Tackling CML Treatment Resistance with Inclusig

1. Tackling CML Treatment Resistance with Inclusig Chronic myeloid leukemia (CML) is a type of cancer that affects the blood and bone marrow. It originates in the blood-forming myeloid stem cells found in the bone marrow, leading to the uncontrolled production of abnormal white blood cells.1 These abnormal cells gradually outnumber healthy cells, impairing the body’s ability to fight infections, carry oxygen, and control bleeding.2 CML is considered one of the more common types of leukemia, accounting for approximately 15% of all cases. It can develop at any age but is most often diagnosed in older adults. The disease progresses slowly in its early stages, which is why many people may not experience noticeable symptoms until the condition has advanced.1 Common symptoms of CML In its initial stages, CML may cause few or no symptoms. However, as the disease progresses, patients may begin to experience signs such as1: • Persistent fatigue or a general feeling of weakness • Shortness of breath (dyspnea) • Low-grade fever or night sweats • Unexplained weight loss • Discomfort or swelling in the upper left part of the abdomen (due to an enlarged spleen) • A sense of fullness after eating only a small amount of food Individuals with CML are generally diagnosed during routine blood tests. Abnormal levels of white blood cells or platelets often provide the first clue that something is wrong. If untreated, CML can advance to a more aggressive phase and become life-threatening within three to four years.1 Advances in CML treatment: tyrosine kinase inhibitors (TKIs) The discovery of targeted therapies known as tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of CML. These drugs work by targeting the BCR: ABL1 fusion gene—a genetic abnormality that is characteristic of CML. This gene produces an abnormal protein BCR-Abl that promotes cancer cell growth.3 First- and second-generation TKIs such as imatinib, dasatinib, and nilotinib have been highly effective for many patients. However, resistance to these therapies can occur, especially in patients with certain mutations. One such mutation, known as T315I, is particularly problematic because it makes the cancer resistant to most available TKIs.4 What is Inclusig? Inclusig is a third-generation tyrosine kinase inhibitor specifically designed to overcome resistance caused by the T315I mutation and other single-mutation variants.4 It is approved for use in adults with5: • Chronic myeloid leukemia (CML) in chronic, accelerated, or blast phase • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)

2. The Philadelphia chromosome is an abnormality found in most CML cases and some ALL cases. It results from a genetic rearrangement that forms the BCR::ABL1 fusion gene, leading to uncontrolled cell division.5 Inclusig is typically prescribed to patients who5: • Are resistant to or cannot tolerate dasatinib or nilotinib • Have failed treatment with imatinib • Have the T315I mutation How does Ponatinib works? Inclusig contains ponatinib as the active substance, which blocks the action of Bcr-Abl tyrosine kinase, thereby inhibiting the signals that stimulate cancer cell growth. This targeted approach slows or stops the proliferation of leukemic cells and can help restore normal blood cell production.5 Unlike earlier TKIs, ponatinib has a unique structure that allows it to bind effectively to BCR-Abl even when the T315I mutation is present. This makes it a vital option for patients who have limited treatment alternatives due to resistance.6 Dosage and administration guidelines Inclusig is available in tablet form and comes in three strengths: 15 mg, 30 mg, and 45 mg. The recommended starting dose for most patients is 45 mg taken once daily. The treatment duration depends on the patient’s response and tolerability.5 Patients should only begin treatment under the supervision of a healthcare professional experienced in managing leukemia. During treatment, doctors may adjust the dose, pause, or discontinue the drug depending on the patient’s response and any side effects.5 Safety and monitoring Ponatinib carries serious risks that require close monitoring. It has been associated with blood clots and blockages in arteries and veins, which can lead to heart and circulation complications. Therefore, patients should undergo cardiovascular evaluations before starting therapy and be monitored regularly during treatment.5 Common and serious side effects Like all medications, Inclusig can cause side effects. Some of the most common and serious side effects include pneumonia, pancreatitis, fever, abdominal pain, heart attack, irregular heartbeat, peripheral arterial occlusive disease, anemia, high blood pressure, kidney injury, urinary tract infections, etc. Serious arterial blockages were reported in 20–25% of patients, while serious venous clots were seen in about 5%. It is important for patients and healthcare providers to recognize these risks early and take preventive measures where possible.5 Comparison with other therapies While first- and second-generation TKIs offer high response rates and relatively fewer side effects when used in early treatment, their effectiveness is compromised in patients with resistant mutations.4 Combination therapies involving TKIs and chemotherapy (such as vincristine and dexamethasone or more intensive regimens like hyper-CVAD) are used in some settings but come with added toxicity.7

