ObjectivesToxic death is a big problem in the treatment of childhood acute lymphoblastic leukemia (ALL), especially in low-income countries. Studies of ciprofloxacin as single agent prophylaxis vary widely in success rate. We conducted a double-blind, randomized study to test the effects of ciprofloxacin monotherapy as prophylaxis for sepsis and death in induction treatment of the Indonesian childhood ALL protocol.MethodsPatients were randomized to the ciprofloxacin arm (n = 58) and to the placebo arm (n = 52). Oral ciprofloxacin monotherapy or oral placebo was administered twice a day. All events during induction were recorded: toxic death, abandonment, resistant disease, and complete remission rate.ResultsOf 110 patients enrolled in this study, 79 (71.8%) achieved CR. In comparison to the placebo arm, the ciprofloxacin arm had lower nadir of absolute neutrophil count during induction with median of 62 (range: 5–884) versus 270 (range: 14–25,480) × 109 cells/L (P < 0.01), greater risks for experiencing fever (50.0% versus 32.7%, P = 0.07), clinical sepsis (50.0% versus 38.5%, P = 0.22), and death (18.9% versus 5.8%, P = 0.05).ConclusionIn our setting, a reduced intensity protocol in a low-income situation, the data warn against using ciprofloxacin prophylaxis during induction treatment. A lower nadir of neutrophil count and higher mortality were found in the ciprofloxacin group.
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Background: Randomized trials report that, compared to prednisone, dexamethasone has reduced CNS relapse and improved event-free survival (EFS), despite a trend toward a higher risk for induction death. Because toxic death is a specific problem in the Indonesian setting, this study compares the outcome of dexamethasone versus prednisone. Methods: In the period [2006][2007][2008][2009][2010][2011] 196 vs. 25.5%, P = 0.91), death rate (17.7% vs. 14.9%, P = 0.54), or leukemic events (13.7 vs. 11.7%, P = 0.59). After stratification for risk group, a trend towards a higher death rate was found in the dexamethasone arm of SR patients (16.2 vs.6.1%, P = 0.06). The 3-year survival for EFS in SR and HR patients for dexamethasone versus prednisone was 31.5% ± 6.6% vs. 41.5% ± 5.9% (P = 0.51), for leukemia-free survival (LFS) it was 63.7% ± 9.3% vs. 74.5% ± 7.6% (P = 0.47), and for overall survival (OS) it was 49.5% ± 7.7% vs. 69.3% ± 6.1% (P = 0.09). Conclusions: In our setting, a trend toward higher induction deaths 736was observed in the dexamethasone arm of SR patients and the 3-year EFS; LFS and OS rates were lower in the dexamethasone group; however, these differences were not significant.
Background. Maintenance of induced responses remains a significant unmet medical need in patients with acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) not eligible for allogeneic hematopoietic stem cell transplantation (HSCT). The allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown to generate both humoral and cellular immune responses and is safe for clinical practice (van de Loosdrecht et al., Cancer Immunol. Immunother. 2018). In this study we show additional data on long-term follow up and patient-related risk factors from the phase 1 study. Methods. AML- or MDS-patients (n=12), ineligible for HSCT, were included in a post-hoc clinical analysis of the DCP-001 phase I trial, receiving DCP-001 vaccination at the Amsterdam University Medical Center, VU University Medical Center, Amsterdam, the Netherlands (NCT01373515). All clinical data, including baseline characteristics as cytogenetics, pre-and post-vaccination treatment and morphologic blast counts in follow up, were retrospectively collected from corresponding patient files. Targeted next generation sequencing (NGS) gene panel data and cytogenetics were utilized to determine (cyto-)genetic risks following the European Leukemia Net (ELN) 2017 criteria. We defined 'response' as decreased or stable morphologic blast counts in bone marrow at day 126 (last day of official study evaluation) compared to study entry. Results. Seven out of twelve patients responded to treatment, the other patients showed progressive disease (data are summarized in table 1). The median relapse free survival (RFS) for the responding patients was 420 days (range 90-1849) and overall survival (OS) was 1090 days (90-2160); two patients died early in complete remission (CR) due to infection (respectively at 90 and 184 days). Notably, three of these patients were intermediate risk and four were poor risk patients based on the ELN risk classification for AML or