Ariad Pharmaceuticals Inc fka ARIA

[LUMA14]

Cutaneous Lesions Anticipating Accelerated Phase of Multidrug Resistant Chronic Myeloid Leukemia Responsive to Ponatinib

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Imatinib
Dastinib
Nilotinib und zuletzt:
Ponatinib

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Compassionate use ponatinib was then initiated at the dose of 45 mg/day.
After 1 week, patient reached a CHR with persistence of anemia and after 2 weeks showed an improvement of skin lesions that completely disappeared after 4 weeks of treatment (figure 2).

After 5 weeks, patient developed a bronchopneumonia that required discontinuation of the drug and antibiotic treatment: during the discontinuation of Ponatinib for 3 weeks, the skin lesions reappeared.
When the drug was restarted at the same dose, the skin lesions disappeared again after two weeks, indirectly suggesting that skin lesions are direct manifestation of disease. After achieving CHR and PCyR, patient progressed and finally died for sepsis.

In a phase I trial with Ponatinib, 74 patients (64 with refractory CML or Ph+-ALL) were recruited. Patients received the drug at doses ranging from 2 to 60 mg once daily. The most common side effects were thrombocytopenia (23%), rash (22%) and arthralgia (15%).4
Recently, the efficacy and safety of ponatinib were evaluated in a phase II trial, named PACE:5 of 449 patients enrolled, 270 were in CP and the majority had previously received two or more lines of therapy. After a median follow-up of 9 months, overall 56% of patients achieved the primary endpoint (MCyR) in a median time of 2.8 months, with 51% of patients being previously resistant to dasatinib and/or nilotinib and 70% of patients having a T315I.
A CCyR was achieved in 46% of cases, MMR in 34% and MR4.5 in 15%.
Ninety-one percent of patients maintained MCyR at 12 months.
The results of the trial also proved that Ponatinib inhibits both wild-type (IC50=0.37 nM) and T315I mutated (IC50=2.0 nM) BCR-ABL1, while having activity against several common BCR-ABL1 mutations such as E255K, Y253H and G250E.
The most important adverse events reported were abdominal pain, skin rash and increase of amylase with pancreatitis, which occurred in 7% of patients.
As shown also in present case, skin lesions should be considered as a possible sign of progression and ponatinib can be safely used, also in patients in advanced CML phase associated with extramedullary manifestations of disease.
Further studies in patients with extramedullary localizations are warranted and in particular in patients with skin localization to understand if ponatinib is able to overcome this possible sanctuary of disease.