Ponatinib‐review of historical development, current status, and future research

Kantarjian, Hagop M.; Chifotides, Helen T.; Haddad, Fadi G.; Short, Nicholas J.; Loghavi, Sanam; Jabbour, Elias

doi:10.1002/ajh.27355

Cited by 5 publications

(1 citation statement)

References 72 publications

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“…In conclusion, data obtained from this analysis, in a population of Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, support the feasibility of PONA as a maintenance strategy after Allo-SCT, resulting in a low rate of discontinuation due to PONA-related toxicity with a high probability of OS and DFS. However, in the majority of cases where a daily dose of 45 mg was started a dose reduction to 30–15 mg/day was required, which could be the appropriate dose to balance efficacy and tolerability [ 26 ].…”

Section: Discussionmentioning

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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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: 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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Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring

Jabbour,

Kantarjian

2024

American J Hematol

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Disease overviewChronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of two cases/100 000. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.DiagnosisCML is characterized by a balanced genetic translocation, t(9;22) (q34;q11.2), involving a fusion of the Abelson murine leukemia (ABL1) gene from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein.Frontline therapyFour tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first‐line treatment of newly diagnosed CML in the chronic phase (CML‐CP). Clinical trials with second and third‐generation TKIs in frontline CML‐CP therapy reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of their potent efficacy and the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. All four TKIs are equivalent if the aim of therapy is to improve survival. In younger patients with high‐risk disease and in whom the aim of therapy is to induce a treatment‐free remission status, second‐generation TKIs may be favored.Salvage therapyFor CML post‐failure on frontline therapy, second‐line options include second and third‐generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities and financial status, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP and failure (due to resistance) of at least two TKIs and for all patients in advanced‐phase disease. Older patients who have a cytogenetic relapse post‐failure on all TKIs can maintain long‐term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non‐TKI anti‐CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others).

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