁴:

• Diarrhea
• Nausea
• Thrombocytopenia
• Rash
• Increased alanine aminotransferase level
• Abdominal pain

Drug Interactions

Concomitant use of bosutinib with the following medications should be avoided²⁴:

• Strong or moderate CYP3A inhibitors (ketoconazole, aprepitant)
• Strong CYP3A inducers (rifampin)
• Proton pump inhibitors (lansoprazole)
• P-gp substrates (dabigatran etexilate mesylate) 

Special Populations

The pregnancy status of female patients should be checked before starting treatment with bosutinib. Pregnant patients should be apprised of the risk of fetal harm with bosutinib therapy. Pregnancy should be avoided during treatment and for at least 1 month following the last dose of bosutinib. Breastfeeding should be discontinued during and for at least 1 month after bosutinib treatment.²⁴ 

The safe and effective use of bosutinib has not been established in pediatric patients. The dose of bosutinib should be reduced in patients with moderate to severe renal impairment and patients with hepatic impairment.²⁴ 

Ponatinib

Ponatinib is a third-generation TKI that can target the BCR-ABL1 T315I mutant.²⁷ It is the most potent TKI of BCR-ABL1. Based on the results of the PACE trial, which showed strong cytogenetic and molecular response across all phases of CML and against the T315I BCR-ABL1 mutation,²⁸ and the OPTIC trial, which demonstrated the safety and efficacy of a response-adjusted dosing regimen,²⁹ ponatinib was approved by the FDA for the treatment of²⁷:

• Adult patients with chronic, accelerated, or blast-phase CML
• Adult patients with chronic, accelerated, or blast-phase CML with T315I mutation

Dosage and Administration

The dosage of ponatinib is 45 mg orally once daily taken with or without food. Ponatinib may be taken at a starting dose of 45 mg, then the dose can be reduced to 15 mg once BCR::ABL1 (IS) less than or equal to 1% is reached.²⁷

Adverse Reactions

Serious adverse reactions reported with ponatinib include²⁷:

• Arterial occlusion
• Venous thromboembolism
• Heart failure
• Hepatotoxicity
• Hypertension
• Pancreatitis
• Neuropathy
• Ocular toxicity
• Hemorrhage
• Fluid retention
• Cardiac arrhythmias
• Bone marrow suppression
• Tumor lysis syndrome
• Posterior reversible encephalopathy syndrome (PRES)
• Impaired wound healing
• Gastrointestinal perforation
• Embryo-fetal toxicity

Other common side effects of ponatinib include²⁷:

• Abdominal pain
• Rash
• Constipation
• Headache
• Fatigue
• Hypertension
• Arthralgia
• Nausea and vomiting
• Diarrhea
• Myalgia

Drug Interactions

As ponatinib is metabolized by CYP3A, CYP2C8, and CYP2D6, taking other medications that may affect ponatinib metabolism should be avoided.²⁷ 

Concomitant use of ponatinib with the following medications should be avoided²⁷:

• Strong inhibitors of CYP3A (boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole)
• Strong inducers of CYP3A (carbamazepine, phenytoin, rifampin, St John’s wort)

Concomitant use of ponatinib with the following additional medications should be avoided²⁷:

• Gastric acid drugs (lansoprazole)
• Substrates of P-gp or ABCG2

Special Populations

Pregnancy status of female patients should be verified prior to starting ponatinib treatment. Pregnant patients should be advised of the risk of harm to the fetus with ponatinib therapy. Pregnancy should be avoided during the treatment and for 3 weeks after the completion of ponatinib treatment. Breastfeeding should be discontinued during and for 6 days after ponatinib treatment.²⁷ 

The safe and effective use of ponatinib has not been established in pediatric patients. 

Patients with chronic-phase CML who were aged 65 years and older had a lower rate of MCyR than younger patients. Reduction of the dosage of ponatinib to 30 mg once daily is advised for patients with hepatic impairment.²⁷ 

Asciminib

Asciminib is a TKI that inhibits BCR-ABL1 by binding to a myristoyl site and inactivating the kinase.³⁰ Asciminib inhibited wild-type and mutant forms of BCR-ABL1 kinase, including the T315I mutation, in both in vitro and animal model studies.³⁰ Based on the results of a phase 3 trial (ASCEMBL) that showed higher molecular response rates and a more favorable safety profile than bosutinib 500 mg,³¹ asciminib gained accelerated approval from the FDA in 2021 for the treatment of the following patient populations^32,30:

• Adult patients with chronic-phase Ph+ CML previously treated with more than 2 TKIs 
• Adult patients with chronic-phase Ph+ CML with the T315I mutation     

Dosing and Administration

The dosage of asciminib for the treatment of chronic-phase Ph+ CML is 80 mg orally once daily or 40 mg twice daily. The dosage of asciminib for the treatment of chronic-phase Ph+ CML with the T315I mutation is 200 mg twice daily. Food should be avoided for at least 2 hours before and 1 hour after taking asciminib.³⁰  