3. Ponatinib, as a third-generation TKI, has been shown to suppress a broad spectrum of BCR::ABL1 mutations—including T315I—and may prevent the emergence of compound mutations.6 Accessing Inclusig in India: The Named Patient Program (NPP) As of now, Inclusig may not be easily available in standard retail pharmacies across India. However, Indian patients who need this therapy can access it through a special channel known as the Named Patient Program (NPP).8 This program allows individual patients to receive medications that are not commercially available in their country, under the guidance of their treating physician. To obtain Inclusig through NPP in India, patients or caregivers must: • Work with a licensed importer or access partner like Rx4U • Submit a prescription from their treating hematologist/oncologist • Provide documentation including diagnosis and treatment history • Comply with local regulatory requirements This pathway ensures that Indian patients with resistant forms of CML or Ph+ ALL have access to potentially life-saving treatment. Summary: Is Inclusig right for you? Inclusig offers hope for CML and Ph+ ALL patients who have limited treatment options due to resistance to first- or second-generation TKIs.5 It is particularly effective against the T315I mutation and has shown promising outcomes when used appropriately and monitored closely.5,6 However, due to its potential risks, careful patient selection and ongoing monitoring are essential for safe use.5 Frequently asked questions (FAQs) about Inclusig Q. How long do I need to take Inclusig? Treatment typically continues as long as you are responding well and not experiencing intolerable side effects.5 Q. Can I take Inclusig if I have heart problems? Patients with a history of cardiovascular disease need thorough evaluation before starting.5 Q. When is Inclusig prescribed for CML patients? It is usually prescribed for patients who no longer respond to or cannot tolerate first- or second- generation TKIs like imatinib, dasatinib, or nilotinib, or for those who test positive for the T315I mutation.5 Q. Can Inclusig cure CML? While Inclusig can significantly control the disease and prolong survival, it is not considered a cure.5 Note: The information provided is for education purpose only and is subjected to prescribing information of the drug and the guidance of your treating physician. Always consult your health care provider before making any medical decision for starting your treatment.

4. Disclaimer: Rx4U procures prescribed medicines directly from manufacturers or authorized distributors. It does not claim ownership of any trademarks and complies with the provisions of the Trademark Act, 1999, particularly Sections 30 and 30(1) concerning ‘Fair Use’. It solely facilitates access to new launches through named patient import. References: 1.Chronic myeloid leukemia. Cleveland Clinic. Updated February 14, 2023. Accessed July 14, 2025.https://my.clevelandclinic.org/health/diseases/21845-chronic-myelogenous-leukemia- cml 2.Leukemia. Cleveland Clinic. Updated May 18, 2022. Accessed July 14, 2025. https://my.clevelandclinic.org/health/diseases/4365-leukemia 3.Targeted therapy drugs for chronic myeloid leukemia. American Cancer Society. Updated June 16, 2025. Accessed July 14, 2025. https://www.cancer.org/cancer/types/chronic-myeloid- leukemia/treating/targeted-therapies.html 4.Kantarjian HM, Jabbour E, Deininger M, Abruzzese E, Apperley J, Cortes J, et al. Ponatinib after failure of second‐generation tyrosine kinase inhibitor in resistant chronic‐phase chronic myeloid leukemia. Am J Hematol. 2022;97(11):1419-26. 5.Inclusig. Europeam Medicines Agency. Updated February 14, 2025. Accessed July 14, 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/iclusig#product-details 6.Nascimento M, Moura S, Parra L, Vasconcellos V, Costa G, Leite D, et al. Ponatinib: a review of the history of medicinal chemistry behind its development. Pharmaceuticals (Basel). 2024;17(10):1361. 7.Fullmer A, Kantarjian H, Cortes J, Jabbour E. New developments in the treatment of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia. Leukemia & lymphoma. 2011;52(sup1):81-91. 8.Patil S. Early access programs: Benefits, challenges, and key considerations for successful implementation.Perspect Clin Res. 2016;7(1):4-8. doi:10.4103/2229-3485.173779