Revised International Prognostic Scoring System (IPSS-R) for MDS. The median OS for the non-responders was 144 days (range 59-209). These five patients had relapsed or refractory disease at start of vaccination with detectable circulating peripheral blasts; four of them received additional azacitidine (AZA) therapy prior to vaccination. Moreover, they were vaccinated after induction and consolidation therapy with a median time between diagnosis and first vaccination of 611 days (219-2310) compared to 240 days (105-1398) for the seven responding patients. Of the latter, all were in complete remission (CR) (n=5) or had morphologic marrow blast counts <10% (n=2) at the start of vaccination. Two responders that progressed and two that relapsed after vaccination were treated with AZA, resulting in one complete remission and two partial responses (one non-evaluable due to sample failure), see figure 1. Conclusion/discussion. Clinical data of the phase 1 trial show that DCP-001 may prolong duration of remission or smoldering disease in intermediate and high risk AML or MDS patients. Response was associated with treatment by vaccination shortly after achieving CR. This should be taken into account in selection criteria of future vaccination studies. Hence, an international multi-center phase 2 study (ADVANCE II; NCT03697707) is currently being conducted to determine the effect of DCP-001 on measurable residual disease (MRD) in AML patients, aiming to convert them to a MRD negative state. Furthermore, we demonstrated that AZA can be applied as rescue therapy upon progression after vaccination. Disclosures Rovers: DCprime: Employment. Cloos:Daiicchi Sankyo: Speakers Bureau; Glycomimetics: Research Funding; Takeda: Research Funding; Novartis: Other: MRD assessments of clinical trials, Research Funding; Merus: Other: MRD assessment of a clinical trial , Research Funding; Genentech: Consultancy, Research Funding; Helsinn: Other: MRD assessment of a clinical trial; DCPrime: Other: MRD assessment of a clinical trial. de Gruijl:DCprime: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Background Midostaurin, a multikinase inhibitor with significant activity against FLT3, was approved in combination with chemotherapy (CT) for treatment of pts with newly diagnosed (ND) FLT3-mutated AML based on the CALGB 10603/RATIFY trial (NCT00651261; Stone et al, NEJM 2017). The A2408 study (NCT03379727) confirmed the efficacy/safety of midostaurin in FLT3-mutated AML and extended the findings to older pts (≥60 y) and different CT regimens (Sierra et al, ASH 2020). As midostaurin inhibits both mutant and wild-type (WT) FLT3 (Weisberg et al, Cancer Cell 2002), the UNIFY trial (NCT03512197) was conducted to evaluate midostaurin in FLT3-mutation negative (MN) AML. Here, we report clinical outcomes and MRD results from UNIFY. Methods This randomized, double-blinded, multicenter, placebo (PBO)-controlled, ph 3 study evaluated midostaurin + CT in pts with ND FLT3-MN (mutant to WT signal ratio <0.05) AML. Starting Jul 2018, pts were randomized 1:1 to midostaurin or PBO and stratified by age (<60 y vs ≥60 y). Pts received midostaurin/PBO combined with daunorubicin or idarubicin + cytarabine for induction (IND; 1-2 cycles [cyc]) and with intermediate-dose cytarabine for consolidation (CONS; 3-4 cyc), followed by post-CONS (12 cyc) with midostaurin/PBO alone. Midostaurin (50 mg BID)/PBO was given from d4 or d8 (first IND) until 48 h prior to the start of the next cyc during IND/CONS and in 28-d cyc during post-CONS. The primary endpoint was EFS; secondary endpoints were OS, safety, and MRD, which was assessed by multiparameter flow cytometry (Cloos et al, J Vis Exp 2018;133:56386) using the leukemia-associated immune-phenotype (LAIP) approach. Complete panels were assessed during disease monitoring, which also allowed MRD analysis based on the different-from-normal (DfN) approach, taking into account upcoming aberrant cell populations not detected at diagnosis. Since pt remission status was not available at the time of MRD evaluation, all samples were assessed irrespective of remission. Results UNIFY was stopped in Sep 2019 on the recommendation of the data monitoring committee, based on an interim analysis of EFS (N = 359; HR, 1.08 [95% CI, 0.78-1.5]; data cutoff, 15 May 2019) that met the futility criterion. Final analysis occurred after the last pt discontinued and the study was closed (data cutoff, 31 Mar 2021). 