Optimizing Outcomes in Resistant/Intolerant CP-CML and Newly Diagnosed Ph+ ALL with ICLUSIG

Authored and Sponsored by Takeda Oncology

This article is intended for U.S. HCP audiences only.

Please see Indications, Usage, and Important Safety Information, including Boxed Warning, at the end of this article.

Current Therapeutic Approaches in CML and Ph+ ALL

The cancer treatment landscape is evolving rapidly, as seen with advances in personalized medicine and combination therapies. Specifically, targeted therapies are now reshaping the future for people living with rare hematological malignancies like chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Once defined by limited treatment options, these diseases are now at the forefront of a new era of precision oncology, which is bringing a renewed sense of hope among patients and their healthcare teams.

CML and Ph+ ALL, both marked by the Philadelphia chromosome, are complex diseases due to factors like drug resistance and treatment-related toxicities.^1-3 Historically, chemotherapy followed by stem cell transplantation (SCT) was the standard of care, but the advent of tyrosine kinase inhibitors (TKIs) revolutionized treatment by directly targeting the BCR::ABL1 gene.^3-5 Nevertheless, resistance persists and therefore treatment obstacles remain.

BCR::ABL1 mutations can undermine first- and second-generation TKIs and in CML specifically, approximately 30 percent of patients do not survive beyond five years due to treatment resistance.^6-9 For those with chronic-phase CML (CP-CML), ≥ 40 percent of patients receiving a second-generation TKI in the second line experience resistance or intolerance to early-generation TKIs over the course of treatment.^10-12 As a result, these patients commonly cycle through multiple TKIs – moving from one second-generation agent to another – and when response wanes or toxicity limits further use, treatment options become increasingly narrow.¹³

Similar challenges are seen in Ph+ ALL, as this disease is fast progressing and aggressive, making treating it a complex endeavor, as BCR::ABL1 mutations can hinder treatment efficacy and older patients are often left with few alternatives because of comorbidities.^2,14-15

Despite these challenges, ongoing advances in targeted therapy are reshaping what’s possible for patients with CP-CML and Ph+ ALL who face resistance or intolerance to existing treatments.

The Role of ICLUSIG in CP-CML and Ph+ ALL Treatment

ICLUSIG^® (ponatinib) is a third-generation TKI and a meaningful option for those with resistant/intolerant CP-CML after at least two prior TKIs or newly diagnosed Ph+ ALL in combination with chemotherapy.^*16

Given the limitations of sequential TKI therapy, clinical studies, like the Phase 2 OPTIC trial, have sought to explore alternatives that can overcome resistance and intolerance. The OPTIC study was designed to evaluate three starting doses of ICLUSIG (15 mg, 30 mg, 45 mg) in patients with resistant CP-CML, or who had documented history of T315I mutation after receiving any number of prior TKIs.¹⁶ The primary endpoint was achievement of ≤1% BCR::ABL1^IS at 12 months.¹⁶ In the trial, 44% (41 out of 93) of patients achieved a molecular response at 12 months.¹⁶ After five years of follow-up, 60.2% (95% CI 49.5, 70.0) of patients who began treatment with a 45 mg starting dose of ICLUSIG and subsequently reduced to 15 mg achieved ≤1% BCR::ABL1^IS. ¹⁶ Of the 45 patients who had a dose reduction after achieving this response, 25 patients (56%) maintained response at the reduced dose for at least one year, and 16 of these patients (64%) maintained response for greater than 60 months.¹⁶ The median duration of molecular response was not reached at a minimum follow-up of 60 months, demonstrating the drug’s durable response for patients whose disease is resistant or intolerant to both first- and second-generation TKIs.¹⁶

Beyond CP-CML, ICLUSIG also demonstrated strong clinical benefit in people with Ph+ ALL. This was demonstrated in the pivotal Phase 3 PhALLCON trial, which evaluated whether first-line treatment of Ph+ ALL with a third-generation BCR::ABL1 TKI could improve outcomes versus a first-generation BCR::ABL1 TKI, as measured by minimal residual disease (MRD)-negative complete response (CR)** rate at the end of induction.¹⁷ This head-to-head trial compared ICLUSIG in combination with chemotherapy against imatinib, a first-generation TKI, and chemotherapy, in adult patients with newly diagnosed Ph+ ALL.¹⁷ In this trial, patients treated with ICLUSIG achieved an MRD-negative CR rate of 30% compared to 12% in the imatinib arm at the end of induction (risk difference, 0.18; 95% CI, 0.08-0.28; p=0.0004).¹⁶

These data marked a breakthrough for the Ph+ ALL community, as they showed a greater than two-fold improvement in MRD-negative CR rate.^16,17 Notably, these results highlight that ICLUSIG in combination with chemotherapy can provide deeper responses compared to imatinib in these patients.

