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1.
Acta Pharmaceutica Hungarica ; 91(3-4):95-96, 2021.
Artigo em Inglês | EMBASE | ID: covidwho-2033587

RESUMO

Introduction Pfizer-BioNTech collaboration started in 2018 in order to develop mRNA flu vaccine. Because of the covid19 pandemic the two companies started to focus on mRNA vaccine development for the prevention of covid19 infection. In March they signed the Letters of Intent. Initially there were four vaccine candidates including unmodified mRNA, nucleoside-modified mRNA and self-amplifying mRNA. For further development the nucleoside- modified mRNA was chosen. In April Phase 1/2 study was completed in Germany and in May in the USA. Two 30 μg doses 3 weeks apart induced neutralizing antibody titers comparable to natural infection and strong CD4+ and CD8+ Tcell responses were observed. Phase 2b/3 clinical trial started in July involving more than 43.000 participants in 153 sites. The result showed 95% efficacy with mild and moderate local and systemic events. For safety reason all participants will be followed for 2 years after the second dose. Based on rolling review regulatory agencies were able to approve within a short period of time in December 2020, first MHRA in UK, then FDA authorized for Emergency Use and EMA granted Conditional Marketing Authorization on 21 December 2021 for 16 years old and older. The first shipments were sent all European countries on 27 December. Direct shipments to vaccination centers on ultra-low temperature (minus 9060 degree of centigrade) using dry ice. Each thermal shipping container has a temperature monitoring device. All shipments are tracked via GPS monitoring device to ensure end-to-end distribution within required temperatures. In May EMA granted an extension of indication for covid-19 vaccine to include in children aged 12-15. The effect of vaccine was investigated in 2260 children aged 12-15, about half of them received dummy injection. Of the 1,005 children receiving the vaccine, none developed COVID-19 compared to 16 children out of the 978 who received the dummy injection. This means that, in this study, the vaccine was 100% effective at preventing COVID-19. The most common side effects in children aged 12 to 15 are similar like those in people aged 16 and above. They include pain at the injection site, tiredness, headache, muscle and joint pain, chills and fever. These effects are usually mild or moderate and improve within a few days from the vaccination. EMA granted approval for booster dose (third dose) for immune weakened people 28 days after the second dose, and 6 months after the second dose for 18 years of age and older. Approval is based on the clinical program evaluating the safety, tolerability and immunogenicity of a booster dose of covid-19 vaccine. A booster dose of the vaccine elicited significantly higher neutralizing antibody titers against the initial SARS-CoV-2 virus (wild type), as well as the Beta and Delta variants, when compared with the levels observed after the two-dose primary series. The reactogenicity profile within seven days after the booster dose was typically mild to moderate, and the frequency of reactions was similar to or lower than after dose two. The efficacy is this trial was 95,6%. In October 2021 FDA authorized for emergency use of covid-19 for children 5 through 111 years of age. For this age group, the vaccine is to be admin-istered in a two-dose regimen of 10 μg (0,2 ml) doses given 21 days apart. EUA is supported by clinical data showing a favorable safety profile and high vaccine efficacy of 90.7% in children 5 through 11 years of age during a period when Delta was the prevalent strain. In 2021 we have already distributed 1,8B doses to 146 countries by end of September. In 2022 we plan to distribute 4B doses. (Figure Presented).

