Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

e15124 Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) accounts for 20–30% of adult ALL cases and is characterized by high mortality and aggressive progression. Standard treatments with tyrosine kinase inhibitors (TKIs) and chemotherapy often lead to severe side effects. Recent innovations, such as the third-generation TKI ponatinib and the T-cell stimulator blinatumomab, promise to reduce mortality and treatment-related adverse events. This study evaluates their effectiveness and tolerability in the treatment of Ph+ ALL. Methods: A systematic search of PubMed, Embase, Scopus, and Cochrane databases was conducted from inception until December 2024. Statistical pooling was performed using OpenMeta Software (version 5.3) and a random-effects model. Occurrence rates were pooled with 95% confidence intervals. Heterogeneity was evaluated using I² and χ² statistics, with I² > 50% considered significant. Sensitivity and subgroup analyses were performed to address heterogeneity. Results: Seven studies met the eligibility criteria, yielding a total of 338 patients (294 newly diagnosed and 44 refractory) with a mean age of 52.43 years (SD: 15.21). Pooled analysis revealed the following findings: the overall survival rate at 24 months was 84% (95% CI: 0.751–0.930; I² = 79.7%; P < 0.001), while the disease relapse rate remained low at 11% (95% CI: 0.037–0.196; I² = 82%; P = 0.000). A statistically significant progression-free survival rate of 62% was observed over a 24-month follow-up period (95% CI: 0.353–0.896; I² = 94.15%; P = 0.000). Subgroup analysis identified that the heterogeneity was caused by the inclusion of newly diagnosed patients. After 24 months, 51% of patients (95% CI: 0.264–0.759; I² = 96.99%; P = 0.000) achieved a hematologic complete response (CR), with heterogeneity reported in both subgroups, i.e., refractory (I² = 98.67%) and newly diagnosed patients (I² = 92.18%). Similarly, the complete molecular response (CMR) rate at 24 months was 87% (95% CI: 0.792–0.964; I² = 76.06%; P = 0.000). Subgroup analysis showed that newly diagnosed patients had a CMR rate of 84% (95% CI: 0.727–0.953; I² = 75.86%; P = 0.006). Additionally, the incidence of grade 1–4 adverse events remained low, at 16% (95% CI: 0.055–0.282; I² = 77.51%; P = 0.004). In contrast, the rate of negative measurable residual disease was 78% (95% CI: 0.677–0.896; I² = 75.91%; P = 0.006), which was statistically insignificant. Conclusions: The combination of ponatinib and blinatumomab shows promising results in achieving event-free survival, overall survival, and complete molecular response in Ph+ ALL patients, with a manageable safety profile (16% adverse effects) at 24 months. However, well-defined studies with larger sample sizes are needed for definitive conclusions.

A Comprehensive Cancer Center Experience with Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Allogeneic Hematopoietic Stem Cell Transplantation, Especially Haploidentical, May Improve Long-Term Survival for High-Risk Pediatric Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era.

Ponatinib, chemotherapy, and transplant in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

Imatinib (IM) dramatically improved the prognosis of chronic myeloid leukemia (CML), particularly with newly diagnosed patients in a chronic phase (CP) [1]. The most robust source of data about IM efficacy in this setting is the IRIS trial. However, every day clinical practice data are still scarce. We analyzed IM efficacy and safety in the first-line therapy of 152 consecutive adult CP-CML patients from a defined region. The estimated 4-year cumulative incidences of complete hematologic, complete cytogenetic, major, and complete molecular responses were 95.3%, 80.6%, 65.4%, and 39.2%, respectively. The 4-year probability of overall and progression-free survival (PFS) defined as with the IRIS [2] was 91.5% and 78.1%, respectively. We thus confirmed very good IM efficacy also in patients not participating in clinical trials. However, the estimated 4-year event-free survival (EFS), which also counted failure events according to valid recommendations [3] or IM discontinuation due to intolerance, was only 60.7%. The 4-year probability of an alternative treatment-free survival, our newly defined parameter, which better reflects the proportion of patients remaining on IM despite an event, was 67.6%. Therefore, more appropriate selection and unification of survival analyses end-points is desirable to describe and compare IM real efficacy.

Outcomes with dasatinib in Philadelphia Chromosome–Positive acute lymphoblastic leukemia: A systematic review and meta-analysis

Long-Term Safety and Efficacy of Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

ObjectivesTo investigate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in the management of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL).DesignA systematic review and meta-analysis.Data sourcesElectronic searches were conducted...

Additional Chromosomal Abnormalities in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Tyrosine Kinase Inhibitors: Differential Outcomes According to Type of Chromosomal Abnormality

Evolution of TKIs Patients with CML and ALL Imatinib (Gleevec—Novartis) was approved more than a decade ago as a targeted leukemia therapy (i.e., Bcr-Abl TKI). Since that time, researchers have uncovered much information regarding its resistance mechanisms and potential ways to overcome resistance. Imatinib resistance reportedly occurs in approximately 33% of patients and can be subclassifi ed as Bcr-Abl–dependent or Bcr-Abl–independent. The BcrAbl–dependent mechanisms involve Bcr-Abl mutation and amplifi cation, resulting in an alteration of imatinib’s binding affi nity to the Bcr-Abl tyrosine kinase. One of the most frequently identifi ed mutations is T315l. Second-generation TKIs such as dasatinib (Sprycel—Bristol-Myers Squibb) and nilotinib (Tasigna—Novartis) are more potent than imatinib and can be used as fi rst-line agents for the management of chronic-phase CML as well as for imatinib-resistant or -intolerant patients. The new agent bosutinib is also classifi ed as a second-generation TKI. It targets the Bcr-Abl kinase and inhibits Scr-family kinases including Src, Lyn, and HcK. Pharmacologic data have shown that bosutinib inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl kinases expressed in experiential cell lines. This agent, however, has no effect on T315I mutant cells. Ponatinib is classifi ed as a thirdgeneration TKI. The agent is unique in that it targets cells with a T315I mutation, which makes these cells resistant to all other currently approved TKIs. Medullary thyroid cancer Cabozantinib has a different indication and, therefore, targets another set of tyrosine kinases. It has been shown to inhibit proinvasive receptor tyrosine kinases implicated in tumor growth, metastasis, and angiogenesis, including RET, MET, and VEGFR-1, -2, and -3. Activating mutations in RET have been shown to play a central role in tumorigenesis in both inherited and sporadic forms of medullary thyroid cancer. MET and VEGF have also been implicated in the pathogenesis of this rare thyroid disease.

Treatment of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia using hypercvad with ponatinib is associated with excellent survival with selective use of blinatumomab and allogeneic hematopoietic cell transplantation

Dasatinib: A tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome—positive acute lymphoblastic leukemia

Chemotherapy-Free Combination of Blinatumomab and Ponatinib in Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Updates from a Phase II Trial

Imatinib for Chronic Myeloid Leukemia Patients: A Single Institution Experience

First Report of the Gimema LAL1811 Phase II Prospective Study of the Combination of Steroids with Ponatinib As Frontline Therapy of Elderly or Unfit Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia