INTRODUCTION: Prophylaxis has become standard of care for all persons with haemophilia (PWH) with a severe phenotype. However, 'standard prophylaxis' with either factor or non-factor therapies (currently only emicizumab available) is prohibitively expensive for much of the world. We sought to address the question of 'How much prophylaxis is enough?' and 'Can it be individualized?' and specifically 'Can emicizumab be individualized?'. METHODS: We reviewed the literature on prophylaxis in haemophilia since its inception in the 1950s to the present, the development of more and less intense factor prophylaxis regimens and their outcomes and additionally the published outcomes of prophylaxis with low dose emicizumab. RESULTS: What these experiences collectively show is that low dose emicizumab does result in significant benefits to patients whilst being much less expensive than a "one size fits all" emicizumab prophylaxis approach. We also took note that some non-factor therapies still in development are individualized given that high doses of these can potentially put patients at risk. CONCLUSIONS: Prophylaxis is now clearly accepted as standard of care for PWH with a severe phenotype but now in a very short time a large assortment of different treatment options for prophylaxis have become/are becoming available and the haemophilia community will need to determine how to best use these recognizing that no 'one treatment fits all'.
- MeSH
- faktor VIII terapeutické užití MeSH
- hemofilie A * farmakoterapie prevence a kontrola MeSH
- lidé MeSH
- protilátky bispecifické * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
INTRODUCTION: Significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) is refractory or relapse (R/R) after the treatment. The prognosis of this patient cohort remains poor. Novel strategies mainly based on immunotherapy and targeted agents are currently being studied. Glofitamab is novel T-cell-engaging bispecific antibody possessing a 2:1 structure with bivalent CD20 binding. Its safety and efficacy in R/R B-cell non-Hodgkin lymphoma including DLBCL were evaluated in phase I-II NP30179 trial. AREAS COVERED: The article summarizes the milestones and latest reports on glofitamab development in the field of B-cell lymphoma treatment. EXPERT OPINION: Recently, phase II part of the NP30179 study and several other reports were published proving glofitamab potential in R/R DLBCL patients. Based on the published data, glofitamab was approved by regulatory authorities worldwide for the monotherapy of R/R DLBCL in conventional time-limited manner. It is readily accessible in case of rapidly progressing disease, and it compares well with other novel treatment options. Its side effects are similar to those of other T-cell-engaging agents and can be mitigated by pretreatment with obinutuzumab or step-up dosing. Its safety profile with manageable toxicities heads the clinical development toward combination strategies and its use in earlier therapeutic phases.
Mosunetuzumab představuje novou koncepci léčby B-lymfoidních malignit, která je založena na konstrukci bispecifické protilátky (bsAb) zaměřené současně proti receptoru CD20 nádorové buňky a molekule CD3 efektorového T-lymfocytu. Možnosti různých konstruktů anti- -CD20xCD3 jsou v době technologií CRISP téměř neomezené a jejich pochopení má zásadní význam pro účinnost a další vlastnosti bsAb. V klinických hodnoceních je aktuálně mnoho často velmi odlišných CD20xCD3 bsAb. Mosunetuzumab prokázal dobrou účinnost v léčbě relabujícího folikulárního lymfomu po nejméně dvou předchozích liniích léčby s dosažením léčebné odpovědi u 80 % a kompletní odpovědi u 60 % pacientů, což vedlo k jeho schválení FDA v této indikaci. Nejčastěji pozorovanou toxicitou byl syndrom z uvolnění cytokinů (CRS), a to u 39 % pacientů, avšak pouze u 3 % z nich se jednalo o CRS stupně ≥ 3 a CRS byl vždy dobře řešitelný.
Mosunetuzumab represents a new concept of B-cell lymphoma therapy, which is based on the construct of bispecific antibody (bsAb) directed simultaneously against to the CD20 receptor of tumor cell and CD3 molecule of effector T-cell. In the CRISP era, there are almost unlimited possibilities of anti-CD20xCD3 constructs and their understanding has fundamental importance for efficacy and other properties of bsAb. Many different CD20xC3 bsAB are being tested in clinical trials. Mosunetuzumab has shown good efficacy in the therapy of relapsed follicular lymphoma after at least two prior systemic treatment with the overall response in 80% and complete response in 60% patients, leading to its FDA approval for this indication. The most common toxicity was cytokine released syndrome (CRS) in 39% patients, but only 3% had grade ≥ 3 CRS and it was always manageable.
BACKGROUND: KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy. METHODS: We studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with KMT2A-rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed KMT2A-rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 μg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial. RESULTS: The median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (<5×10-4 [i.e., <5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8). CONCLUSIONS: Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed KMT2A-rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.).
- MeSH
- akutní lymfatická leukemie * farmakoterapie imunologie MeSH
- antitumorózní látky * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- kojenec MeSH
- lidé MeSH
- pre-B-buněčná leukemie farmakoterapie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protilátky bispecifické * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- reziduální nádor diagnóza MeSH
- T-lymfocyty imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.
