Drugs for CML (Chronic Myelogenous Leukemia)

Drugs for CML

All the drugs used for the treatment of CML are listed here. These include the most latest FDA-approved drugs, their MOA, uses, brands, and contraindications.

Drugs for CML aim to achieve remission of the disease [Ref]. Remission in patients with CML is of three types:

  • Hematologic remission:

Hematologic or clinical remission is the regression of splenomegaly and normalization of blood counts.

  • Cytogenetic remission:

The disappearance of Philadelphia chromosomes is cytogenetic remission.

  • Molecular remission:

Molecular remission is an attempt to cure the disease and is observed when the PCR for BCR/ABL gene mutation is absent.

With the latest generations of Tyrosine kinase inhibitors, the target of curing the disease is the goal. Here is a list of TKIs (Tyrosine kinase inhibitors approved for the treatment of CML:

TKIs for Chronic Myelogenous Leukemia (CML):

TKIs (Tyrosine kinase inhibitors) have changed the treatment of CML. All guidelines consider TKIs as the first line of treatment in patients with CML.

2nd-generation TKIs are preferred by most guidelines as the first-line in patients with chronic phase CML.

Here is a list of all the TKIs:

GenerationDrugDate of Approval
1st generationImatinib mesylateMay 2003
2nd generationDasatinibJune 2006
NilotinibOctober 2007
BosutinibSeptember 2012
3rd generationPonatinibDecember 2012
AsciminibOctober 2021

CML has three phases:

  • Chronic phase
  • Accelerated Phase, and 
  • Blast Crisis

The chronic phase would usually last for 2 to 3 years with hydroxyurea. However, with the advent of TKIs, people may go into complete remission and the disease may not recur during the lifetime of the patient.

The first line of treatment for most patients in the chronic phase of CML in most developed countries is now second-generation TKIs.

Here is a list of all the drugs used to treat CML:

Antineoplastic agentsHydroxyurea
Tyrosine kinase inhibitorsImatinib mesylate
FGFR InhibitorsPemigatinib
InterferonsPeginterferon alfa 2a

Hydroxyurea (Hydrea) for the treatment of CML:

Hydroxyurea is one of the oldest drugs to treat patients with the chronic phase of CML. It delays the progression of CML from the chronic phase to the accelerated phase or blast crisis by more than 2 years.

In addition, it is less toxic than most chemotherapeutic drugs and alkylating agents. It is used to reduce cell counts and hence reduce the symptoms of hyperviscosity and the risks of renal failure, stroke, and angina.

Hydroxyurea is now rarely used to treat CML. It may be used when other potent and safe drugs like TKIs are not available.

Generic name:Hydroxyurea
Trade name:Droxia, Siklos, hydroxycarbamide, Hydrea
Company name:Bristol-Myers Squibb
Date of approval:June 26, 2003 [ref]
MOAIt is unknown exactly how hydroxyurea exerts its cytotoxic and cytoreductive effects.

But several investigations back up the idea that hydroxyurea inhibits DNA synthesis right away by functioning as a ribonucleotide reductase inhibitor, unaffected by ribonucleic acid or protein synthesis.

Uncertainty surrounds the processes through which hydroxyurea helps people with sickle cell anemia (SCA).

Increases in hemoglobin F levels in red blood cells (RBCs), a decrease in neutrophils, an increase in RBC water content, an increase in the deformability of sickled cells, and changes to RBC adhesion to endothelium are just a few of the known pharmacologic effects of hydroxyurea that may help explain its positive effects.

UsesIt is indicated in the treatment of patients with Chronic myeloid leukemia (CML), a malignancy of the white blood cells.

It may also be administered in conjunction with radiation therapy for head and neck cancer.

ContraindicationsHypersensitivity, lactation, Pregnancy, and Severe anemia.
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Busulfan (Myleran, Busulfex) for the treatment of CML:

Busulfan is a potent cytotoxic drug that causes marked myelosuppression. It is rarely used nowadays for the treatment of CML.

However, Busulfan may be utilized in combination with cyclophosphamide before a person is planned to undergo autologous hematopoietic stem cell transplantation for CML.