2.
Acta Pharmaceutica Hungarica ; 90(2-3):61, 2020.
Artigo em Inglês | EMBASE | ID: covidwho-2033585

RESUMO

Vaccines, currently used for prophylactic purposes, prevent more than three million deaths every year from diseases like diphtheria, pertussis, tetanus, poliomyelitis, measles and influenza. The general six stages of the development of a new vaccine are: i) Exploratory stage;ii) Pre-clinical stage;iii) Clinical development;iv) Regulatory review and approval;v) Manufacturing;vi) Quality control. Clinical development is a three/four-phase process. During Phase I, small groups of people receive the trial vaccine. In Phase II, the clinical study is expanded. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety. Many vaccines undergo Phase IV formal, ongoing studies after the vaccine is approved and licensed. Phase IV studies, also referred to as postmarketing surveillance studies (PMS). These processes are very similar to drug developments. However, there are several differences compared to drug development, namely: i) unlike drugs, which are given to patients, vaccines are received by healthy individuals, thus the safety margin should be very high;ii) as vaccines have to be stored under refrigeration, there are always logistical challenges during clinical trials;iii) Adjuvants are incorporated into vaccine formulations to modulate and improve the immune response (antigen/adjuvant formulation are important aspects of clinical development);iv) The immune response primarily measured during early stages of vaccine development (Phase I/II) should evaluate: Humoral/ cell-mediated/ cross-reactive antibodies or immune complexes/ immune landscape. A challenge in responding to pandemic diseases is that vaccines may not exist for them. For newly emerging threats without licensed vaccines, such as SARS, MERS, Marburg virus, Nipah virus, SARS CoV-2 and the like, the time required to develop and produce a safe, effective vaccine is unknown and would depend on the nature of the threat and the state of current vaccine research for that threat. In almost all cases, several months would be needed to respond with the first doses of vaccines. Unfortunately, six month later than WHO declared the public health emergency of international concern (27/01/2020) there are five important questions, essential for vaccine development that remain open for scientists, namely: 1) Why do people respond so differently to infection? 2)Has the virus developed any worrying mutations? 3)How well will a vaccine work? 4)Can we develop immunity and if so, how long does it last? 5)What is the origin of the virus? Until a safe, effective vaccine was ready, other public health and medical measures (social distancing, quarantine, and aspecific medications) would need to be employed to try to limit disease spread.

3.
Current Journal of Neurology ; 21(2):83-90, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2033507

RESUMO

Background: Fatigue is one of the most frequent complaints in patients with motor neuron diseases (MNDs), with a significant impact on the quality of life (QOL). There is lack of enough evidence for current pharmacological or non-pharmacological treatments of fatigue in this population to be applied in clinical setting. Energy conservation strategies are one of the key interventions for fatigue management in chronic diseases. We aimed to investigate the effect of applying these techniques in the fatigue management of patients with MND. Methods: This randomized controlled trial (RCT) study was carried out on 28 patients with MND. Participants were randomly assigned to either the intervention or control group. In addition to routine treatment, patients in the intervention group participated in 3 weekly 1-hour energy conservation programs provided by an experienced occupational therapist. The Fatigue Severity Scale (FSS) score, 36-Item Short Form Survey (SF-36), and Canadian Occupational Performance Measure (COPM) were measured at baseline, immediately after the last intervention session, and one month later. Results: FSS and COPM significantly changed after the course in the intervention group (P < 0.001 and P = 0.001, respectively). Both FSS and COPM improved significantly toward the final assessment only in the intervention group. The SF-36 changes were not significant in each of the groups. Conclusion: According to the findings of the present study, using energy conservation strategies could lead to better mid-term fatigue management and occupational performance improvement, but it did not improve QOL in patients with MND.

