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Can olutasidenib help in acute myeloid leukemia treatment?


Acute myeloid leukemia

Acute myeloid leukemia (AML) is a malignancy of the blood and bone marrow (the spongy tissue found inside bones that is responsible for producing blood cells). The word "acute" in acute myeloid leukemia refers to the quick development of the condition. Myeloid cells, a subset of white blood cells, typically mature into other types of mature blood cells such as red blood cells, white blood cells, and platelets. These are the cells responsible for the name myelogenous leukemia (my-uh-LOHJ-uh-nus). It is otherwise known by terms such as acute granulocytic leukemia, acute myeloblastic leukemia, acute nonlymphocytic leukemia, and acute myeloid leukemia [1].


What are the existing therapies for AML?

Treatment for AML comprises of:


Chemotherapy: Cytarabine, daunorubicin, cladribine, fludarabine, mitoxantrone, etoposide, 6-thioguanine, hydroxyurea, methotrexate, 6-mercaptopurine, azacitidine, and dexamethasone are the medications that are most usually prescribed to treat this type of leukemia. But due to their negative effects like hair loss, low blood cell counts, diarrhea, constipation, nausea, vomiting, and recurring infections, caution should be taken while administering these medications.


Chemotherapy with stem cell transplant: Chemotherapy can have negative side effects, like reduction in the number of healthy blood cells. To get around this, it can be followed by a stem cell transplant. Stem cells are immature blood cells that are taken from the patients’ or donors’ blood or bone marrow, frozen and stored. These frozen stored cells are thawed and administered to the patient via infusion following chemotherapy. They restore the regular cell count and replace the blood-forming cells.


Radiotherapy: Radiation therapy can be applied either before or after chemotherapy to reduce the extent of leukemia remission and eliminate any leukemia cells that may still be present. External radiation therapy and internal radiation therapy are the two most commonly used radiation therapy modalities in AML.


Chemoradiotherapy: Chemoradiotherapy is a medical procedure that combines chemotherapy and radiation therapy. Sometimes, chemoradiation is utilized to eliminate any remaining cancer cells after chemotherapy and radiotherapy have been completed.


Immunotherapy: Patients with myeloid leukemia can be advised to take immunotherapeutic medications for the treatment of high-risk, early-stage leukemia. Examples include monoclonal antibodies, CAR T-cell therapy, and monalizumab (a protein kinase inhibitor).


Targeted therapy: Compared to traditional chemotherapy, targeted drugs work differently and typically have different side effects. Occasionally, they might be added to chemotherapy or used in conjunction with it to increase its efficacy. Patients with myeloid leukemia may benefit from using drugs like ivosidenib, enasidenib, olutasidenib, midostaurin, gilteritinib, gemtuzumab, and venetoclax [2].


The two stages of AML treatment are remission induction therapy and post remission therapy. The intention of remission induction therapy is to eradicate leukemia cells in the bone marrow and blood. Post remission therapy, on the other hand, should be directed towards killing leftover leukemia cells that may not be active but could start to develop and trigger a recurrence. It is also known as remission continuation therapy [2].


What are isocitrate dehydrogenase inhibitors?


  • IDH1 and IDH2 gene mutations are frequently seen in AML and can occur in up to 30% of cases. IDH mutations prevent differentiation in AML cells by causing abnormal genetic regulation.

  • In recent years, a number of potent and well-tolerated IDH1 inhibitors have been created, paving the way for precision cancer treatment based on the distinctive characteristics of each patient's genetic mutation.

  • Examples of these inhibitors that got FDA approval for treating relapsed/refractory AML are ivosidenib and enasidenib. Ivosidenib is also approved for treating newly diagnosed AML patients who cannot receive conventional chemotherapy.

  • Isocitrate dehydrogenase (IDH1) inhibitors have fundamentally changed the way that acute myeloid leukemia is treated, improving patient survival and quality of life [3].


How does olutasidenib helps in treating AML?


  • One such inhibitor that was recently introduced is olutasidenib (FT-2102).It is an oral small molecule inhibitor that potentially inhibits IDH1 mutant in leukemia patients.

  • By inhibiting IDH1 mutant enzyme, it reduces the accumulation of 2-R-HG (hydroxyglutarate), a component that plays an important role in leukemogenesis (induction of leukemia).

  • The Food and Drug Administration (FDA) authorized olutasidenib, available under the trade name Rezlidhia®, on December 1, 2022, for use in treating adult patients with acute myeloid leukemia (AML) who have experienced relapses or in cases that are resistant to conventional treatment and have a vulnerable IDH1 mutation [3].

  • Several clinical trials were conducted to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical efficacy of olutasidenib in patients with acute myeloid leukemia or myelodysplastic syndrome who had mutant IDH1 either alone or in combination with azacitidine, a chemotherapeutic agent.

  • The results of these trials evaluated that in patients with IDH1-mutated acute myeloid leukemia, olutasidenib, with or without azacitidine, was well tolerated and demonstrated clinically significant efficacy [4].


Are there any drawbacks for olutasidenib?


Current treatments for acute myeloid leukemia, particularly in those with refractory or recurrent AML, are not that much beneficial for improving progression-free and overall survival. Therefore, more research is needed to determine whether this treatment is effective for people with refractory situations, especially when combined with chemotherapy [5].


Bottom line!


Current treatments for acute myeloid leukemia, particularly in those with refractory or recurrent AML, are not significantly beneficial in improving progression-free and overall survival. The results of ongoing clinical trials examining olutasidenib and other IDH1 inhibitors will be crucial in determining if they can improve clinical outcomes for individuals with refractory AML.


References


1. A. Vakiti and P. Mewawalla,Acute Myeloid Leukemia,” in StatPearls, Treasure Island (FL): StatPearls Publishing, 2023. Accessed: Jun. 26, 2023. [Online]. Available: http://www.ncbi.nlm.nih.gov/books/NBK507875/

2. Acute Myeloid Leukemia Treatment - NCI,” Jun. 07, 2023. https://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq (accessed Jun. 28, 2023).

3. C. for D. E. and Research, FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation,”FDA, Dec. 2022, Accessed: Jun. 27, 2023. [Online]. Available: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olutasidenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-idh1-mutation

4. J. M. Watts et al., Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial,Lancet Haematol, vol. 10, no. 1, pp. e46–e58, Jan. 2023, doi: 10.1016/S2352-3026(22)00292-7.

5. C. Kang, Olutasidenib: First Approval,”Drugs, vol. 83, no. 4, pp. 341–346, Mar. 2023, doi: 10.1007/s40265-023-01844-1.

Opmerkingen


Collaborators

IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
IIT Delhi
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