Efficacy of Ponatinib Versus Earlier Generation Tyrosine Kinase Inhibitors for Front-line Treatment of Newly Diagnosed Philadelphia-positive Acute Lymphoblastic Leukemia

Jabbour, Elias; DerSarkissian, Maral; Duh, Mei Sheng; McCormick, Nora; Cheng, Wendy Y.; McGarry, Lisa; Souroutzidis, Ariadne; Huang, Hui; O’Brien, Susan; Ravandi, Farhad; Kantarjian, Hagop M.

doi:10.1016/j.clml.2018.02.010

Cited by 40 publications

(28 citation statements)

References 59 publications

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“…The 5-year event-free survival (EFS) and OS rates were 68% and 74%, respectively. It is worth noting that while none of the TKIs have been compared head-tohead in Ph-positive ALL, one meta-analysis and one propensity-matched score analysis both showed superiority of ponatinib-based regimens over regimens containing earlier generation TKIs [77,78]. Depth of remission, EFS, and OS rates all favored ponatinib.…”

Section: Intensive Chemotherapy + Tkimentioning

confidence: 99%

Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions

et al. 2020

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Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable residual disease has fine-tuned our prognostic models and guided our treatment decisions. The treatment paradigms of ALL have been revolutionized with the advent of tyrosine kinase inhibitors targeting BCR-ABL1, monoclonal antibodies targeting CD20 (rituximab), antibody-drug conjugates targeting CD22 (inotuzumab ozogamicin), bispecific antibodies (blinatumomab), and CD19 chimeric antigen receptor T cell therapy (tisagenlecleucel). These highly effective new agents are allowing for novel approaches that reduce reliance on intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation in first remission. This comprehensive review will focus on the recent advances and future directions in novel therapeutic strategies in adult ALL.

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Section: Intensive Chemotherapy + Tkimentioning

confidence: 99%

Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions

et al. 2020

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“…In an indirect comparison with dasatinib plus hyper-CVAD in first-line Ph+ ALL, ponatinib plus hyper-CVAD was associated with significantly higher 3-year EFS and OS rates, based on propensity-score matched analysis of 41 patients from each cohort (EFS: 69 vs. 46%; p = 0.04; OS: 83 vs. 56%; p = 0.03), probably resulting mainly from faster achievement of deep molecular response [31]. In a recent meta-analysis of studies in newly diagnosed Ph+ ALL patients, ponatinib in combination with chemotherapy was significantly more likely to obtain CMR than first-generation/2G TKIs in combination with chemotherapy (79 vs. 34%; OR 6.09; p = 0.034) [32]. Achieving CMR was coupled with a significantly higher 3-year OS (79 vs. 50%; OR 4.49; p = 0.050).…”

Section: Efficacy Of Ponatinibmentioning

confidence: 99%

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

et al. 2019

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Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib’s safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit–risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib’s efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.

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“…Patients treated with intensive chemotherapy in combination with ponatinib do not require allo-HSCT, due to high percentage of complete molecular response (CMR, BCR-ABL1 undetectable). The recently reported 3-year OS of those patients reached 79% [127,138].…”

Section: Regimenmentioning

confidence: 95%

“…An industry-sponsored study comparing imatinib at a dose of 600 mg with ponatinib at a dose of 30 mg is ongoing (NCT03589326). Based on the results from single-arm studies and the propensity score matching, second-and third-generation TKIs were superior to imatinib considering treatment outcomes and clinical benefits for Ph+ B-ALL [127,130]. In contrast, a non-randomized, retrospective comparison of imatnib vs. second-generation TKIs reveals no difference [131].…”

Section: Tkis In the Treatment Of Ph+ Allmentioning

confidence: 99%

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

Komorowski

Fidyt

Patkowska

et al. 2020

IJMS

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Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.

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Efficacy of Ponatinib Versus Earlier Generation Tyrosine Kinase Inhibitors for Front-line Treatment of Newly Diagnosed Philadelphia-positive Acute Lymphoblastic Leukemia

Cited by 40 publications

References 59 publications

Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions

Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

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