4.
NeuroQuantology ; 20(10):5508-5516, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2033485

RESUMO

Hypovitaminosis D was shown to be prevalent in this research of 124 people who were COVID-19 positive. With a p-value of 0.001, greater serum concentrations of inflammatory markers like COVID-19 were significantly related with lower vitamin D levels (D-dimer, CRP, and ferritin). One way to gauge the severity of COVID-19 infection is by looking at the serum vitamin D level. An increased risk of acute respiratory infection is linked to vitamin D deficiency. The processes through which vitamin D influences the immune system are complex. The usual immunomodulatory activity appears to be inhibited with reduced serum vitamin D concentrations, favoring a pro-inflammatory phase. Less effective macrophage activity and antigen presentation may be caused by insufficient vitamin D levels. As a result, low vitamin D levels may potentially contribute to a delayed or dysregulated response to the body's initial contact with SARS-CoV-2 or prevent the construction of an effective defense in cases of established SARS-CoV-2 infection. Inflammation and the biological functions of the innate and adaptive immune systems are linked to vitamin D. Coronavirus illness risk or severity have been observed to be inversely correlated with blood 25-hydroxyvitamin D (25(OH)D) levels in observational studies (COVID-19). The significance of vitamin D in COVID-19 has been attributed to a number of pathways, such as the modulation of immunological and inflammatory responses, control of the renin-angiotensin-aldosterone systems, and participation in glucose metabolism and the cardiovascular system. Patients with COVID-19 may be more likely to experience catastrophic consequences if their 25(OH)D levels are low, not only because of the hyperinflammatory state that is often present but also because it aggravates cardiovascular disease and impaired glucose metabolism that already exist. Some randomized controlled trials have demonstrated that supplementing with vitamin D is helpful for lowering coronavirus 2 RNA positivity in SARS, but not for lowering intensive care unit admission or all-cause death in patients with moderate-to-severe COVID-19. According to the most recent research, taking a vitamin D supplement to keep your serum 25(OH)D level at or above 30 ng/mL (recommended range: 40–60 ng/mL) may help lower your risk of developing COVID-19 and its serious consequences, such as death. According to worldwide recommendations, it is prudent to suggest vitamin D supplements to those who have vitamin D shortage or insufficiency during the COVID-19 pandemic, even though additional well-designed research are necessary.

5.
International Journal of Pharmaceutical Sciences and Research ; 13(9):3762-3767, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2033426

RESUMO

Natural products can be the alternative of synthetic medicine and antiviral drugs can be potential from natural products. An attempt was made to evaluate the antiviral activity from the extract of Desmodium gangeticum (L.) DC. as a phytomedicine (GanjhuVirR) for the treatment of dengue fever associated with thrombocytopenia. The present study was evaluated acute and subacute toxicity in rat as well as clinical trial in treated and without treated patients who admitted in hospital due to dengue fever associated with thrombocytopenia. The rats were grouped into group 1 (control) and 2, 3 and 4 (treated) for toxicity test while 51 patients were included in the clinical trial and 25 were treated and 26 provided only standard management as control. The parameters viz. platelet count, fever profile, average hospitalization period, clinical profiles and viral load reduction were tested for both the group. All the data related to morbidity, mortality and behavioural features were observed similar between exposed and control group. The haematological and biochemicals findings were comparable between the group. The platelet counts were significantly (P<0.001) increased and body temperature and hospital stay were significantly (P<0.001) decreased in the treated group than control group. Moreover, GanjhuVirR is a phytomedicine extracted from studied plant and capable to treat viral activity especially for Dengue virus. This is non-toxic as per animal study and is safe without any adverse events and normalize the clinical findings among patients. Future research is suggested to know the efficacy of mild to moderate Covid-19 Patients.

6.
Current Bioinformatics ; 17(3):217-237, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032698

RESUMO

Drug repositioning invovles exploring novel usages for existing drugs. It plays an important role in drug discovery, especially in the pre-clinical stages. Compared with the traditional drug discovery approaches, computational approaches can save time and reduce cost significantly. Since drug repositioning relies on existing drug-, disease-, and target-centric data, many machine learning (ML) approaches have been proposed to extract useful information from multiple data resources. Deep learning (DL) is a subset of ML and appears in drug repositioning much later than basic ML. Nevertheless, DL methods have shown great performance in predicting potential drugs in many studies. In this article, we review the commonly used basic ML and DL approaches in drug repositioning. Firstly, the related databases are introduced, while all of them are publicly available for researchers. Two types of preprocessing steps, calculating similarities and constructing networks based on those data, are discussed. Secondly, the basic ML and DL strategies are illustrated separately. Thirdly, we review the latest studies focused on the applications of basic ML and DL in identifying potential drugs through three paths: drug-disease associations, drug-drug interactions, and drug-target interactions. Finally, we discuss the limitations in current studies and suggest several directions of future work to address those limitations.