Adverse Reactions

Serious adverse reactions associated with asciminib include³⁰:

• Bone marrow suppression
• Pancreatic toxicity
• Hypertension
• Hypersensitivity
• Cardiovascular toxicity
• Embryo-fetal toxicity

Other common side effects of asciminib include³⁰:

• Upper respiratory infections
• Musculoskeletal pain
• Fatigue
• Nausea
• Rash
• Diarrhea

Drug Interactions

As the following medications may affect asciminib metabolism, concomitant use with asciminib should be avoided³⁰:

• Strong CYP3A4 inhibitors
• CYP3A4 and CYP2C9 substrates
• Itraconazole oral solution containing hydroxypropyl-β-cyclodextrin
• P-gp substrates

Special Populations

Pregnancy status of female patients should be verified before starting asciminib treatment. Pregnant patients should be advised of the risk of harm to the fetus with asciminib treatment.  Pregnancy should be avoided during and for 1 week after the completion of treatment with asciminib. Breastfeeding should be discontinued during treatment and for 1 week following the last dose of asciminib.³⁰ 

Omacetaxine

Omacetaxine is a protein synthesis inhibitor that causes a decrease in levels of short-lived proteins such as BCR-ABL1.^33,34 Omacetaxine was shown to reduce the levels of wild-type and mutant (T315I mutation) BCR-ABL1. Omacetaxine was effective in producing hematologic and cytogenetic responses, some complete, in patients with chronic-phase CML with the T315I mutation that was resistant to prior TKI therapy.^35,36 Omacetaxine is indicated for the treatment of adult patients with chronic or accelerated-phase CML with resistance and/or intolerance to 2 or more TKIs.³³ 

Dose and Administration

Omacetaxine is administered via subcutaneous injection at an induction dosage of 1.25 mg/m² twice a day for 14 consecutive days of a 28-day cycle. The recommended maintenance dosage is 1.25 mg/m² twice a day for 7 consecutive days of a 28-day cycle.³³

Adverse Reactions 

Serious adverse reactions reported with omacetaxine include³³:

• Bone marrow suppression
• Hemorrhage
• Hyperglycemia
• Embryo-fetal toxicity

Other common side effects of omacetaxine include³³:

• Thrombocytopenia
• Anemia
• Neutropenia
• Diarrhea
• Nausea
• Fatigue
• Asthenia
• Injection site reaction
• Pyrexia
• Infection
• Lymphopenia

Special Populations

Pregnant patients should be advised of the risk of harm to the fetus with omacetaxine treatment. Breastfeeding should be discontinued during omacetaxine treatment. Patients aged 65 years and older undergoing treatment with omacetaxine experienced toxicity — especially hematologic toxicity — at a higher rate.³³

Chronic Myeloid Leukemia Treatment Guidelines

The following guidelines have been created as resources to assist clinicians in treatment decision-making when managing patients with CML:

• NCCN Clinical Practice Guidelines in Oncology – Chronic Myeloid Leukemia. Version 2.2023. National Comprehensive Cancer Network^® 
• Chronic Myelogenous Leukemia Treatment (PDQ^®) – Health Professional Version. National Cancer Institute 