Importantly, ICLUSIG is not indicated for the treatment of patients with newly diagnosed CP-CML and should only be used to treat adult patients who have shown resistance or intolerance to at least two prior TKIs or who have the T315l mutation.¹⁶

Optimized Dosing Strategies: An Approach to Proactively Manage Tolerability

While ICLUSIG has the potential to deliver meaningful results, it requires careful management of adverse effects (AEs) over time.¹⁶ An optimized dosing strategy can help balance safety and efficacy by allowing clinicians to initiate treatment at a higher dose – providing sufficient time for a disease such as CP-CML to respond – then reduce treatment dose based on patient response.¹⁶ Throughout this type of dosing regimen, regular bloodwork and cardiovascular assessments are recommended to detect early signs of adverse events.¹⁶ If adverse events do occur, dose adjustments or temporary discontinuation may be necessary to ensure patient safety.¹⁶

The pivotal Phase 2 PACE study was the basis of ICLUSIG’s U.S. FDA approval in 2012; however, more recent findings from the OPTIC trial demonstrated the effectiveness of an optimized, dose-reduction strategy designed to manage tolerability without compromising efficacy.^13,16

After five years of follow-up, the OPTIC trial results, now reflected in the latest FDA-approved label, demonstrate that the optimized ICLUSIG dosing regimen—starting at 45 mg per day and reducing to 15 mg per day—maintains a low incidence of severe AOEs while supporting sustained treatment, thereby reinforcing its favorable benefit-risk profile. OPTIC data showed that the 45-to-15 mg/day optimized dosing regimen resulted in 7% of patients experiencing Grade 3/4 treatment-emergent arterial occlusive events (TE-AOEs) and 4.3% experiencing Grade 5 TE-AOEs.¹⁶ Serious adverse reactions occurred in 40% of patients, fatal adverse reactions occurred in 4.3% of patients, and 24% of patients permanently discontinued treatment due to adverse reactions.¹⁶ Nearly half of the patients who experienced any-grade AOEs were able to continue study treatment, underscoring the regimen's overall tolerability compared with the other starting doses evaluated in the trial.¹⁶

This dosing strategy also showed promise in Ph+ ALL patients, as evidenced in the PhALLCON study. In this trial, patients with newly diagnosed Ph+ ALL were randomly assigned to two groups.¹⁷ The first group received ICLUSIG at a starting dose of 30 mg along with reduced-intensity chemotherapy, with the dose being reduced to 15 mg upon achieving MRD-negative CR.¹⁷ The second group received imatinib combined with reduced intensity chemotherapy, without a dose-reduction strategy.¹⁷ The study reported serious AEs in 63% of patients receiving ICLUSIG and 57% of those on imatinib.^16,18 Both treatment arms had a 6% incidence of fatal AEs.^16,18 Additionally, 13% of patients on ICLUSIG permanently discontinued treatment due to AEs.¹⁶ The overall safety profile of ICLUSIG was comparable to that of imatinib, with treatment-emergent arterial occlusive events (TE-AOEs) occurring in 2.5% of ICLUSIG-treated patients and 1.2% of those on imatinib.^17,19 Importantly, no new safety signals were identified in the study.¹⁷ The substantial improvement in MRD-negative CR and a manageable safety profile underscores the importance of the optimized dosing strategy with ICLUSIG in newly diagnosed Ph+ ALL.

Together, these examples illustrate the potential of optimized dosing strategies, and by educating clinicians and patients about this treatment approach, we can better address the treatment challenges associated with TKIs and ultimately, optimize both efficacy and safety.

Advancing Leukemia Care

ICLUSIG represents an important advancement in the management of Philadelphia-chromosome positive leukemias. By demonstrating efficacy irrespective of mutations, ICLUSIG addresses one of the most persistent challenges in treatment.¹⁶ With optimized dosing strategies validated in the OPTIC and PhALLCON trials, clinicians can seek to deliver efficacy while maintaining a focus on safety and long-term disease control.

Takeda is committed to improving patient outcomes by advancing research and innovation to better serve patients with leukemia and other blood cancers.

For more information about ICLUSIG, visit https://www.iclusig.com/hcp.

*The Ph+ ALL indication of ICLUSIG is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).¹⁶

**MRD-negative CR is a composite endpoint defined in alignment with the FDA that reflects deep molecular and clinical responses, serving as an important prognostic indicator for long-term outcomes for patients with Ph+ ALL.¹⁷

INDICATIONS AND USAGE

ICLUSIG is indicated for the treatment of adult patients with:

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

• Newly diagnosed Ph+ ALL in combination with chemotherapy.
  This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s).
• As monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL.

Chronic Myeloid Leukemia (CML)

• Chronic phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors.
• Accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated.
• T315I-positive CML (chronic phase, accelerated phase, or blast phase).

Limitations of Use: ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG. These included cardiovascular, cerebrovascular, and peripheral vascular events, and occurred in patients with and without cardiovascular risk factors. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose, or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk before restarting ICLUSIG.

Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG, including events such as deep vein thrombosis, embolism, pulmonary embolism, superficial vein thrombosis, thrombosis, jugular vein thrombosis, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose, or discontinue ICLUSIG based on recurrence/severity.

Heart Failure: Fatal, serious, or severe heart failure events have occurred, including increased brain natriuretic peptide (BNP), left ventricular hypertrophy, left ventricular dysfunction, congestive cardiac failure, cardiac failure, left atrial dilatation, and decreased ejection fraction. Monitor for signs or symptoms of heart failure and manage as clinically indicated. Interrupt, then resume at reduced dose, or discontinue ICLUSIG for new or worsening heart failure.

Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death has occurred. The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase, and decreased albumin and blood fibrinogen. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose, or discontinue ICLUSIG based on recurrence/severity.

Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred. Patients may require urgent intervention for hypertension with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage as clinically indicated. Interrupt, dose reduce, or discontinue ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis.

Pancreatitis: Serious or severe pancreatitis has occurred. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2-3 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose, or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG increased the risk of serious adverse reactions. The trial was halted for safety. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Neuropathy: Peripheral and cranial neuropathy occurred in ICLUSIG-treated patients, including Grade 3 or 4 events. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Interrupt, then resume at the same or reduced dose, or discontinue ICLUSIG based on recurrence/severity.

Ocular Toxicity: Serious or severe ocular toxicities leading to blindness and blurred vision have occurred. The most frequent ocular toxicities were dry eye, blurred vision, and eye pain. Retinal toxicities included retinal vein occlusion, retinal hemorrhage, age-related macular degeneration, arteriosclerotic retinopathy, retinal vascular disorder, macular edema, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Fatal and serious hemorrhages have occurred. Intracranial hemorrhage, gastrointestinal hemorrhage, and subdural hematoma were the most frequently reported serious hemorrhages. Most hemorrhages occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage as clinically indicated. Interrupt, then resume at the same or reduced dose, or discontinue ICLUSIG based on recurrence/severity.

Fluid Retention: Fatal and serious events, including one instance of fatal brain edema and serious events of pleural effusion, pericardial effusion, and angioedema have occurred. The most frequent occurrences of fluid retention in patients who received ICLUSIG were peripheral edema, pleural effusion, hydrothorax, pericardial effusion, and peripheral swelling. Monitor for fluid retention and manage as clinically indicated. Interrupt, then resume at the same or reduced dose, or discontinue ICLUSIG based on recurrence/severity.

Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular and atrial arrhythmias, tachycardia, bradycardia, cardio-respiratory arrest, syncope, atrial fibrillation, and supraventricular tachycardia, have occurred, including some patients with serious or severe (Grade 3 or 4) events leading to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations, or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose, or discontinue ICLUSIG based on recurrence/severity.

Myelosuppression: Grade 3 or 4 neutropenia, thrombocytopenia, and anemia have occurred. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. Interrupt ICLUSIG if ANC <1 × 10⁹/L or platelets <50 × 10⁹/L, and resume when ANC ≥1.5 × 10⁹/L and platelets ≥75 × 10⁹/L, at same or reduced dose.

Tumor Lysis Syndrome (TLS): Serious TLS has occurred. Ensure adequate hydration and treat elevated uric acid prior to initiating ICLUSIG.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported. Patients can present with hypertension, seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. MRI is necessary to confirm diagnosis. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG upon resolution of RPLS is unknown.

Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week before elective surgery and for at least 2 weeks after major surgery until adequate wound healing. Gastrointestinal perforation or fistula have occurred. Permanently discontinue ICLUSIG in patients with gastrointestinal perforation.

Embryo-Fetal Toxicity: ICLUSIG can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to the fetus. Females of reproductive potential should use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.

ADVERSE REACTIONS
The most common adverse reactions (occurring in >20% of patients) are:

• ICLUSIG as a single agent: rash and related conditions, arthralgia, abdominal pain, fatigue, headache, constipation, hypertension, dry skin, hepatotoxicity, fluid retention and edema, pyrexia, pancreatitis/lipase elevation, nausea, hemorrhage, anemia, AOEs, and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.
• ICLUSIG in combination with chemotherapy: hepatotoxicity, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase, and increased alanine aminotransferase.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided.
Strong CYP3A Inducers: Avoid coadministration.

USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 1 week following last dose.

Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG. Ponatinib may impair fertility in females, and it is not known if these effects are reversible.

Pre-existing Hepatic Impairment: For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG to 30 mg orally once daily for patients with pre-existing hepatic impairment. For patients with newly diagnosed Ph+ ALL, no dosage adjustment is recommended when administering ICLUSIG to patients with mild hepatic impairment.

Please see full Prescribing Information, including Boxed Warning.

References

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18. Data on file. Takeda Pharmaceutical Company Limited, 2025.
19. Data on file. Takeda Pharmaceutical Company Limited, 2023.

US-ICL-0245
12/2025