Generic name:Busulfan
Trade name:Myleran, Busulfex
Company name:Otsuka Pharmaceutical, GlaxoSmithKline
Date of approval:June 28, 2002 [ref]
MOAA 4-carbon alkyl chain with two labile methanesulfonate groups connected at either end is called busulfan.

The methanesulfonate groups are liberated from busulfan after hydrolysis, and carbonium ions are created as a result.

These carbonium ions alkylate DNA, which interferes with DNA replication and RNA transcription and ultimately causes nucleic acid activity to be disrupted.

Guanine-adenine intrastrand crosslinks are produced explicitly by its mode of action by alkylation.

These crosslinks are created by guanine N7’s nucleophilic assault on the carbon next to the mesylate leaving the group in an SN2 reaction.

The cell goes through apoptosis because the cellular machinery is unable to heal this sort of damage.

UsesThis is employed in the therapy of Chronic Myelogenous Leukemia prior to autologous stem cell transplantation.
ContraindicationsHypersensitivity, Patients without a confirmed CML diagnosis, resistance towards busulfan
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Omacetaxine (Synribo) for the treatment of CML:

Omacetaxine (Synribo) is a protein synthesis inhibitor. It is less commonly used to treat patients with CML.

It is indicated in the treatment of the accelerated phase of CML only when the patient is not responsive to two or more TKIs.

Generic name:Omacetaxine
Trade name:Synribo
Company name:Teva Pharmaceutical Industries Ltd
Date of approval:October 26, 2012 [ref]
MOAOmacetaxine inhibits protein synthesis since it doesn’t attach to Bcr-Abl directly.

It inhibits chain elongation and halts protein synthesis by attaching to the large ribosomal subunit’s A-site cleft.

UsesIt is utilized to treat Chronic Myeloid Leukemia (CML) which has developed a resistance to two or more tyrosine kinase inhibitors or is tolerant to only one.
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Imatinib mesylate (Gleevec) for the treatment of CML:

Tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for all patients with CML including the chronic, accelerated phases, and blast crisis.

It is indicated in the treatment of all patients with Ph1-positive leukemic cells during the chronic phase. It may also be used to treat the accelerated and blast phase in patients who do not respond to interferon therapy.

In the chronic phase the dose is small while in the accelerated phase, a higher dose is used.

Generic name:Imatinib mesylate
Trade name:Gleevec
Company name:Novartis
Date of approval:May 20, 2003 [ref]
MOAA protein-tyrosine kinase inhibitor called imatinib mesylate blocks the constitutively active BCR-ABL tyrosine kinase, which is produced by the Philadelphia chromosomal abnormalities in CML.

ABL activation is highly associated with cancer cell proliferation and survival and is overexpressed in a variety of malignancies, despite the fact that the role of normal BCR is yet unknown.

Imatinib blocks the phosphorylation of the target protein downstream by binding to the ATP pocket in the active site of the BCR-ABL protein.

Inhibiting PDGF- and SCF-mediated cellular processes, imatinib also inhibits the receptor tyrosine kinases for a platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit.

Imatinib slows down GIST cells’ division in culture and causes them to go through apoptosis when they exhibit an activating c-Kit mutation.

UsesIt is used in the therapy of CML and Acute lymphoblastic leukemia with the Philadelphia chromosome in both adults and children
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Dasatinib (Sprycel) for the treatment of CML:

Dasatinib (Sprycel) is a second-generation TKI. It is indicated as one of the first-line treatments in patients with CML.

The dose varies depending on whether the patient is in chronic phase CML or accelerated phase. In the accelerated phase and in patients with blast crisis, the dose is higher than that used to treat the chronic phase of CML.

It is also utilized in the treatment of patients who develop resistance to Imatinib.

Generic name:Dasatinib
Trade name:Sprycel
Company name:Bristol-Myers Squibb Company.
Date of approval:June 28, 2006 [ref]
MOAThe following kinases are inhibited by dasatinib at nanomolar concentrations: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR.

Dasatinib is projected to bind to many ABL kinase conformations based on modeling research.

Dasatinib proved effective in leukemic cell lines that had imatinib mesylate sensitive and resistant disease variations in vitro.

Cell lines with BCR-ABL overexpression in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) were unable to proliferate.

