Abstract
Background
Multidrug-resistant Gram-negative bacterial (MRGNB) infections represent a major public health threat. Cancer patients and, among them, hematological patients are most vulnerable ...to these infections. Gut colonization by MRGNB is a common phenomenon occurring during hospitalization and chemotherapy exposure. In the neutropenic phase that occurs after chemotherapy, MRGNB translocation occurs increasing patient’s mortality. Fluoroquinolone prophylaxis with ciprofloxacin or levofloxacin efficacy is now being questioned due to the increase of incidence in MRGNB.
Methods
A phase III randomized, controlled, clinical trial, open-label parallel-group with a 1:1 ratio, aimed to demonstrate the non-inferiority of oral fosfomycin versus oral ciprofloxacin for febrile neutropenia prevention in patients with acute leukemia (AL) or hematopoietic cell transplant (HSC) receptors. Weekly surveillance cultures are planned to detect gut colonization. Changes in fecal microbiome at the beginning and end of prophylaxis will also be analyzed.
Discussion
This trial will provide evidence of the efficacy of an alternative drug to ciprofloxacin for febrile neutropenia prevention in high-risk hematological patients. The battery of planned microbiological studies will allow us to evaluate prospectively the microbiological safety of both pharmacological strategies in terms of the selection of MRGNB occurring in each arm. In addition, valuable information on the way in which each drug changes the fecal microbiome of the patients throughout the treatment will be generated.
Trial registration
Clinical trials NCT05311254, Registered on 5 April 2022,
https://clinicaltrials.gov/ct2/show/NCT05311254?term=FOVOCIP&cntry=ES&draw=2&rank=1
. Protocol version: 3.0, dated 20 May 2022.
•The novel combination of tafasitamab ± lenalidomide + R-CHOP showed signs of efficacy in patients with untreated DLBCL, with no new safety signals.•The results, including a post hoc analysis in ...patients with high-risk disease (IPI 3-5), support the ongoing phase 3 frontMIND trial.
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Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.
In a phase 1b trial of the addition of the anti-CD19 antibody tafasitamab to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), Belada et al randomly assigned patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) with a poor prognosis (International Prognostic Index score of 2-5) to also receive lenalidomide. The authors’ data from 66 patients suggest acceptable safety and encouraging efficacy with 2-year progression-free survival exceeding 74%, thereby forming the basis for a phase 3 trial in high-risk patients with DLBCL.
OPB-111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid ...leukemia (AML), in preclinical models. In the present study, a phase 1b, two-stage, 3+3 dose-escalation clinical trial dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28-day cycles was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB-111077 in patients with high-risk AML. A preliminary preclinical analysis evaluated the anti-proliferative activity of OPB-111077 in 19 patients with AML with a Vivia Biotech ex vivo PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB-111077. Dose-limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment-emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB-111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high-risk AML. A biomarker-driven design is useful for selecting the study population upfront.OPB-111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid leukemia (AML), in preclinical models. In the present study, a phase 1b, two-stage, 3+3 dose-escalation clinical trial dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28-day cycles was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB-111077 in patients with high-risk AML. A preliminary preclinical analysis evaluated the anti-proliferative activity of OPB-111077 in 19 patients with AML with a Vivia Biotech ex vivo PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB-111077. Dose-limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment-emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB-111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high-risk AML. A biomarker-driven design is useful for selecting the study population upfront.
(A) Correlation matrix of unsupervised co‐regulated genes, based on the 208 genes included in the NanoString platform. Some of the clusters of co‐regulated genes corresponded to the following: ...Inflammatory cells; Epstein–Barr virus; B‐cells; Cytotoxic T‐cells; T‐cells; and Proliferation. (B) Analysis of genomic alterations by targeted sequencing. Distribution of mutations in the 62 analyzed genes. Rows correspond to sequenced genes, columns represent individual patients. Color coding: green, missense; blue, synonymous; pink, frameshift; violet, Indel; red, stop gained; yellow, UTR.
BACKGROUND
Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without ...venetoclax, and supportive care. This multicenter, randomized, open‐label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA).
METHODS
Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow‐up phase.
RESULTS
The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1‐year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval CI, 5.6‐14 months) versus 4.1 months (95% CI, 2.7‐5.5 months; P = .005), respectively. The median event‐free survival was 4.9 months (95% CI, 2.8‐7 months) with AZA and 3 months (95% CI, 2.5‐3.5 months) with FLUGA (P = .001).
CONCLUSIONS
FLUGA achieved more remissions after 3 cycles, but the 1‐year OS rate was superior with AZA. However, long‐term outcomes were disappointing in both arms (3‐year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.
Azacitidine improves 1‐year overall survival in comparison with a semi‐intensive chemotherapy schedule (FLUGA). The complete remission/complete remission with incomplete blood count recovery rate after 3 cycles is lower in an azacitidine arm than a FLUGA arm, but the best response achieved is similar for the 2 groups.
•Targeted sequencing of dysplastic cells and blasts at diagnosis identifies evolutionary patterns from dysplasia to the onset of AML.•Patients with AML may present different clonal involvement in ...dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance.
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Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workups. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and fluorescence-activated cell sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly diagnosed patients with AML. Presence of dysplasia according to MFC and World Health Organization criteria had no prognostic value in older adults. NGS of dysplastic cells and blasts isolated at diagnosis identified 3 evolutionary patterns: stable (n = 12 of 21), branching (n = 4 of 21), and clonal evolution (n = 5 of 21). In patients achieving complete response (CR), integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in ∼80% of patients with newly diagnosed AML, using techniques other than single-cell multiomics.
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