7.
HemaSphere ; 6:3982, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032174

RESUMO

Background: Rituximab is one of the second-line treatments for ITP. At present, there are few studies on low-dose rituximab, lacking of a large number of prospective and randomized trials to support the efficacy and safety of lowdose rituximab, especially in children's ITP. Influenced by COVID-19, we used two low-dose rituximab regimens before and after March 2020 for second-line treatment of children's ITP. Aims: To compare the efficacy and safety of two different regimens for low-dose rituximab of children patients with chronic /refractory ITP, so as to provide basis for clinical treatment. Methods: 83 children patients were enrolled in this study and non-randomly assigned to receive 100mg/200mg (body weight 30kg) rituximab weekly for 4 weeks (group A, 53 cases) or a single dose of 375mg / m2 rituximab (group B, 30cases). The study was follow-up for at least half a year. Results: The baseline data of group A and B were the same. For group A: Overall and complete response (OR and CR) rates were 35.8% and 15%, respectively;the side effects rate is 3.8%. In responders, the median time to response was 4 (1 -12) weeks, with a median follow-up time of 12 (6 ∼ 36) months, 6 of 19 responders (31.6%) relapsed. For group B: OR and CR rates were 36.7% and 23%, respectively;the side effects rate is 10%. In responders, the median time to response was 1 (1 ∼ 4) weeks, with a median follow-up time of 11.5 (6 ∼ 17) months, 4 of 11 responders (36.4%) relapsed. No significant difference in the OR, NR, relapse free survival and incidence of side effects was observed in patients between the two groups. Image: Summary/Conclusion: The two low-dose rituximab regimens in the treatment of ITP in children both are safe and effective;The single-agent scheme is more recommended because of easier use and not increasing safety events.

8.
HemaSphere ; 6:1350-1351, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032173

RESUMO

Background: The efficacy of ravulizumab (intravenous [IV] formulation;administered every 8 weeks) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been demonstrated in several randomized trials (NCT02946463, NCT03056040, NCT03406507). In study 303 (NCT03748823), subcutaneous (SC) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic non-inferiority to IV ravulizumab in adult patients with PNH who were clinically stable on prior IV eculizumab treatment. Here, we report results from the first 1 year of SC treatment, starting at day 15 for patients who continued SC ravulizumab during the extension period (SC/SC) and day 71 for patients who switched from IV ravulizumab to SC ravulizumab (IV/SC). Aims: To evaluate the efficacy, treatment administration satisfaction and safety of SC ravulizumab through the first 1 year (day 351) of treatment in adult patients with PNH previously treated with eculizumab. Methods: Patients (≥ 18 years) with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) and ≥ 3 months prior eculizumab treatment were enrolled in the study, which consisted of a screening period (day-1 to day-30), a 10-week randomized treatment period and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1 ratio) to receive either SC ravulizumab or IV ravulizumab;all patients received SC ravulizumab during the extension period. Efficacy endpoints included: change in LDH from baseline;incidence of breakthrough hemolysis;transfusion avoidance;and stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Treatment administration satisfaction was assessed via the Treatment Administration Satisfaction Questionnaire (TASQ), which has been validated in a PNH population. Safety, including adverse events (AEs), serious AEs (SAEs) and adverse device effects (ADEs), were also assessed up to the 1-year data cut-off. Results: In total, 128 patients received SC ravulizumab (SC/SC: n = 84;IV/SC: n = 44;mean [range] duration of SC treatment: 486.4 [37-709] days). Efficacy endpoints (SC/SC and IV/SC) remained stable over time through 1 year of SC ravulizumab treatment. Mean (standard deviation [SD]) percentage change in LDH from baseline to SC day 351 was 0.9% (20.5%). Breakthrough hemolysis events were infrequent: 5/128 patients (3.9%);no event was considered free C5-related. Transfusion avoidance was maintained in 83.6% of patients during SC treatment, and 79.7% achieved stabilized hemoglobin. Improvement in total TASQ score with SC ravulizumab (compared with baseline IV eculizumab) was apparent at the first post-SC treatment assessment (SC day 29) and maintained until data cut-off (Figure). The most common AEs (reported by ≥ 10% of patients, excluding ADEs related to device product issues) during SC treatment were headache (14.1%, all grade ≤ 2), COVID-19 (14.1%, one death) and pyrexia (10.9%);injection site reaction (4.7%) was the most common non-device related ADE. Treatment-emergent SAEs were experienced by 21.1% of patients through to data cut-off. Although many patients had ≥ 1 device issue ADE, full SC dose administration was achieved in 99.9% of attempts. ADE incidence decreased over time. Image: Summary/Conclusion: The SC method of administration provides an additional treatment option for patients with PNH receiving ravulizumab therapy. Patients may be switched from IV eculizumab or IV ravulizumab to SC ravulizumab without loss of efficacy.

