Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report

Cerveira, Nuno; Ferreira, Rosa Branca; Bizarro, Susana; Correia, Cecília; Torres, Lurdes; Lisboa, Susana; Vieira, Joana; Santos, Rui M; Campilho, Fernando; Vaz, Carlos Pinho; Leite, Luís; Teixeira, Manuel R.; Campos, António

doi:10.1186/s12885-018-5100-4

Cited by 9 publications

(4 citation statements)

References 19 publications

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“…In this study, patients in CP- CML treated with ponatinib had a better PFS and OS. This information should be considered with caution since data were pooled from the ponatinib PACE study and the EBMT registry to conduct an indirect comparison (59). Although this study included only patients harboring the T315 mutations, similar results (based on results from the PACE study) would be expected for patients without such mutations.…”

Section: Efficacy Of Tkis In Different Clinical Scenariosmentioning

confidence: 99%

Tyrosine Kinase Inhibitors Available for Chronic Myeloid Leukemia: Efficacy and Safety

2019

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Chronic myeloid leukemia (CML) is currently a disease in which patients can enjoy a near normal life-expectancy. However, since the majority of patients will need to remain on treatment indefinitely, physicians in care of CML patients need be familiar with the indications and toxicities of all approved tyrosine kinase inhibitors (TKI). In clinical practice, there are five TKI (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib) that are available in different scenarios and have distinct safety profiles. Decisions regarding first line treatment must be based on CML risk, comorbidities, and patients expectations. Despite the excellent outcome, half of the patients will eventually fail (due to intolerance or resistance) to first line treatment, with many of them requiring a third or even further lines of therapy. When selecting for such patients, it is essential to distinguish between failure and intolerance to previous TKIs. In the present review, we will address all these issues from a practical point of view.

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Section: Efficacy Of Tkis In Different Clinical Scenariosmentioning

confidence: 99%

Tyrosine Kinase Inhibitors Available for Chronic Myeloid Leukemia: Efficacy and Safety

2019

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“…All patients were diagnosed in chronic phase, their median age was 69 years (range, 56–79), 64% were men, and 36% women. Patients received imatinib (8), or second-generation TKIs (3) as first line of therapy and during the median follow-up of 24 months; 4 switched therapy, 3 for unsatisfactory response and one for grade-4 toxicity (Supplementary Table 5).…”

Section: Resultsmentioning

confidence: 99%

“…About 4% of failing cases presents ABL1 mutations, even at the low level (sub-clonal), detectable only by NGS whose sensitivity is higher than offered by the Sanger sequencing (2). The T315I mutation confers resistance to the TKIs imatinb, dasatinib, nilotinib, and bosutinib, whereas it is sensitive to ponatinib (3). Nevertheless, combination with other mutations (compound mutations), also ponatinib is ineffective, and other therapeutical approaches are necessary, such as asciminib (4).…”

Section: Introductionmentioning

confidence: 99%

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia

et al. 2019

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Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a “real-life” setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were “resistant;” after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a “low” up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a “high” gene over-expression ( p = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a “low” up-regulation were event-free vs. 33% of those who presented a “high” gene expression ( p = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.

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“…Second-generation dasatinib and third-generation ponatinib TKI have potent activity in Ph-positive ALL with wild-type and mutated BCR-ABL, 10 – 13 and ponatinib is more effective in some mutations, including T315I. 14 , 15 Dasatinib holds clinical potential in managing CNSL, 16 , 17 and ponatinib is also effective in CNSL. 18 , 19 However, the priority of dasatinib and ponatinib treatments has not been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Efficacy and Safety of Ponatinib and Dasatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia With Central Nervous System Relapse: A Retrospective Study

Zhu

Zhu²,

Miao

et al. 2023

Technol Cancer Res Treat

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Introduction Central nervous system leukemia (CNSL) is the most common extramedullary relapse site in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL), with a poor prognosis and high relapse rate. Methods We characterized the clinical data of 21 Ph-positive B-ALL patients to analyze the efficacy and safety of ponatinib for patients with central nervous system relapsed Ph-positive ALL retrospectively. Results There were 11 males and 10 females in the cohort, and their median age was 45 (9-58) years old. The total CR (complete remission) rate was 90.5%. All 9 patients achieved CR in the ponatinib group, and 10 patients achieved CR in the dasatinib group (100% vs 83.3%, respectively; P = .486) and minimal residual disease-positive CR in the ponatinib group and dasatinib group (88.9% vs 58.3%, P = .178). The medium time after achieving CR was 5 and 8 weeks ( P = .047). The total median overall survival (OS) was 31.1 months, and the 3-year OS was 49.0%. The median relapse-free survival (RFS) was 31.0 months, and the 3-year RFS was 45.2%. Patients in the ponatinib group showed a significantly longer OS than those patients in the dasatinib group with (medium OS not reached vs 27.6 months, P = .045) or without (medium OS not reached vs 27.6 months, P = .039) T315I mutations. The median RFS between the ponatinib group and the dasatinib group with T315I was not reached and 16.2 months, P = .065. The median RFS between the ponatinib group and the dasatinib group without T315I was not reached and 16.2 months, P = .036. No treatment-related deaths were observed during the therapy. Conclusion (1) Ph-positive CNSL patients seemed to have a high rate of response and postinduction MRD negativity with ponatinib and dasatinib, but ponatinib seemed to show a shorter time to achieve remission than dasatinib. (2) Ponatinib maintenance treatment might show superior survival for Ph-positive CNSL patients with or without the T315I mutation. (3) Ponatinib and dasatinib seemed to be both safe for the clinical application of Ph-positive CNSL.

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Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report

Cited by 9 publications

References 19 publications

Tyrosine Kinase Inhibitors Available for Chronic Myeloid Leukemia: Efficacy and Safety

Tyrosine Kinase Inhibitors Available for Chronic Myeloid Leukemia: Efficacy and Safety

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia

Comparison of the Efficacy and Safety of Ponatinib and Dasatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia With Central Nervous System Relapse: A Retrospective Study

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