- MeSH
- antagonista receptoru pro interleukin 1 terapeutické užití MeSH
- imunoterapie adoptivní škodlivé účinky MeSH
- konsensus MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie MeSH
- protilátky bispecifické * škodlivé účinky MeSH
- syndrom uvolnění cytokinů etiologie prevence a kontrola farmakoterapie MeSH
- T-lymfocyty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is poor. Glofitamab is a bispecific antibody that recruits T cells to tumor cells. METHODS: In the phase 2 part of a phase 1-2 study, we enrolled patients with relapsed or refractory DLBCL who had received at least two lines of therapy previously. Patients received pretreatment with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles total). The primary end point was complete response according to assessment by an independent review committee. Key secondary end points included duration of response, survival, and safety. RESULTS: Of the 155 patients who were enrolled, 154 received at least one dose of any study treatment (obinutuzumab or glofitamab). At a median follow-up of 12.6 months, 39% (95% confidence interval [CI], 32 to 48) of the patients had a complete response according to independent review. Results were consistent among the 52 patients who had previously received chimeric antigen receptor T-cell therapy (35% of whom had a complete response). The median time to a complete response was 42 days (95% CI, 42 to 44). The majority (78%) of complete responses were ongoing at 12 months. The 12-month progression-free survival was 37% (95% CI, 28 to 46). Discontinuation of glofitamab due to adverse events occurred in 9% of the patients. The most common adverse event was cytokine release syndrome (in 63% of the patients). Adverse events of grade 3 or higher occurred in 62% of the patients, with grade 3 or higher cytokine release syndrome in 4% and grade 3 or higher neurologic events in 3%. CONCLUSIONS: Glofitamab therapy was effective for DLBCL. More than half the patients had an adverse event of grade 3 or 4. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT03075696.).
- MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie imunologie MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- nehodgkinský lymfom farmakoterapie imunologie MeSH
- protilátky bispecifické * škodlivé účinky imunologie terapeutické užití MeSH
- syndrom uvolnění cytokinů chemicky indukované prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- mosunetuzumab, Lunsumio,
- MeSH
- folikulární lymfom * farmakoterapie imunologie MeSH
- indukce remise MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- protilátky bispecifické * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- schvalování léčiv ekonomika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- zprávy MeSH
Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Design, Setting, and Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization. Intervention: Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. Main Outcomes and Measures: The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events. Results: A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group. Conclusions and Relevance: Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT02393859.
- MeSH
- akutní lymfatická leukemie farmakoterapie mortalita terapie MeSH
- antitumorózní látky škodlivé účinky terapeutické užití MeSH
- chemoterapie konsolidační škodlivé účinky MeSH
- dítě MeSH
- imunoterapie * MeSH
- Kaplanův-Meierův odhad MeSH
- kojenec MeSH
- kombinovaná terapie MeSH
- leukemie B-buněčná farmakoterapie mortalita MeSH
- lidé MeSH
- míra přežití MeSH
- mladiství MeSH
- následné studie MeSH
- předškolní dítě MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protilátky bispecifické škodlivé účinky terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- recidiva MeSH
- rizikové faktory MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
Bispecifické protilátky (bsAb) se od svých předchůdců, monoklonálních protilátek, liší schopností vázat dva různé antigeny: antigen na povrchu nádorové buňky a antigen na povrchu efektorové buňky. V klinickém testování se zatím nejdál dostaly protilátky, které jsou cílené na antigen CD3 efektorových T-lymfocytů. Aktivace endogenních T-lymfocytů vede k nastartování cytotoxické reakce a usmrcení nádorové buňky. Blinatumomab, konstrukt bsAb, je aktuálně schválený v léčbě akutní B-lymfoblastické leukemie. Většina protilátek určených k léčbě non-hodgkinských lymfomů (NHL) teprve vstupuje do II. fáze klinického hodnocení. Blinatumomab se zkouší jako konsolidační terapie u předléčených pacientů po alogenní transplantaci kostní dřeně nebo v 1. linii po klasické chemoimunoterapii. Slibné výsledky zejména v léčbě indolentních NHL dosahují bsAb, které stavebně řadíme mezi imunoglobuliny třídy G (IgG). Limitujícím faktorem všech bsAb v této chvíli zůstává jejich specifická toxicita (syndrom z uvolněných cytokinů a neurologická toxicita). Zásadní pro zvládnutí nežádoucích účinků se zdá být použití kortiko steroidů a časná aplikace monoklonálních protilátek proti interleukinu-6 (IL-6) nebo jeho receptoru.
- MeSH
- antigeny CD20 účinky léků MeSH
- antigeny CD3 antagonisté a inhibitory MeSH
- imunoterapie metody MeSH
- lidé MeSH
- nehodgkinský lymfom * farmakoterapie imunologie MeSH
- neurotoxické syndromy etiologie patofyziologie prevence a kontrola MeSH
- protilátky bispecifické * farmakologie škodlivé účinky terapeutické užití MeSH
- syndrom uvolnění cytokinů chemicky indukované patofyziologie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