9.
HemaSphere ; 6:3291-3292, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032172

RESUMO

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Approximately 2% of patients with CLL develop immune thrombocytopenic purpura (ITP) during the course of the disease. When resistant to steroids, this constitutes as indication for treatment of the CLL. Here we report a patient with refractory ITP secondary to CLL successfully treated with venetoclax. Aims: To present an interesting case with CLL related refractory ITP treated successfully with novel agent venetoclax. Methods: Patient data was taken from the patient herself and Hospital records. Informed consent to publish the case is obtained from patient. Permission for off-label venetoclax and eltrombopag was obtained from Ministry of Health of Turkey. Results: 46-year-old female patient presented with lumps on her neck that were present for the last 9 months in November 2020. She has a history of frequent pneumonia and otitis but no constitutional symptoms. Her physical examination reveals multiple 2cm lymphadenopathies on her neck and no organomegaly or other pathological features. Blood work shows mild lymphocytosis (6800/mm3) with no serious cytopenias. Peripheral blood smear, flow cytometry and bone marrow biopsy were all compatible with CLL. She was classified as Binet A CLL and was followed up with no treatment after appropriate vaccinations against capsulated pathogens. In July and August 2021 she received two doses of mRNA vaccination against COVID-19. On 1st November 2021 she experienced excessive menstrual bleeding and blood work showed platelet count of 23000/mm3, she was started on steroids (1 mg/kg/day) and after 4 days platelet count has risen to 55000/mm3, she discontinued steroids on her own against medical advice. On 13th of November she presented with extensive petechiae and purpura and was again started on steroids and was given the courses of intravenous immunoglobulins (IVIG) without any sustained response. She was refractory to platelet transfusions too. She was transferred to our clinic. She was found to have del11q and del13q. She refused bone marrow examination. She was treated with rituximab, steroids, vincristine, IVIG and eltrombopag for ITP without success (Fig. 1). She had a minimal response to IVIG only. She received two courses of bendamustine (90 mg/kg for two days) also without success. Three courses of plasmapheresis yielded no response either. After mild success with immunadsorbtion apharesis she was started on venetoclax plus rituximab with ramp-up. Sustained response was achieved within the first week of venetoclax therapy. (Figure Presented ) Summary/Conclusion: Gordon et al. reported 2 CLL cases one with ITP and other with Evans syndrome successfully treated with venetoclax. We think, this treatment should be considered in patients with refractory immune cytopenias secondary to CLL and assessed with prospective clinical trials.

10.
HemaSphere ; 6:1647-1648, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032170

RESUMO

Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1-21;IXA 4 mg on days 1, 8 and 15;and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41-83) and 64 yrs (range 52-85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371;p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXAPOM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.

