The proto-oncogene Rearranged During Transfection (RET) encodes a receptor tyrosine kinase that is essential for neural, renal, and thyroid development. Pathogenic RET alterations, including mutations and fusions, drive oncogenesis, most notably medullary and papillary thyroid carcinomas and non-small cell lung cancer, by constitutively activating downstream RAS–MAPK, PI3K–AKT, and JAK–STAT signaling. Early multi-kinase inhibitors such as vandetanib and cabozantinib demonstrated modest efficacy with significant toxicity, whereas the selective RET inhibitors selpercatinib and pralsetinib have achieved improved response rates and tolerability. However, resistance remains a key clinical challenge, arising from secondary RET mutations and bypass signaling via MET or EGFR pathways. Continued investigation into next-generation inhibitors and rational combination therapies aims to overcome resistance and optimize treatment sequencing, advancing precision oncology for RET-altered malignancies. Nonetheless, resistance, driven by secondary mutations and bypass signaling, presents a major therapeutic challenge. Ongoing development of next-generation inhibitors and combination strategies aims to overcome resistance and improve patient outcomes.

Background: Peripheral T-cell lymphoma (PTCL) has high relapse rates and poor response to various therapies. This meta-analysis evaluates the efficacy of various therapies for RR-PTCL, including Epigenetic modifiers (HDIs, DNA methyltransferase inhibitors, EZH1/2 inhibitors), Small molecule inhibitors (targeting PI3K/AKT/mTOR, JAK/STAT, ALK, aurora kinase, farnesyl transferase), Combination therapies (various multi-class drug combinations), Pralatrexate-based regimens, monoclonal antibodies (e.g., Pembrolizumab, Alemtuzumab, Zanolimumab, etc.) and Others (Acimtamig, CAR T-cell therapy, etc.). Aims: To evaluate pooled efficacy outcomes across therapeutic categories in relapsed/refractory peripheral T-cell lymphoma (RR-PTCL) by assessing overall response rate (ORR), complete response (CR), progression-free survival (PFS), and overall survival (OS), including analyses within major histologic subtypes. Methods: We systematically searched PubMed, Scopus, EMBASE, and Cochrane Library using MeSH terms for studies on RR PTCL. Eligible clinical trials reported at least one efficacy outcome. All statistical analysis was conducted using R (v4.5.3). Meta-analysis was performed to assess ORR and CR of each treatment. PFS and OS were summarized using weighted median survival estimates derived from the included studies and presented descriptively in forest plots. Formal pooled time-to-event meta-analysis was not performed. Subgroup analysis was done across PTCL-NOS, ALCL (ALK-), and AITL patient groups. Results: The study included 68 clinical trials, revealing significant influences of treatment type on both ORR (QM (df = 6) = 37.6, p < 0.001) and CR (QM (df = 6) = 36.7, p < 0.001). It demonstrated an overall ORR of 39.57% (95% CI: 0.36–0.43, p < 0.0001). Subgroup analyses for ORR with each treatment showed the highest rates with Combination therapies at 57.4% (95% CI: 0.50–0.65, p < 0.001), followed by Small molecule inhibitors (SMI) at 39.91% (p < 0.0001), Pralatrexate-based regimens at 39.5% (p < 0.001), Epigenetic modifiers at 39.1% (p < 0.001), Others at 34.7% (p < 0.001) and Monoclonal Antibodies showing the lowest at 31.9% (p < 0.0001). The pooled CR rate was 16.59% (95% CI: 0.14–0.19, p < 0.0001), with Combination therapies again leading at 32.0% (95% CI: 0.24–0.40, p < 0.001), followed by SMIs at 19.02%, Epigenetic modifiers at 16.0%, monoclonal antibodies at 11.6%, Pralatrexate-based regimens at 10.1%, and Others at 9.5% (all p < 0.001). Forest plots showed a pooled median OS of 14.6 months, highest with SMIs (17.9), followed by Pralatrexate (14.5), Combination therapies (14.4), Others (13.8), monoclonal antibodies (12.72), and Epigenetic modifiers (11.3). The pooled PFS was 4.18 months, led by Combination therapies (5.6), followed by Epigenetic modifiers (4), SMIs and Pralatrexate (3.5), Others (3.5), and monoclonal antibodies (2.7). Analysis by histological subtype, among PTCL-NOS and AITL subgroups, Combination Therapies showed highest ORR of 52.8% and 74.9% (both p < 0.001) respectively. Similar to ORR, in both subgroups, the highest incidence of CR was seen with Combination Therapy as 18.6% (95% CI: 0.082–0.29, p < 0.001) and 51.9% (95% CI: 0.31–0.73, p < 0.001). In ALCL (ALK-negative), pralatrexate-related regimens showed the highest ORR (56.44%, p = 0.0015), whereas therapeutic antibodies showed the highest CR (53.07%, p = 0.019). Conclusions: This analysis found that combination therapies demonstrated the highest pooled response rates, while small-molecule inhibitor and pralatrexate-based regimens were associated with the longest reported survival outcomes. The observed differences across therapeutic categories are descriptive and hypothesis-generating and warrant confirmation in prospective comparative studies. Despite recent therapeutic advances, outcomes in RR-PTCL remain suboptimal and novel treatment strategies continue to be needed.

From the 2026 National Summit on Hematologic Cancers

Allogeneic Haploidentical stem cell transplantation, CD34+ graft cell dose, outcomes.