PATIENTS AND METHODS: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).
RESULTS: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.
CONCLUSION: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
METHODS: Autologous HSCT patients aged 18 years old and above were recruited from Hospital Ampang, Malaysia, between April 2019 to December 2020. Mucositis assessments were conducted daily, whilst blood and saliva were collected prior to conditioning regimen, on Day 0, Day+7 and 6-month. Baseline and inflammatory predictors in a repeated time measurement of moderate-severe mucositis were assessed by multiple logistic regression and generalized estimating equations, respectively.
RESULTS: Of the 142 patients analyzed, oral mucositis and diarrhea (representing GI mucositis) were reported as 68.3% and 95.8%, respectively. Predictive factors for moderate-severe oral mucositis were BEAM or busulphan-based regimens (odds ratio (OR)=9.2, 95% confidence interval (CI)=1.16-72.9, p-value (p) = 0.005) and vomiting (OR=4.6, 95% CI 1.68-12.3, p = 0.004). Predictive factors for moderate-severe GI mucositis were BEAM or busulphan-based regimens (OR=3.9, 95% CI 1.05-14.5, p = 0.023), female sex (OR = 3.3, 95% CI 1.43-7.44, p = 0.004) and body mass index (OR=1.08, 95% CI 1.02-1.15, p = 0.010). Cytokines analyses were performed in 96 patients. Saliva and plasma interleukin-6 (OR=1.003, 95% CI 1.001-1.004, p < 0.001 and OR=1.01, 95% CI 1.001-1.015, p = 0.029), and plasma tumor necrosis factor-alpha (OR=0.91, 95% CI 0.85-0.99, p = 0.019) were predictive of moderate-severe oral mucositis in a time-dependent model.
CONCLUSION: This study provides real-world evidence and insights into patient- and treatment-related factors affecting oral and GI mucositis in HSCT.
MATERIALS AND METHODS: Antithrombocytopenic activity was assessed on busulfan induced thrombocytopenic Wistar rats. The antithrombocytopenic activity of different bio-guided fractions was evaluated by monitoring blood platelet count. Bioactive compound carpaine was isolated and purified by chromatographic methods and confirmed by spectroscopic methods (LC-MS and 1D/2D-1H/13C NMR) and the structure was confirmed by single crystal X-ray diffraction. Quantification of carpaine was carried out by LC-MS/MS equipped with XTerra(®) MS C18 column and ESI-MS detector using 90:10 CH3CN:CH3COONH4 (6mM) under isocratic conditions and detected with multiple reaction monitoring (MRM) in positive ion mode.
RESULTS: Two different phytochemical groups were isolated from decoction of Carica papaya leaves: phenolics, and alkaloids. Out of these, only alkaloid fraction showed good biological activity. Carpaine was isolated from the alkaloid fraction and exhibited potent activity in sustaining platelet counts upto 555.50±85.17×10(9)/L with no acute toxicity.
CONCLUSIONS: This study scientifically validates the popular usage of decoction of Carica papaya leaves and it also proves that alkaloids particularly carpaine present in the leaves to be responsible for the antithrombocytopenic activity.