11.
HemaSphere ; 6:1395-1396, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032168

RESUMO

Background: Persistent cytopenia due to poor graft function (PGF) is a life-threatening complication in patients undergoing allogeneic HSCT (allo-HSCT). Several therapeutic approaches have been tested in this subset of patients with poor clinical results. Aims: The objective of this multicenter open-label interventional prospective phase II Novartis study (ELTION, ClinicalTrials.gov id: NCT03718533), was to analyze efficacy and safety of EPAG in patients with post-allo-HSCT poor graft function. Methods: Adult patients diagnosed with PGF (defined as severe cytopenia after day +30 post-transplant, with two or more of the following: platelets <20000/μL-mandatory-, ANC <1000/μL, hemoglobin< 10 g/dL), and full donor chimerism, were eligible to enter the trial. Study treatment consisted of EPAG. at 150 mg/day administered up to 36 weeks;dose adjustments were contemplated as per protocol on an individual basis. The primary efficacy endpoint was the overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of EPAG. Results: Although the aim of the study was to include 33 patients, recruitment stopped prematurely due to the difficulties for hospital visits posed during COVID-19 pandemic, and eventually only 10 patients were included. The decision for this premature termination is not related to any safety concern related to the drug. Patient characteristics are shown in the table 1 attached below. At EPAG. initiation, all 10 patients showed thrombocytopenia (<20000/μcL), 5 presented with anemia (Hgb <10 g/dL), and 4 had neutropenia (ANC <1000/μcL). Four patients discontinued EPAG before week 12 due to: disease progression/relapse (2 patients), protocol deviation (1 patient), and CMV infection (1 patient). In none of the cases, the event was related to study drug. At week 16, 4 patients (4/10, 40%) and at week 24, 5 patients, showed improvement in at least one of the 3 hematologic cell lines (partial response), respectively. Counts pre-and post-EPAG and global response in patients who stayed on treatment > 12 weeks are displayed below: Image: Summary/Conclusion: In our experience, EPAG worked well in subjects with PGF, an otherwise life-threatening condition for patients, and its use at 150 mg/day is safe and well tolerated in this setting. Our data suggest that eltrombopag might improve hematologic cell counts in patients with PGF, especially in those patients who remained on treatment at week 24, however further research is warranted to extend its applicability for larger cohorts.

12.
HemaSphere ; 6:1596-1597, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032166

RESUMO

Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a standard of care for newly diagnosed multiple myeloma (NDMM). Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism: direct cell kill and anti-myeloma tumor immune response. Belamaf has demonstrated deep and durable responses as a monotherapy in the DREAMM-2 study of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. Aims: To evaluate the safety and tolerability of this combination in adult pts with transplant-ineligible (TI) NDMM and establish the recommended Phase III dose. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized study of belamaf + VRd. The belamaf dose cohorts currently being evaluated are Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Belamaf is given with VRd Q3W until Cycle 8, and with Rd Q4W thereafter. After evaluation of safety data for Cohort 1, Cohorts 2-5 were opened in parallel and enrolled pts were randomized 1:1:1:1. Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: As of data cutoff (07 Dec 2021), 64 pts were analyzed across all cohorts. Median age (range) was 73.0 (51- 88) years, 55% were male, 80% were white, 8% had extramedullary disease, 59% were International Staging System stage II or III, 20% had amp1q, and 17% had high-risk cytogenetics (≥1 of: t(4;14), t(14;16), del17p). The median duration of follow-up varied: Cohort 1 (17.4 months [mo]), Cohort 2 (5.9 mo), Cohort 3 (6.1 mo), Cohort 4 (4.7 mo), Cohort 5 (5.8 mo). Median number of belamaf cycles were: Cohort 1 (6), Cohort 2 (3), Cohort 3 (3.5), Cohort 4 (4.5), and Cohort 5 (5). Most common adverse events (AEs) across cohorts included thrombocytopenia (49%), constipation (43%), diarrhea (32%), and peripheral sensory neuropathy (30%). AEs related to study treatment were experienced by 61 (97%) pts. Belamaf-related grade 3/4 AEs occurred in 24 (38%) pts. Belamaf dose reductions occurred in 11 (18%) pts, with dose delays in 10 (16%) pts. Three pts experienced a fatal severe AE (unrelated to study treatment);2 due to COVID-19 infection, 1 due to pancreatic adenocarcinoma. Early deep responses were observed;67-92% pts achieved ≥very good partial response (VGPR) (Table), with median time to VGPR of 2.1-2.9 months across cohorts. Of pts with ≥VGPR, 17 were minimal residual disease (MRD) negative, 10 in Cohort 1. As of data cutoff, 8-75% of pts achieved best response of complete response (CR) or stringent CR (sCR). Grade 3 corneal exam findings were reported in 25-58% of pts;grade 3 visual acuity changes were reported in 21-75% of pts. No grade 4 corneal exam findings or visual acuity changes were reported in pts receiving belamaf Q6/8W, compared with 0-17% and 0-8%, respectively, in the Q3/4W cohorts. Belamaf PK profile was similar to that in pts with RRMM, accounting for baseline characteristics. Image: Summary/Conclusion: Belamaf + VRd demonstrated high response rates in pts with TI NDMM, with a high rate of MRD negativity indicating deep responses. No new safety signals were observed relative to DREAMM-2. Study is ongoing to evaluate the safety and efficacy of variable dose intensities of belamaf in combination with VRd.