501 pts were randomized to midostaurin (n = 250) or PBO (n = 251). Median age was 56 y (54% <60 y, 46% ≥60 y); 55% of pts were female and 31%/25%/35% had adverse/intermediate/favorable risk (per ELN 2017). For midostaurin and PBO, respectively, 245 and 249 pts entered IND1 and 43 and 52 entered IND2. Median exposure to study drug was 45 d for midostaurin and 50 d for PBO. Final HR for EFS was 1.00 (95% CI, 0.78-1.29); the majority of events in both treatment arms were induction failures (Table). HR for OS was 0.85 (95% CI, 0.57-1.25) in favor of midostaurin. The safety profile of midostaurin was consistent with prior reports (Table). There were no new safety signals or notable differences in toxicity between pts aged <60 y vs ≥60 y. The most common AEs leading to discontinuation were infections (7.8%) and GI disorders (4.5%) with midostaurin and infections (3.6%) with PBO. Deaths occurred on treatment in 10.2% vs 8.4% of pts receiving midostaurin vs PBO. MRD was analyzed irrespective of treatment because no difference in MRD− rates was found between midostaurin and PBO (Table). Among randomized pts, 205 (41%) were MRD− (<0.1%) at any time on study, while MRD was undetermined (UND) in 95 (19%) due to a lack of suitable LAIP or material at diagnosis. Therefore, for the 95 pts who were MRD-UND, flow data was analyzed using the DfN approach and 70 (74%) could be assigned to either MRD− (n = 51) or MRD+ (n = 19). Among pts in CR/modified CRi (defined in Table footnote) at the end of IND, 1-y survival rates stratified by MRD were 90% for MRD− vs 72% for MRD+ (Figure). Conclusion Results from UNIFY are consistent with the safety/tolerability profile previously reported for midostaurin, but do not show efficacy for midostaurin in FLT3-MN AML; this suggests that the clinical effect of midostaurin in AML is primarily in the FLT3-mutated setting. Exploratory MRD analyses (to be interpreted with caution due to limited follow-up, as the study was stopped 1.2 y after first pt was randomized) suggest a trend toward longer survival for pts in remission who are MRD− at the end of IND and support the utility of assessing MRD via a combined LAIP/DfN approach. Figure 1 Figure 1. Disclosures Cloos: Takeda: Research Funding; Helsinn: Other: MRD assessments; Navigate: Patents & Royalties: Royalties for MRD analyses; DC-One: Other: MRD assessments, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Other: MRD assessments, Research Funding; Astellas: Speakers Bureau; Merus: Other: MRD assessments, Research Funding. Montesinos: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Glycomimetics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Fiedler: Daiichi Sankyo: Consultancy, Other: support for meeting attendance; Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Morphosys: Consultancy; Abbvie: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance; Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding; Servier: Consultancy, Other: support for meeting attendance; Stemline: Consultancy; Novartis: Consultancy; ARIAD/Incyte: Consultancy. Müller: GSK: Consultancy; Janssen: Other: Honoraria for educational event; Celgene/BMS: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Sandoz/Novartis: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Sica: Pfizer: Honoraria. Westermann: Astellas: Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria. Döhner: Pfizer: Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria. Levis: Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; Astellas and FujiFilm: Research Funding; Takeda: Honoraria. Ossenkoppele: Jazz: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Agios: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Stone: Astellas: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Innate: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Boston Pharmaceuticals: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Gemoab: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Macrogenics: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding. Koenen: Novartis Pharma AG: Current Employment. Bengoudifa: Novartis Pharma AG: Current Employment. Cheng: Novartis Pharmaceuticals Corporation: Current Employment. Medts: Novartis Pharma AG: Current Employment. Heidinger: Novartis Pharma AG: Current Employment. Sachs: Novartis Pharma AG: Current Employment. Sierra: Janssen: Other: Educational grant; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Other: Educational grant; Amgen: Other: Educational grant; Pfizer: Honoraria; BMS Celgene: Honoraria, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Alexion: Other: Educational grant; Jazz Pharmaceuticals: Research Funding.
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