3 research outputs found
Gilteritinib maintenance after allogeneic stem cell transplantation for FLT3 mutated acute myeloid leukemia
A proportion of FLT3m AML patients remain in prolonged CRs on Gilteritinib maintenance after alloSCT despite prior exposure to Midostaurin, Gilteritinib and Venetoclax. Conversion from positive MRD to negative MRD was confirmed in several cases. Relapses post-Gilteritinib maintenance were enriched with RAS pathway mutations and clinically relevant clonal evolution such as loss of FLT3m or gain of BCR-ABL1. The toxicity of Gilteritinib was manageabl
Azacitidine in combination with 14-day venetoclax versus azacitidine monotherapy for myelodysplastic syndrome with increased blasts-2 in clinical practice setting
Background: Azacitidine (AZA) is the standard-of-care for myelodysplastic syndromes with increased blasts-2 (MDS-IB2), however, due to the limited efficacy there is an unmet need for more effective therapies. Recently, promising phase 1 data of Azacitidine and Venetoclax (AZA+VEN) have been published and the phase 3 Verona trial is ongoing. Herein, we compared our institutional experience of AZA+VEN doublet with AZA monotherapy for the treatment of MDS-IB2. Aims: The aim of our study was to compare the efficacy and toxicity of AZA+VEN with AZA monotherapy for MDS-IB2 treatment. Methods: We conducted an observational, retrospective study. The patients were older than 18 years of age, had newly diagnosed MDS-IB2, and were treated with either AZA+VEN or AZA monotherapy. All patients provided informed consent for treatment and data collection. The AZA+VEN regimen consisted of Venetoclax 400mg/d on days 1-14 with Azacitidine 75mg/m2 on days 1-7. AZA patients received Azacitidine 75mg/m2 on days 1-7. The treatment cycles were administered every 28 days or with longer intervals depending on the hematological recovery and adverse events. Eligible responders could proceed to allogeneic stem cell transplantation (alloSCT). We evaluated baseline characteristics, IPSS-R, IPPS-M values, marrow CR (mCR), CR, CRi rates, overall survival (OS), time to ANC>1x109 and PLT>100x109 recovery from the start of the treatment, CTCAE v5.0 grade 3-5 non-hematological toxicity, day-30, day-60 mortality rates. Results: 16 patients (10 female) were treated with AZA+VEN whereas 17 (7 female) patients received AZA. Median age and ECOG values were 59 years (38-71) and 1 (0-2) in the AZA+VEN cohort compared to 74 years (53-84) and 2 (1-3) in the AZA group, respectively (p<0.001, p=0.026). The median IPSS-R value was 7.5 (5-10) in the AZA+VEN group and 6 (5-8) in AZA patients (p=0.004). The median IPSS-M value was 2.57 (0.55-4.57) in the AZA+VEN group, whereas data was not available for AZA patients. Complex karyotype was identified in 5/16 (31%) and 3/17(18%) in AZA+VEN and AZA patients, respectively (p=0.438). A median of 1 (1-3) AZA+VEN treatment cycle was administered, whereas AZA was given for a median of 4 (1-27) cycles. The mCR rate was 12/15 (75%) in the AZA+VEN patients and 6/15 (40%) in the AZA group (p=0.06). The CR+CRi rate was 9/15 (60%) in the AZA+VEN group in comparison to 5/15 (33%) in the AZA patients (p=0.272). 5/16 (31%) of AZA+VEN patients were bridged to alloSCT, whereas none of the AZA was allotransplanted. The median follow-up was 10.3 months in the AZA+VEN cohort and 31.3 months in the AZA group. The median OS was 6.8 months (3.2-22.1) and 14.1 months (6.9-17.6) in the AZA+VEN and AZA groups, respectively (p=0.436). 2-year OS was 20% in both groups (Figure 1). The median time to ANC and PLT recovery was 50 (4-165) and 60 days (21-94) in the AZA+VEN cohort compared to 38 (35-74) and 48 days (28-129) in AZA patients, respectively (p=0.66, p=0.464). Grade 3-5 adverse events occurred in 7/16 (44%) of AZA+VEN patients in comparison to 7/17 (41%) in the AZA group (p=0.881). Day-30 and day-60 mortality rates were 2/16 (13%) and 3/16 (19%) in the AZA+VEN group. No early deaths occurred in the AZA cohort. Summary/Conclusion: AZA+VEN treatment demonstrated higher response rates in MDS-IB2 patients however, this did not translate into prolonged survival compared to AZA monotherapy. Trends toward longer hematological recovery and higher early mortality were evident in the AZA+VEN group. Nevertheless, our real-life results should be interpreted with caution due to the small patient numbers, significant intergroup differences, and the retrospective nature of the study
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Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial
Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT.
In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34).
Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001).
This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated.
Merck & Co., Inc