13.
HemaSphere ; 6:161, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032164

RESUMO

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with faorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improed response rate and progression free-surial in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improed outcome of HR TE NDMM patients (EMN02, STAMINA). Aims: The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is ealuating an intensie strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensie strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with preiously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to seere aderse eent (COVID-19 infection, n=1 ;drug-induced hepatitis, n=1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related aderse eent (>5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-ein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Oerall response rate was 96%, including 92 % > ery good partial response. Among 37/46 ealuable patients post induction, Minimal Residual Disease negatiity rate (NGS, 10-5) was 62%. Summary/Conclusion: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to ealuate safety and efficacy of the oerall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients.

14.
HemaSphere ; 6:1985-1987, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032163

RESUMO

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

15.
HemaSphere ; 6:1104-1105, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032162

RESUMO

Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 - 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 -16). Patients were treated with a median of 2 (range 1-9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 -29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 -not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation;3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient's death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter's transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.

16.
HemaSphere ; 6:322-323, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032159

RESUMO

Background: Patients with relapsed or refractory (R/R) LBCL after first-line treatment who are unable to undergo high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) hae poor outcomes and limited treatment options. Aims: PILOT (NCT03483103) ealuated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as second-line treatment in patients with R/R LBCL not intended for HSCT. Methods: Eligible patients were adults with R/R LBCL after first-line treatment who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria as follows: age ≥ 70 years, Eastern Cooperatie Oncology Group performance status (ECOG PS) of 2, diffusing capacity for carbon monoxide ≤ 60%, left entricular ejection fraction < 50%, creatinine clearance < 60 mL/min, or alanine aminotransferase/aspartate aminotransferase > 2 × the upper limit of normal. Bridging therapy was allowed. Patients receied lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by liso-cel infusion at a target dose of 100 × 106 CAR+ T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria. Neurological eents (NE) were defined as inestigator-identified neurological aderse eents related to liso-cel and graded using the National Cancer Institute Common Terminology Criteria for Aderse Eents, ersion 4.03. The primary endpoint was objectie response rate (ORR) per independent reiew committee;all patients had ≥ 6 months of follow-up from first response. Results: Of 74 patients who underwent leukapheresis, 61 receied liso-cel and 1 receied nonconforming product (ie, product wherein one of the CD8 or CD4 cell components did not meet one of the requirements to be considered lisocel). Common reasons for preinfusion dropout included death