Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia Maury, Sébastien; Chevret, Sylvie; Thomas, Xavier ...
New England journal of medicine/The New England journal of medicine,
09/2016, Volume:
375, Issue:
11
Journal Article
Peer reviewed
Open access
The addition of rituximab to every phase of treatment (induction, consolidation, and maintenance) in adults with acute lymphoblastic leukemia improves outcomes, as compared with chemotherapy alone.
...The outcome for adults with acute lymphoblastic leukemia (ALL) has significantly improved over the past decade, notably because of treatment with more intensive chemotherapy, similar to that used for pediatric ALL, and risk-adapted use of allogeneic hematopoietic stem-cell transplantation.
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Biologic features of some ALL subtypes have also offered opportunities for targeted treatments. Although tyrosine kinase inhibitors are now used to treat Philadelphia chromosome (Ph)–positive ALL, one of the most promising new approaches relies on the use of monoclonal antibodies targeting the CD19, CD20, CD22, CD33, and CD52 surface antigens expressed by ALL blast cells.
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The use of rituximab, . . .
STOP second generation (2G)–tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving ...first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval CI, 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.
•First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with deep and long-lasting molecular responses.•A suboptimal response or resistance prior to dasatinib or nilotinib is associated with significantly worse treatment-free remission.
Purpose Magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) are important imaging techniques in multiple myeloma (MM). We conducted a prospective trial in ...patients with MM aimed at comparing MRI and PET-CT with respect to the detection of bone lesions at diagnosis and the prognostic value of the techniques. Patients and Methods One hundred thirty-four patients received a combination of lenalidomide, bortezomib, and dexamethasone (RVD) with or without autologous stem-cell transplantation, followed by lenalidomide maintenance. PET-CT and MRI were performed at diagnosis, after three cycles of RVD, and before maintenance therapy. The primary end point was the detection of bone lesions at diagnosis by MRI versus PET-CT. Secondary end points included the prognostic impact of MRI and PET-CT regarding progression-free (PFS) and overall survival (OS). Results At diagnosis, MRI results were positive in 127 of 134 patients (95%), and PET-CT results were positive in 122 of 134 patients (91%; P = .33). Normalization of MRI after three cycles of RVD and before maintenance was not predictive of PFS or OS. PET-CT became normal after three cycles of RVD in 32% of the patients with a positive evaluation at baseline, and PFS was improved in this group (30-month PFS, 78.7% v 56.8%, respectively). PET-CT normalization before maintenance was described in 62% of the patients who were positive at baseline. This was associated with better PFS and OS. Extramedullary disease at diagnosis was an independent prognostic factor for PFS and OS, whereas PET-CT normalization before maintenance was an independent prognostic factor for PFS. Conclusion There is no difference in the detection of bone lesions at diagnosis when comparing PET-CT and MRI. PET-CT is a powerful tool to evaluate the prognosis of de novo myeloma.
More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated ...loss of major molecular response (MMR) as a criterion for resuming therapy.
A multicenter observational study (A-STIM According to Stop Imatinib) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR.
Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients.
Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.
Large dsDNA viruses are involved in the population control of many globally distributed species of eukaryotic phytoplankton and have a prominent role in bloom termination. The genus Phaeocystis ...(Haptophyta , Prymnesiophyceae) includes several high-biomass-forming phytoplankton species, such as Phaeocystis globosa , the blooms of which occur mostly in the coastal zone of the North Atlantic and the North Sea. Here, we report the 459,984-bp-long genome sequence of P. globosa virus strain PgV-16T, encoding 434 proteins and eight tRNAs and, thus, the largest fully sequenced genome to date among viruses infecting algae. Surprisingly, PgV-16T exhibits no phylogenetic affinity with other viruses infecting microalgae (e.g., phycodnaviruses), including those infecting Emiliania huxleyi , another ubiquitous bloom-forming haptophyte. Rather, PgV-16T belongs to an emerging clade (the Megaviridae) clustering the viruses endowed with the largest known genomes, including Megavirus, Mimivirus (both infecting acanthamoeba), and a virus infecting the marine microflagellate grazer Cafeteria roenbergensis . Seventy-five percent of the best matches of PgV-16T–predicted proteins correspond to two viruses Organic Lake phycodnavirus (OLPV)1 and OLPV2 from a hypersaline lake in Antarctica (Organic Lake), the hosts of which are unknown. As for OLPVs and other Megaviridae, the PgV-16T sequence data revealed the presence of a virophage-like genome. However, no virophage particle was detected in infected P. globosa cultures. The presence of many genes found only in Megaviridae in its genome and the presence of an associated virophage strongly suggest that PgV-16T shares a common ancestry with the largest known dsDNA viruses, the host range of which already encompasses the earliest diverging branches of domain Eukarya.
To date, few empirical estimates of the IFR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been published owing to challenges in measuring infection rates.1,2 Outside of ...closed, closely observed populations where infection rates can be monitored through viral surveillance, we must rely on indirect measures of infection, such as antibodies. Representative seroprevalence studies provide an important opportunity to estimate the number of infections in a community, and when combined with death counts can lead to robust estimates of the IFR. Despite having among the highest per-capita incidence of confirmed COVID-19 in Switzerland, Geneva's health system, with additional COVID-19 surge capacity, accommodated the influx of cases needing intensive care (peak of 80 of 110 surge capacity intensive care unit beds were in use at one time) while maintaining care quality standards.
In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD ...(cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio HR, 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.
•Initial imatinib-based therapy of Ph+ adult ALL is associated with lower early mortality and higher CR rate.•In adults with Ph+ ALL, allogeneic SCT in first CR prolongs relapse-free survival and OS.
Summary
Dasatinib is a second‐generation BCR‐ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk ...of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib‐associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed (C)min ≥ 3 nmol/l) were randomised between a dose‐reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).
Oxygen reduction catalyzed by cofacial metalloporphyrins at the 1,2-dichlorobenzene–water interface was studied with two lipophilic electron donors of similar driving force, 1,1′-dimethylferrocene ...(DMFc) and tetrathiafulvalene (TTF). The reaction produces mainly water and some hydrogen peroxide, but the mediator has a significant effect on the selectivity, as DMFc and the porphyrins themselves catalyze the decomposition and the further reduction of hydrogen peroxide. Density functional theory calculations indicate that the biscobaltporphyrin, 4,5-bis5-(2,8,13,17-tetraethyl-3,7,12,18-tetramethylporphyrinyl)-9,9-dimethylxanthene, Co2(DPX), actually catalyzes oxygen reduction to hydrogen peroxide when oxygen is bound on the “exo” side (“dock-on”) of the catalyst, while four-electron reduction takes place with oxygen bound on the “endo” side (“dock-in”) of the molecule. These results can be explained by a “dock-on/dock-in” mechanism. The next step for improving bioinspired oxygen reduction catalysts would be blocking the “dock-on” path to achieve selective four-electron reduction of molecular oxygen.
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