Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL

Kawano, Noriaki; Kimura, Shinya; Miura, Masatomo; Tochigi, Tatsuo; Nakaike, Takashi; Yamashita, Kiyoshi; Mashiba, Koichi; Kikuchi, Ikuo; Takahashi, Naoto

doi:10.1007/s12185-021-03186-8

Cited by 3 publications

(3 citation statements)

References 28 publications

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“…Therefore, in the cohort of patients we analyzed, the largest group reported to date who received maintenance with PONA after Allo-SCT, we confirm the feasibility with a favorable safety profile of PONA treatment, particularly in the prophylactic group (MRD neg), for which lower PONA doses were used [ 11 , 23 ]. What we observed confirms the favorable data already reported on post-Allo-SCT maintenance therapy with first- and second-generation TKIs and is in line with what is indicated by both the EBMT-2016 and Leukemia NET-2024 recommendations, which support the post-transplant maintenance with TKIs in Ph + ALL as both a prophylactic and pre-emptive strategy [ 1 , 2 , 6 , 8 ].…”

Section: Discussionmentioning

confidence: 65%

“…It is a potent inhibitor of both the native BCR-ABL tyrosine kinase and isoforms carrying mutations responsible for resistance to other targeted drugs (including imatinib, dasatinib and nilotinib). PONA is also able to target several other kinases and is therefore classified as a multi-targeted kinase inhibitor [ 1 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission

Candoni,

Chiusolo,

Lazzarotto

et al. 2024

Cancers

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The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach (prophylactic, pre-emptive or salvage) is still heterogeneous in transplant centers. In this context, very little is known about the feasibility and safety of third-generation TKIs. In this paper, we analyze the efficacy and safety of ponatinib (PONA) administered after Allo-SCT to prevent cytologic relapse of Ph + ALL. This is a multicenter observational study including 48 patients (pts) with Ph + ALL (median age 49 years) who received PONA after Allo-SCT while in complete cytological remission (cCR); 26 (54%) had positive minimal residual disease (MRD pos) before Allo-SCT. PONA was administered after Allo-SCT prophylactically (starting with MRD neg) in 26 pts or pre-emptively (starting with MRD pos post-SCT and without hematological relapse) in 22 pts. Patients treated prophylactically with PONA started treatment earlier, at a median of 4.3 months (range 1.5–6) after Allo-SCT, than those treated pre-emptively, who started PONA at a median of 7.4 months (range 2–63) after Allo-SCT (p = 0.01). The median starting dose of PONA was 30 mg/day (range 15–45). A dose reduction was required in 10/48 (21%) of cases, but a permanent discontinuation of PONA, due to toxicity, was required in only 5/48 pts (10.5%). No deaths due to PONA-related adverse events (AEs) were reported. The median follow-up time after Allo-SCT was 34 months (range 7.7–118). At the last follow-up, the median duration of PONA therapy was 22 months (range 2–100). The 5-year OS and RFS after Allo-SCT were 92% and 71%, respectively. The 5-year RFS after Allo-SCT of pts who received PONA prophylaxis was 95%, and it was 57% for those who received PONA pre-emptively (log-rank p = 0.02). In conclusion, this multicenter analysis of 48 patients with Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, supports the feasibility of PONA maintenance strategy after Allo-SCT with a low rate of discontinuations (10.5%) due to PONA-related AE.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission

Candoni,

Chiusolo,

Lazzarotto

et al. 2024

Cancers

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“…More recently, Kawano et al reported a serial determination of PON plasma levels in one patient with chronic-phase CML, one in the advanced phase of CML, and in another patient affected by Ph’+ ALL [ 29 ]. All these subjects received PON at low doses: 15 mg every other day or 15 mg/day.…”

Section: Discussionmentioning

confidence: 99%

A New Algorithm Integrating Molecular Response, Toxicity, and Plasma Level Measures for Ponatinib Dose Choice in Patients Affected by Chronic Myeloid Leukemia

Galimberti,

Abruzzese,

Luci

et al. 2024

Pharmaceutics

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Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. The present study was aimed at investigating any possible correlations among ponatinib dose, plasma concentration, molecular response (MR), and tolerability in a real-world setting. Clinical and laboratory records (including MR and drug plasma concentrations) of 32 CML patients treated with ponatinib were harvested and analyzed. Twenty-seven patients (71%) had ponatinib Cmin values > 21.3 ng/mL, but Cmin values > 10.7 ng/mL (considered efficacious in BCR-Abl unmutated patients) were achieved by 80% of the patients receiving ≥30 mg/day and 45% of the subjects treated with 15 mg/day. No significant correlations were identified among clinical efficacy, tolerability, daily dose, and plasma concentration. Notably, patients who underwent dose tapering for tolerability or safety reasons did not experience treatment failure. In a real-world setting, adjustment of ponatinib daily doses lower than those registered may maintain therapeutic efficacy while reducing the risk of vascular events and improving tolerability. Further studies are warranted to confirm the present results in a larger cohort of patients.

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Multiple drugs

2021

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Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL

Cited by 3 publications

References 28 publications

Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission

Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission

A New Algorithm Integrating Molecular Response, Toxicity, and Plasma Level Measures for Ponatinib Dose Choice in Patients Affected by Chronic Myeloid Leukemia

Multiple drugs

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