References

1. Minciacchi VR, Kumar R, Krause DS. Chronic myeloid leukemia: a model disease of the past, present and future. Cells. 2021;10(1):117. doi:10.3390/cells10010117
2. Chronic Myeloproliferative Neoplasms Treatment (PDQ^®) – Health Professional Version. National Cancer Institute. Updated November 4, 2020. Accessed June 20, 2023. https://www.cancer.gov/types/myeloproliferative/hp/chronic-treatment-pdq
3. Osman AEG, Deininger MW. Chronic myeloid leukemia: modern therapies, current challenges and future directions. Blood Rev. 2021;49:100825. doi:10.1016%2Fj.blre.2021.100825
4. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: leukemia. National Cancer Institute. Accessed June 20, 2023. https://seer.cancer.gov/statfacts/html/leuks.html
5. Cancer facts & figures 2023. American Cancer Society. Published 2023. Accessed June 20, 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
6. Risk factors for chronic myeloid leukemia. American Cancer Society. Updated June 19, 2018. Accessed June 20, 2023. https://www.cancer.org/cancer/types/chronic-myeloid-leukemia/causes-risks-prevention/risk-factors.html
7. Kantarjian H, O’Brien S, Jabbour E, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood. 2012;119(9):1981-1987. doi:10.1182/blood-2011-08-358135
8. Shah NP, Bhatia R, Altman JK, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®): Chronic Myeloid Leukemia. National Comprehensive Cancer Network. Published April 13, 2023. Accessed June 20, 2023. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf
9. Hartmann JT, Haap M, Kopp H-G, Lipp H-P. Tyrosine kinase inhibitors – a review on pharmacology, metabolism and side effects. Curr Drug Metab. 2009;10(5):470-481. doi:10.2174/138920009788897975
10. Kim M, Baek M, Kim DJ. Protein tyrosine signaling and its potential therapeutic implications in carcinogenesis. Curr Pharm Des. 2017;23(29):4226-4246. doi:10.2174%2F1381612823666170616082125
11. Tyrosine kinase inhibitor (TKI) therapy. Leukemia & Lymphoma Society. Accessed June 20, 2023. https://www.lls.org/leukemia/chronic-myeloid-leukemia/treatment/tyrosine-kinase-inhibitor-tki-therapy
12. Cortes J, Lang F. Third-line therapy for chronic myeloid leukemia: current status and future directions. J Hematol Oncol. 2021;14(1):44. doi:10.1186/s13045-021-01055-9
13. Lipton JH, Brümmendorf TH, Gambacorti-Passerini C, Garcia-Gutiérrez V, Deininger MW, Cortes JE. Long-term safety review of tyrosine kinase inhibitors in chronic myeloid leukemia – what to look for when treatment-free remission is not an option. Blood Rev. 2022;56:100968. doi:10.1016/j.blre.2022.100968
14. Gleevec^®. Prescribing Information. Novartis Pharmaceuticals Corporation; 2022. Accessed June 20, 2023. 
15. Sacha T. Imatinib in chronic myeloid leukemia: an overview. Mediterr J Hematol Infect Dis. 2014;6(1):e2014007. doi:10.4084/mjhid.2014.007
16. Sprycel. Prescribing Information. Bristol-Myers Squibb Company; 2018. Accessed June 20, 2023. 
17. Kantarjian H, Pasquini R, Lévy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115(18):4136-4147. doi:10.1002/cncr.24504
18. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541. doi:10.1056/NEJMoa055229
19. Sacha T, Saglio G. Nilotinib in the treatment of chronic myeloid leukemia. Future Oncol. 2019;15(9):953-965. doi:10.2217/fon-2018-0468
20. Martinelli G, Iacobucci I, Soverini S, et al. Nilotinib: a novel encouraging therapeutic option for chronic myeloid leukemia patients with imatinib resistance or intolerance. Biologics. 2007;1(2):121-127.
21. Breccia M, Alimena G. Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia. Leuk Res. 2010;34(2):129-134. doi:10.1016/j.leukres.2009.08.031
22. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis [published correction appears in Leukemia. 2021 Jul;35(7):2142-2143]. Leukemia. 2021;35(2):440-453. doi:10.1038/s41375-020-01111-2
23. Tasigna^®. Prescribing Information. Novartis Pharmaceuticals Corporation; 2017. Accessed June 20, 2023. 
24. Bosulif^®. Prescribing Information. Pfizer Inc.; 2017. Accessed June 20, 2023. 
25. Brümmendorf TH, Cortes JE, Milojkovic D, et al; BFORE Study Investigators. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial. Leukemia. 2022;36(7):1825-1833. doi:10.1038/s41375-022-01589-y
26. Hochhaus A, Gambacorti-Passerini C, Abboud C, et al; BYOND Study Investigators. Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study. Leukemia. 2020;34(8):2125-2137. doi:10.1038/s41375-020-0915-9
27. Iclusig^®. Prescribing Information. Ariad Pharmaceuticals, Inc.; 2020. Accessed June 20, 2023. 
28. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783-1796. doi:10.1056/NEJMoa1306494
29. Pulte ED, Chen H, Price LSL, et al. FDA approval summary: revised indication and dosing regimen for ponatinib based on the results of the OPTIC trial. Oncologist. 2022;27(2):149-157. doi:10.1093/oncolo/oyab040
30. Scemblix. Prescribing Information. Novartis Pharmaceuticals Corporation; 2021. Accessed June 20, 2023. 
31. Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041. doi:10.1182/blood.2020009984
32. FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia. US Food and Drug Administration. Updated October 29, 2021. Accessed June 20, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-asciminib-philadelphia-chromosome-positive-chronic-myeloid-leukemia
33. Synribo. Teva Pharmaceuticals USA, Inc.; 2012. Accessed June 20, 2023. 
34. Gandhi V, Plunkett W, Cortes JE. Omacetaxine: a protein translation inhibitor for treatment of chronic myelogenous leukemia. Clin Cancer Res. 2014;20(7):1735-1740. doi:10.1158/1078-0432.CCR-13-1283
35. Cortes J, Lipton JH, Rea D, et al; Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012;120(13):2573-2580. doi:10.1182/blood-2012-03-415307
36. Cortes J, Digumarti R, Parikh PM, et al; Omacetaxine 203 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol. 2013;88(5):350-354. doi:doi.org/10.1002%2Fajh.23408

Author Bio

Bora Lee, PhD, earned a BS in biology from Boston College and a PhD in Molecular and Cellular Biology from the University of Massachusetts Amherst. She has more than 10 years of translational research experience in reproductive medicine and women’s health, with a focus on fertility and placental health. She is passionate about improving people’s lives by helping them to make informed health decisions.