LBA6007 Background: Standard first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) includes platinum-based chemotherapy (PBC) combined with pembrolizumab or cetuximab; however, these regimens remain inaccessible for many patients globally, particularly in resource-limited settings. Triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy (TMC-I) has demonstrated promising activity and tolerability in earlier studies. We conducted a randomized phase III trial comparing TMC-I with PBC (paclitaxel and carboplatin) in patients with R/M-HNSCC receiving first-line palliative therapy. Methods: In this open-label, multicenter, phase III trial conducted at two centers, 422 patients with R/M-HNSCC were randomized (1:1) to receive paclitaxel 175 mg/m² plus carboplatin AUC 6 every 3 weeks (Arm-A) or TMC-I (oral methotrexate 9 mg/m² weekly, celecoxib 200 mg twice daily, erlotinib 150 mg daily, and nivolumab 20 mg IV every 3 weeks) (Arm-B). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and quality of life (QoL). The planned sample size of 422 patients (211 per arm) provided 80% power with a two-sided α of 0.05. The trial was registered with the Clinical Trials Registry–India (CTRI/2024/01/061661). Results: The median age was 49.5 years (IQR 42–58), 85.5% were male, 78.9% had oral tobacco use, 76.3% had oral cavity primaries, 25.6% had metastatic disease, and 30.6% had ECOG performance status 2. After a median follow-up of 10.8 months (95% CI 8.1–13.6) in Arm-A and 11.9 months (95% CI 10.3–13.4) in Arm-B, the primary endpoint of OS was significantly improved with TMC-I compared with PBC. Twelve-month OS was 46% versus 23%, and six-month OS was 69% versus 52% (p < 0.001). Median OS was 10.3 versus 6.2 months (HR 0.565, 95% CI 0.439–0.728; p < 0.001). Median PFS was 5.5 versus 2.7 months (HR 0.465, 95% CI 0.371–0.582; p < 0.001). ORR was higher with TMC-I than with PBC (53.4% vs 24.1%; p < 0.001), with fewer grade ≥3 adverse events (34.1% vs 46.4%; p = 0.010). No treatment-related deaths were observed, and patient-reported QoL was preserved with TMC-I. Conclusion: TMC-I significantly improved survival outcomes and response rates while reducing severe toxicity and preserving QoL compared with PBC. At approximately USD 230 per month, TMC-I represents a promising and cost-effective first-line treatment option for patients with R/M-HNSCC. Clinical trial information: CTRI/2024/01/061661.
AIMS:Although acute myeloid leukaemia (AML), myelodysplasia-related (AML-MR), can be defined solely by molecular abnormalities, legacy studies did not analyse the KMT2A gene. The KMT2A-partial tandem duplication (KMT2A-PTD) is described in myelodysplastic neoplasms (MDS) as well as AML. We describe the clinical, morphological, immunophenotypic and molecular features of AML harbouring KMT2A-PTD. METHODS:We studied 802 adult AML patients, for whom next-generation sequencing- based mutation and copy number analysis were available. For the patients harbouring KMT2A-PTD, the immunophenotypic analysis including measurable residual disease (MRD), mutational landscape and the patient outcomes were analysed. RESULTS:We identified 45 patients of de novo and secondary AML harbouring KMT2A-PTD. Morphological dysplasia and immunophenotypic abnormalities, described in MDS, were observed in 35.6% and 40% of de novo cases respectively. Furthermore, 44% of AML with KMT2A-PTD could be diagnosed as AML-MR based on cytogenetics or genomics. We observed progenitor abnormalities, commonly aberrant CD7 (33%) and CD15 (59%), and granulocytic abnormalities like loss of side scatter (50%), asynchronous maturation patterns and loss of CD177 in mature granulocytes. Frequent mutations involving IDH2 (30% of which were R172), FLT3 (32% each), RUNX1 (29%), DNMT3A and U2AF1 (24% each) were noted. We also found that more than 25% of patients did not achieve morphological remission, and the remaining 60% were MRD positive. The outcomes of AML with KMT2A-PTD with or without MR-associated abnormalities were similar. CONCLUSIONS:AML harbouring KMT2A-PTD frequently displays MR immunophenotypic abnormalities and is frequently associated with AML-MR type mutations. In addition, they have similar outcomes as compared with AML-MR.
The goal in treating parosteal osteosarcoma is to achieve wide margins while minimizing morbidity. Marginal resections increase local recurrence (LR) risk. The impact of intramedullary involvement on outcomes remains unclear. We examined the role of quantitative margins and the effect of intramedullary involvement on LR and outcomes. We performed a retrospective analysis of 42 surgically treated parosteal osteosarcoma cases over 20 years (2000–2020) at a tertiary cancer centre. Final histopathology confirmed low-grade tumors in 39 cases and dedifferentiated in 3. Of 39 patients, 2 had amputations and 37 underwent limb salvage. Eight needed intra-operative vascular reconstruction. Quantitative margins were assessed in 25 primary cases with adequate follow-up: 10 had margins < 2 mm, 15 had ≥ 2 mm; 15 had margins < 5 mm, 10 had ≥ 5 mm. Among 37 patients with follow-up, 31 are alive and disease-free (22 continuously disease-free), while 6 have died (5 due to disease, 1 cardiac event). Median follow-up was 108 months (range 27–273). Ten patients had LR. Margins of ≤ 2 mm versus > 2 mm did not significantly influence outcomes, indicating that simply exceeding 2 mm was not associated with improved local control. However, a critical threshold effect was observed at ≥ 5 mm, as no patients with margins ≥ 5 mm developed local recurrence (LR). Three had isolated LR, seven combined relapses (LR + distant). Of these ten, five are alive and disease-free, four died of disease, one died of cardiac event. Intramedullary involvement did not affect LR (p = 0.69) but had a trend towards poor disease specific survival (DSS). The above findings underscore that achieving margins ≥ 5 mm represents a clinically meaningful cutoff, beyond which the risk of local or combined relapse is minimized, supporting ≥ 5 mm as the optimal target for oncologic resection margins. Intramedullary involvement and LR have a trend towards poor DSS.