UsesIt is used in the therapy of chronic myelogenous leukemia with the Philadelphia chromosome in both adults and children.
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Nilotinib (Tasigna) for the treatment of CML:

Nilotinib (Tasigna) is a selective TKI that targets three proteins:

  • BCR-ABL kinase
  • Platelet-derived growth factor
  • c-KIT

Nilotinib is indicated as a first line of treatment in patients with CML who are either in the chronic phase or in the accelerated phase (in patients who are resistant to imatinib or another TKI). However, the dosing of Nilotinib differs in the two phases. A higher dose is used in the accelerated phase.

Nilotinib is also used in children with Ph-positive CML who are at least one year of age and who are either resistant to or intolerant to previous treatment with another TKI such as Imatinib.

Generic name:Nilotinib
Trade name:Tasigna
Company name:Novartis
Date of approval:October 29, 2007 [ref]
MOAThe BCR-ABL oncogene is the primary cause of chronic myelogenous leukemia (CML).

The BCR-ABL protein’s tyrosine kinase activity is inhibited by nilotinib.

Higher affinities of nilotinib than imatinib allow it to attach to the ATP-binding site of the BCR-ABL protein and overcome mutation-based resistance.

The potential use of AMN107 for myeloproliferative diseases characterized by these kinase fusions is suggested by the drug’s ability to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukemia, and FIP1-like-1-PDGFRalpha, which causes the hypereosinophilic syndrome.

Additionally, at pharmacologically acceptable doses, AMN107 inhibits the c-Kit receptor kinase, including the D816V-mutated form of KIT, suggesting potential benefit in the treatment of mastocytosis and gastrointestinal stromal tumors.

UsesIt is used in the therapy of chronic myelogenous leukemia with the Philadelphia chromosome in both adults and children.
ContraindicationsHypokalemia, long QT syndrome, hypomagnesemia
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Bosutinib (Bosulif) for the treatment of CML:

Bosutinib (Bosulif) is a 2nd generation TKI. It inhibits Bcr-Abl kinases and SRc-family kinases including 16 of the 18 imatinib-resistant Bcr-Abl mutant forms.

It is indicated as a first-line treatment in patients with chronic phase Ph-positive CML. It is also indicated in the treatment of chronic phase, accelerated phase, or blast phase Ph-positive CML who have failed prior treatment with a TKI.

Generic name:Bosutinib
Trade name:Bosulif
Company name:Pfizer
Date of approval:September 4, 2012 [ref]
MOABosutinib is one kind of tyrosine kinase inhibitor. Despite having the ability to inhibit several tyrosine kinases, including Src, Lyn, and Hck, which are members of the Src family of kinases, its primary target is the Bcr-Abl kinase.

The Bcr-Abl gene, a chimeric oncogene, was created by the union of the breakpoint-cluster (Bcr) and the Abelson (Abl) tyrosine genes.

The Philadelphia translocation, commonly referred to as the Philadelphia chromosome, is the outcome of this chromosomal anomaly.

The Bcr-Abl gene expresses a specific kinase that promotes the development of CML.

The growth and size of the CML tumor were reported to be reduced after bosutinib treatment.

Bosutinib did not prevent the T315I and V299L mutant cells from dividing.

UsesIt is used to treat adult patients with chronic, accelerated, or blast-phase chronic myelogenous leukemia (CML), which has not responded clinically to conventional therapies.
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Ponatinib (Iclusig) for the treatment of CML:

Ponatinib (Iclusig) is a 3rd-generation TKI that is indicated in the treatment of Ph-positive CML or ALL who are intolerant to or resistant to at least one TKI. It is also used in the treatment of patients who have got T315I mutations.

It is associated with an increased risk of thrombosis. Hence, in the treatment of ALL, it is only given if the patient has T315I mutations and is Ph-Positive.

Generic name:Ponatinib
Trade name:Iclusig
Company name:ARIAD Pharmaceuticals
Date of approval:December 14, 2012 [ref]
MOAThe constitutively active Bcr-Abl tyrosine kinase protein, which aids in the development of CML, is its main cellular target.

This protein is produced by the Philadelphia chromosome, which is made up of the fused Bcr and Abl genes.

Because it blocks the tyrosine kinase activity of the Abl and T315I mutant kinases, ponatinib is distinctive in that it is particularly helpful in the treatment of resistant CML.

Due to its ability to block other Bcr-Abl inhibitors from binding to the Abl kinase, the T315I mutation provides resistance in cells.

Members of the VEGFR, PDGFR, FGFR, EPH receptors, and SRC families of kinases, as well as KIT, RET, TIE2, and FLT3 are other targets that ponatinib inhibits.

Rat tumors expressing either native or T315I mutant BCR-ABL showed a reduction in size.

UsesIt is used in the therapy of chronic myelogenous leukemia with the Philadelphia chromosome including those with T315I mutations.
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Asciminib (Scemblix) for the treatment of CML:

Asciminib (Scemblix) inhibits ABL1-kinase activity. It has been granted accelerated approval for the treatment of chronic phase CML who have not responded to two or more TKIs.

In addition, it has been approved for the treatment of patients with CML in the chronic phase who are positive for the Philadelphia chromosome and have T315I mutations.

For T315I mutations, Asciminib and Ponatinib are the only two drugs that have been approved.

Generic name:Asciminib
Trade name:Scemblix
Company name:Novartis
Date of approval:October 29, 2021 [ref]
MOAThe Philadelphia chromosomal translocation that results in the oncogenic fusion gene BCR-ABL1 between the BCR and ABL1 genes is the primary cause of the disease’s development in the majority of chronic myeloid leukemia (CML) patients.

The BCR-ABL1 fusion protein that is created as a result of this fusion gene has enhanced tyrosine kinase and transforming activity that promotes the development of CML.

The BCR-ABL1 tyrosine kinase is allosterically inhibited by Asciminib.

It binds to the myristoyl pocket of the fusion protein’s ABL1 component and locks it there, inhibiting the protein’s oncogenic activity.

Uses It is used in the therapy of chronic myelogenous leukemia with the Philadelphia chromosome who have either failed prior treatment with at least 2 TKIs or have T315I mutations.
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Pemigatinib (Pemazyre) for the treatment of CML:

Pemigatinib (Pemazyre) has been approved recently by the FDA for the treatment of refractory Myeloid and Lymphoid neoplasms with FGFR1 rearrangement.

It resulted in a complete response in 78% of the patients in the chronic phase with or without the extramedullary disease in less than 3 months. The complete cytogenetic response was 79%.

Generic name:Pemigatinib
Trade name:Pemazyre
Company name:Incyte Biosciences Distribution B.V.
Date of approval:August 26, 2022 [ref]
MOAIt functions by preventing the defective protein from signaling the growth of cancer cells. This aids in halting or reducing the growth of cancer cells.
UsesAdults with refractory or relapsing myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement are suggested for therapy with it.
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Peginterferon alfa 2a (Pegasys) for the treatment of CML:

Interferons are rarely used nowadays after the advent of TKIs. It may be used rarely in very refractory cases in combination with TKIs.

It was used as a first line of treatment previously in patients with CML, especially in older patients who were not eligible for transplantation.

Generic name:Peginterferon alfa 2a
Trade name:Pegasys
Company name:Hoffmann-La Roche Inc.
Date of approval:October 16, 2002 [ref]
MOAThe alfa-2a moiety label of recombinant human interferon is the source of peginterferon alfa-2a.

Human type 1 interferon receptors are bound to and activated by it, which causes them to dimerize.

JAK/STAT is therefore activated. The expression of several genes involved in the innate antiviral response is increased in numerous tissues when the JAK/STAT pathway is activated.

UsesPeginterferon alfa-2a is recommended for the treatment of HCV in individuals older than 5 with compensated liver disease when used in conjunction with other antiviral medications.

Patients who are ineligible for or significantly intolerant to other anti-viral treatments may receive it as a monotherapy.

  • Autoimmune hepatitis
  • Its use in neonates and infants
  • Pregnant women, as well as men with female partners who are pregnant, should not get ribavirin as part of combination therapy.
  • Known hypersensitivity reactions
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Written by Dr. Ahmed

I am Dr. Ahmed (MBBS; FCPS Medicine), an Internist and a practicing physician. I am in the medical field for over fifteen years working in one of the busiest hospitals and writing medical posts for over 5 years.

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