Ponatinib: Accelerated Disapproval

Gainor, Justin F.; Chabner, Bruce A.

doi:10.1634/theoncologist.2015-0253

Cited by 52 publications

(47 citation statements)

References 7 publications

(7 reference statements)

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“…However, the mechanism by which this effect occurs is absolutely unclear and there are no data in the medical literature relating to this interesting issue. However, we know from registered studies that the approved daily dose of 45 mg of ponatinib largely exceeds the pharmacokinetic requirements for inhibiting T315I ABL and suppressing the growth of other mutant clones [14] . This aspect could be supported by the persistent molecular remission observed in our patient, also during the drug reduction to a daily dose of 15 mg.…”

Section: Discussionmentioning

confidence: 99%

Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant

Renzi¹,

Marchesi

Angelis

et al. 2016

Chemotherapy

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We describe the case of a patient with a Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with dasatinib plus steroids as the first-line therapy who achieved a molecular complete remission and then underwent a matched, unrelated donor allogeneic transplant. Five months after the transplant, he experienced a disease relapse with an T315I mutation, which was resistant to salvage Key WordsAcute lymphoblastic leukemia · Philadelphia chromosome · Allogeneic transplant · Ponatinib · T315I mutation · Graft-versus-host disease · Graft-versus-leukemia effect · Thyroid dysfunction Established Facts• Ponatinib is a highly effective treatment for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) with T315I mutation, and is well tolerated. Novel Insights• Ponatinib as a single-agent treatment is able to determine the molecular complete response in Ph+ ALL with T315I mutation after early relapse following allogeneic stem cell transplantation, and can induce a graft-versus-host disease/graft-versus-leukemia effect. chemotherapy. Once the details of the T315I mutation were acquired, we initiated ponatinib treatment at a standard dosage and observed a rapid decrease of minimal residual disease (MRD) at molecular assessment. The bone marrow evaluation after 2, 3, 6, 10 and 13 months was negative for MRD. After starting ponatinib, the patient experienced a skin graft-versus-host disease (GVHD), whereas no occurrence of GVHD was observed after transplant, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect, but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib was well tolerated but a thyroid dysfunction mimicking a cardiovascular toxicity was observed and solved with hormonal substitutive treatment.

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Section: Discussionmentioning

confidence: 99%

Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant

Renzi¹,

Marchesi

Angelis

et al. 2016

Chemotherapy

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“…37 Additional follow-up from these ponatinib trials has since revealed a much higher frequency of serious adverse vascular events (48% and 24% in the phase I and II trials, respectively). 38 This concern led the U.S. FDA and Ariad Pharmaceuticals to abruptly withdraw ponatinib from the market in October 2013. Importantly, an ongoing phase III trial (EPIC- Exploring Ponatinib In untreated patients with CML) comparing ponatinib to imatinib for the first-line treatment of CML was also closed, patients were crossed over to imatinib, and their follow-up was terminated.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, an ongoing phase III trial (EPIC- Exploring Ponatinib In untreated patients with CML) comparing ponatinib to imatinib for the first-line treatment of CML was also closed, patients were crossed over to imatinib, and their follow-up was terminated. 38 …”

Section: Introductionmentioning

confidence: 99%

The Role of New Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

2016

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Imatinib mesylate was the first tyrosine kinase inhibitor (TKI) approved for the management of chronic myeloid leukemia (CML). Imatinib produces acceptable responses in ~ 60% of patients; with ~20% discontinuing therapy due to intolerance and ~20% developing drug resistance. The advent of newer TKIs’ such as, nilotinib, dasatinib, bosutinib and ponatinib have provided multiple options for patients. These agents are more potent, have unique side effect profiles and are more likely to achieve relevant milestones such as, early molecular responses (3-6 months) and optimal molecular responses (12 months). The acquisition of BCR-ABL kinase domain mutations is also reportedly lower with these drugs. Thus far, none of the randomized phase III clinical trials have shown a clinically significant survival difference between frontline imatinib versus newer TKIs’. Cost and safety issues with the newer TKIs’ such as, vascular disease with nilotinib and ponatinib and pulmonary hypertension with dasatinib have dampened the enthusiasm of using these drugs as frontline options. While the utility of new TKIs’ in the setting of imatinib failure or intolerance is clear, their use as frontline agents should factor in the age of the patient, additional comorbidities, risk stratification (Sokal score) and cost. Combination therapies and newer agents with potential to eradicate quiescent CML stem cells offer future hope.

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“…The accumulation of these adverse effects caused the trial to be put on hold and then canceled . Due to these risks, ponatinib is now used as a last resort drug . Because of the adverse events associated with ponatinib, there is a motivation to develop other potent BCR‐ABL1(T315I) inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase

et al. 2018

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The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight-year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, about 20 % of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR-ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation. However, ponatinib has severe cardiovascular toxicities; hence, there have been efforts to find safer CML drugs that work against ABL1 secondary mutations. We reveal that isoquinoline- or naphthyridine-based compounds, such as HSN431, HSN576, HSN459, and HSN608 potently inhibit the enzymatic activities of ABL1, ABL1(T315I), and ABL1(E255K). These compounds inhibit the proliferation of ABL1-driven CML cell lines, K652 and KCL22 as well as the drug-resistant cell line, KCL22-IR, which harbors the secondary mutated ABL1(T315I) kinase.

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Ponatinib: Accelerated Disapproval

Cited by 52 publications

References 7 publications

Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant

Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant

The Role of New Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase

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