Safety and efficacy of FLAG-Ida-based therapy combined with venetoclax for the treatment for newly diagnosed and relapsed/refractory patients with AML - A systematic review.

Venetoclax (VEN) in combination with intensive chemotherapy (IC) is increasingly used to treat patients with high-risk acute myeloid leukemia (AML). We conducted a systematic review to assess the safety and efficacy outcomes of FLAG-IDA in combination with VEN. The primary safety outcome was infection rate; the primary efficacy outcome was response to treatment (composite complete remission (CRc) and overall response rate (ORR). Risk of bias was assessed according to the ROBINS-I tool. Six studies including 221 patients with newly-diagnosed (ND AML (n = 120)) and R/R AML (n = 101) disease, were included in this systematic review. Pooling of results was not conducted due to major differences between studies. The reported rates of neutropenic fever, bacteremia, pneumonia and invasive fungal infections were at 44-55 %, 24-48 %, 12-30 % and 11-36 % of assessed patients, respectively. Time to ANC and platelet recovery ranged between 23 and 29 and 23-31 days, respectively. Early death rate was 8.7 % (14/160) patients: four patients at 30 days, additional ten in 60 days. CRc rates ranged between 53 % and 78 % for R/R AML. CRc for ND was reported by one study only (89 %). ORR were reported in 60-78 % of patients with R/R AML. Only one study reported an ORR for ND patients of 98 %. In our systematic review, FLAG-Ida plus VEN proved to be a potentially tolerable and effective regimen in ND and R/R AML patients. We suggest further evaluation and confirmation for the safety and efficacy of this new protocol in future RCTs.

Maintenance therapy with hypomethylating agents for patients with acute myeloid leukemia in first remission not eligible for allogeneic hematopoietic cell transplantation: A systematic review and meta-analysis.

BACKGROUND: Older patients encompass about 75 % of patients with acute myeloid leukemia (AML). Today therapeutic options to prevent relapse in older patients who managed to achieve complete remission (CR) after intensive chemotherapy are scarce. Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-CR maintenance therapy. METHODS: We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with hypomethylating agents (HMA) vs. observation, conventional care or placebo in older patients with AML who are not candidates for allogeneic hematopoietic transplantation (allo-HCT). We searched Cochrane Library, PubMed and conference proceedings up to August 2021. RESULTS: Six trials were included. Treatment with hypomethylating agents significantly improved overall survival (HR 0.80, 95 % CI 0.70 to 0.91, I2 = 30 %), and disease control (HR 0.80, 95 % CI 0.70 to 0.91, I2 = 0). A significant decrease was seen in both one year mortality (Risk Ratio [RR] 0.61, 95 % CI 0.48 to 0.77, I2 = 0) and mortality at the end of follow-up (RR 0.77, 95 % CI 0.67 to 0.88, I2 = 0). The rate of relapse at 6 months and at one-two years was lower in the HMA arm vs. control (RR, 0.59; 95 % CI, 0.47-0.72; RR, 0.74, I2 = 0; 95 % CI 0.69 - 0.91, I2 = 41 %, respectively). HMA were associated with a statistically non-significant increase in the risk of serious adverse events (RR 3.44, 95 % CI 0.93-12.74, I2 = 80 %). CONCLUSIONS: Our meta-analysis shows that in older patients who are not candidates for allo-HCT, maintenance therapy with HMA improves OS and disease control without a statistically significant increase in adverse events.

Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single-centre before-after study.

OBJECTIVES: We aimed to study whether ciprofloxacin prophylaxis reduces infectious complications in patients undergoing autologous haematopoietic cell transplantation (AHCT). METHODS: This is a quasi-experimental, retrospective, before-after study. We compared the incidence of bacterial-related complications among 356 patients with multiple myeloma (MM) (n = 202) and lymphoma (n = 154) who underwent AHCT with (n = 177) or without (n = 179) ciprofloxacin prophylaxis between 03/2007 and 10/2012 and between 10/2012 and 07/2016, respectively, at a single centre. RESULTS: Febrile neutropaenia, bacteraemia, and pneumonia were significantly more common among patients who underwent AHCT during the second study period and did not receive antibacterial prophylaxis compared with patients who underwent AHCT during the first study period and received antibacterial prophylaxis (89.9% (161/179) vs. 83.1% (147/177), difference 6.9%, 95% CI 0-14.1%, P = 0.002; 15.1% (27/179) vs. 4.5% (8/177), difference 10.6%, 95% CI 4.4-16.9%, p < 0.0001; 12.3% (22/179) vs. 6.2% (11/177), difference 6.1%, 95% CI 0-12.3%, p = 0.04, respectively). The number-needed-to-treat to prevent one episode of bacteraemia, pneumonia, and febrile neutropaenia was 8.6, 8.5, and 13.7, respectively. Patients with ciprofloxacin prophylaxis had higher rates of ciprofloxacin-resistant bacteraemia (62.5% (5/8) vs. 18.5% (5/27), difference 44%, 95% CI 7-70%, p = 0.01). In multivariate analysis, ciprofloxacin prophylaxis significantly decreased the odds of bacteraemia (OR 0.19, 95% CI 0.07-0.52; p < 0.0001) and pneumonia (OR 0.37, 95% CI 0.16-0.85, p = 0.02). CONCLUSION: According to our single-centre experience, patients with MM and lymphoma undergoing AHCT may benefit from antibacterial prophylaxis with ciprofloxacin.

Differential downregulation of telomerase activity by bortezomib in multiple myeloma cells-multiple regulatory pathways in vitro and ex vivo.

BACKGROUND: The importance of telomerase in multiple myeloma (MM) is well established; however, its response to bortezomib has not been addressed. METHODS: The effect of bortezomib on telomerase activity and cell proliferation was evaluated in four MM cell lines and in myeloma cells obtained from eight patients. The mechanism of telomerase regulation on epigenetic, transcriptional, and post-translational levels was further assessed in two selected cell lines: ARP-1 and CAG. Clinical data were correlated with the laboratory findings. RESULTS: Bortezomib downregulated telomerase activity and decreased proliferation in all cell lines and cells obtained from patients, albeit in two different patterns of kinetics. ARP-1 cells demonstrated higher and earlier sensitivity than CAG cells due to differential phosphorylation of hTERT by PKCα. Methylation of hTERT promoter was not affected. Transcription of hTERT was similarly inhibited in both lines by decreased binding of SP-1 and not of C-Myc and NFκB. The ex vivo results confirmed the in vitro findings and suggested existence of clinical relevance. CONCLUSION: Bortezomib downregulates telomerase activity in MM cells both transcriptionally and post-translationally. MM cells, both in vitro and in patients, exhibit different sensitivity to the drug due to different post-translational response. The effect of bortezomib on telomerase activity may correlate with resistance to bortezomib in patients, suggesting its potential utility as a pre-treatment assessment.