Citations

Abstract Background: Placebo response is crucial in interpreting treatment efficacy in ulcerative colitis (UC) trials. While it has been broadly studied, it remains underexplored in trials involving the growing number of biologics and small molecules for ulcerative colitis. Methods: We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL from inception to November 13, 2024. Eligible studies were induction-phase RCTs, including adult patients with moderate-to-severe UC who received a biologic and a small-molecule against a placebo. Primary outcomes were pooled clinical and endoscopic response and remission rates. Safety outcomes included adverse events (AEs), serious adverse events (SAEs), and withdrawal rates. Random-effect models were used for meta-analysis. Meta-regression identified predictors of placebo outcomes. Results: 26 induction RCTs with 3,937 placebo-treated patients were included. IL inhibitor trials had the highest placebo clinical response (36%) and endoscopic remission (21%), while JAK inhibitors had the lowest (21% and 2%). Overall placebo rates were 34% for clinical response, 8% for clinical remission, 19% for endoscopic response, and 11% for endoscopic remission. Adverse events occurred in 54%, SAEs in 8%, and withdrawals in 18%. Younger age and longer follow-up were linked to higher placebo responses; recent trials showed reduced endoscopic effects. Conclusion: These findings highlight the need to account for placebo variability in trial design and interpretation, particularly as biologic and small-molecule therapies continue to expand in UC treatment.

Abstract Background: The cytoreductive treatment options for myeloproliferative neoplasms, in those who have indications, may be limited to hydroxyurea and interferon. Busulfan has been reported to have some activity, but used less frequently in the management of BCR/ABL negative MPNs (Haanen CM et al Br J Cancer 1981; Brodsky American J of clinical oncology 1998). One study has shown significant JAK2V617F allele burden reduction with busulfan (Kuriakose ET et al; Haematologica 2013). Ruxolitinib was approved by the FDA for intermediate and high risk myelofibrosis; and as second line therapy for polycythemia vera in those who are intolerant or develop side effect to hydroxyurea. Objective: To assess the utility of busulfan, an old drug, in patients with myeloproliferative neoplasms who are intolerant to other forms of therapy. Methods: The mayo clinic data base from 1970 to 2014 was interrogated using the terms myeloproliferative disorder, polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF) and busulfan. Patients' follow up information was collected till July 2015. Results : Seventy five patients with full demographic, diagnostic and therapeutic information were identified, and those included 37 patients with ET, 22 with PV, 12 with MF, and 4 with myeloproliferative neoplasms unclassifiable. The median age was 64 (range 31-91) years. After a median follow up of 17 years, 40 patients (53 %) died, and leukemic transformation was documented in 4 (5%). The median time for leukemic transformation was 86 months (12-229). 1. Essential Thrombocytopenia (n=37): Twenty nine (79%) were females, and the median (range) age was 67 (33-90) years. At diagnosis the median (range) hemoglobin (Hgb) (gm/dL), white blood cell count (WBC) (X109/L), and platelet count (X109/L) were 13.6 (9.8-16.9), 10.2 (5-231), 1113 (593-2062) respectively. After a median follow up time of 230 months, 15 patients (41%) died, and leukemic transformation was documented in 1 patient who was also treated with radioactive phosphorous (P32). Leukemic transformation was documented 230 months from date of diagnosis. Follow up complete blood count was available in 20 patients and the median (range) Hgb, WBC and platelet count was 12 (9.9-16), 7.4 (3.1-25), and 267 (126-573) respectively. 2. Polycythemia Vera (n=22): Fourteen (61%) were females, and the median (range) age was 64 (46-91) years. At diagnosis the median (range) Hgb, WBC, and platelet count were 17.5 (15.1-20.8), 11.5 (1.2-26.6), and 669 (185-2370) respectively. After a median follow up time of 188 months 13 (57%) patients died, and leukemic transformation was documented in 2 patients and one of them was given P32. Follow up complete blood count was available in 21 patients and their median (range) Hgb, WBC and platelet count was 12.9 (10-15.2), 7.2 (2.8-20), and 303 (124-833) respectively. 3. Myelofibrosis (Primary and Post-PV and Post-ET myelofibrosis) (n=12) : The median age was 52 (31-75) and 5 were females. The median Hgb, WBC, and platelet count were 13.6, 14.5, and 472. Six (50 %) patients did have splenomegaly (and 5 of them have splenic size reduction after busulfan), 3 underwent splenectomy, and 3 have no palpable spleen. At a median follow up of 208 months, and 39 months (range 78-401) from the start of busulfan, 10 (84%) patients died and no leukemic transformation was documented. Conclusion: Busulfan should be considered as alternative therapy in myeloproliferative neoplasms especially in ET and PV that are intolerant to other forms of cytoreductive therapy. Busulfan may be given as pulse therapy in controlling cell counts. Disclosures Off Label Use: Busulfan as alternative therapy in myeloproliferative neoplasms.