Received: January 6, 2016
Accepted: February 2, 2016
Mediterr J Hematol Infect Dis 2016, 8(1): e2016016, DOI 10.4084/MJHID.2016.016
This article is available on PDF format at:
Massimo Breccia1, Gioia Colafigli1, Luisa Quattrocchi1, Elisabetta Abruzzese2 and Giuliana Alimena1
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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Dear Editor,
Ponatinib (formerly known as AP24534, Ariad Pharmaceuticals,
Cambridge, MA) is the first tyrosine kinase inhibitor (TKI) to have
potent and consistent activity against BCR-ABL1 with the T315I
mutation.[1] The drug was developed based on a
scaffold that, unlike current available TKI, does not make a hydrogen
bond with T315, and has a long and flexible ethynil tri-carbon linker
which permits its accommodation in the catalytic domain even in the
presence of the bulky side chain of isoleucine at residue 315.[2]
Results from a recently reported phase I study of Ponatinib in patients
with advanced hematological malignancies showed that among 38 patients
with chronic phase CML (CP-CML) enrolled, a complete hematologic
response (CHR) was obtained in 95% and a complete cytogenetic response
(CCyR) in 53%.[3] To confirm what recently reported,[4]
we describe the activity of ponatinib as fourth line in a CML patient
in accelerated phase (AP) resistant to prior TKIs who had cutaneous
manifestation and achieved improvement of the skin lesions and of
disease. A 43-year old male was diagnosed as having CP-CML, with
intermediate Sokal risk, in February 2006. After a short period of
cytoreduction with hydroxyurea, he was started on standard dose
imatinib and achieved a CHR after 2 weeks, but only reached a minor CyR
at 3 months and a partial CyR at 6 months. At that time mutational test
was negative: patient admitted sporadic scarce adherence and blood
level testing repeated at two different times revealed imatinib in the
considered normal range (> 1100 mg/dl). Dasatinib 100 mg/day was
started because the patient was considered as a failure: after 3 months
CCyR was achieved and molecular analysis performed at that time showed
a consistent but not optimal response (BCR-ABL ratio 2.9% IS). Patient
continued with the drug and maintained CCyR but, after achieving MMR at
12 months, did never reach a stable deep molecular response. After 38
months, he suddenly lost hematologic response while admitting the
discontinuation of the drug for a long period. At that time a CBA
displayed a cytogenetic clonal evolution (47, XY, t(9;22) (q34;q11),
i(17)(q10)[4]/46, XY [17]) and molecular analysis revealed a
significant increase of BCR-ABL ratio (53%). Mutational analysis
repeated at that time did not show the presence of mutations. While a
MUD research was activated, Nilotinib at the dose of 400 mg BID was
started. The patient reached a CHR after 2 weeks and a CCyR after 3
months but again he did never reach a stable molecular response
(BCR-ABL ratio of 1.2% after 6 months). After 5 months of treatment, he
developed diffuse scaly patches of red and white hue that were
initially diagnosed as plaque psoriasis (figure1).
Only local therapy was prescribed, but an inflammation and exfoliation
of the skin over most of the body surface was soon observed,
concomitantly with appearance of thrombocytopenia, anemia, and
leucocytosis. At that time we believed that skin lesions were
associated to progression of disease; a bone marrow analysis showed a
disease progression to accelerated phase: CBA identified a karyotype
mosaicism (46, XY, t(9;22) (q34;q11) [2]/ 46, XY, t(9;22), i(17)(q10)
[3]/ 45,XY,t(9;22), i(17)(q10), -Y [4]/ 46, XY [12]), and mutational
test revealed the emergence of a L387F mutation. Nilotinib was
discontinued and, due to severe leukocytosis, patient was started on
low dose chemotherapy (vindesine 5 mg total dose). 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.
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Figure 1. Maculo-papular and erythematous skin lesions before ponatinib treatment |
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Figure 2. Resolution of skin lesions after onatinib treatment |
References
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