and loss of eligibility (5 each). For liso-cel-treated patients, median age was 74 years (range, 53-84;79% ≥ 70 years) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectiely;26% had ECOG PS of 2 and 44% had Hematopoietic Cell Transplantation-specific Comorbidity Index score ≥ 3. After first-line treatment, 54% were chemotherapy refractory, 21% relapsed within 12 months, and 25% relapsed after 12 months;51% of patients receied bridging chemotherapy. Median (range) onstudy follow-up was 12.3 months (1.2-26.5). ORR and complete response rate were 80% and 54%, respectiely (Table). Median duration of response and progression-free surial were 12.1 months and 9.0 months, respectiely. Median oerall surial has not been reached. The most frequent treatment-emergent aderse eents (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade 3 CRS in 1 patient (2%) and no grade 4/5 CRS eents. Any-grade NEs were seen in 31% (n = 19) of patients;grade 3 NEs occurred in 5% (n = 3) of patients and no grade 4/5 NEs were reported. Seen percent (n = 4) receied tocilizumab only, 3% (n = 2) receied corticosteroids only, and 20% (n = 12) receied both tocilizumab and corticosteroids for treatment of CRS and/or NEs. Oerall, grade ≥ 3 TEAEs occurred in 79% (n = 48) of patients, with grade 5 TEAEs in 2 patients (both due to COVID-19). Two patients (3%) had grade 3/4 infections and 15 (25%) had grade ≥3 neutropenia at Day 29. Summary/Conclusion: In the PILOT study, liso-cel as second-line treatment in patients with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable oerall and complete responses, with no new safety concerns. (Table Presented).

17.
HemaSphere ; 6:2622-2623, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032155

RESUMO

Background: Etavopivat, an investigational, once-daily, selective, activator of erythrocyte pyruvate kinase (PKR) increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers and patients (pts) with sickle cell disease (SCD).1,2 Aims: We report results of an open-label (OL) extension cohort from a Phase 1 study (NCT03815695) designed to characterize the safety and clinical activity of etavopivat at a maximal pharmacodynamic dose in pts with SCD. Methods: 15 pts were enrolled to receive etavopivat 400 mg once daily for 12 wks, followed by a 4-wk follow-up. Assessments included safety, pharmacokinetics, pharmacodynamics, RBC health parameters and systemic markers of SCD pathophysiology. Results: Of 15 pts (age 32.3 ±10.1 yr;HbSS/SC n=13/2), 14 completed 12-wks of treatment (tx);1 pt discontinued tx after ∼2 wks. Etavopivat 400 mg once daily was generally well tolerated. Adverse events (AEs) reported during tx and follow-up were commonly low grade (Gr) and consistent with pts' SCD. Gr1-2 AEs in >2 pts (n [%]) were sickle cell pain events (9 [60%]);headache (5 [33%]);and upper respiratory tract infection (3 [20%]). The Gr3-4 AE in >1 pt was sickle cell vaso-occlusion (VOC;4 [27%]). On-tx serious adverse events (SAEs;1 pt each) were Gr3 VOC post Gr3 COVID (not tx-related) and Gr3 left femoral deep vein thrombosis (possibly related, resulting in tx discontinuation as stated above). SAEs (1 pt each) during the 4-wk follow-up were Gr3 acute chest syndrome + Gr3 VOC, Gr3 non-cardiac chest pain and Gr3 syncope (all unrelated). Observed increases in ATP and decreases in 2,3-DPG were durable over 12 wks of etavopivat tx. Etavopivat tx normalized hemoglobin (Hb)S-oxygen affinity to that of HbA. Etavopivat tx over 12 wks improved overall sickle RBC health, demonstrated by a reduction in point of sickling as well as improved measures of deformability and hydration of sickle RBCs (all P<0.01;Figure). Etavopivat tx over 12 wks was associated with a sustained significant increase in Hb compared with baseline (BL;P<0.0001), with mean maximal increase of 1.5 (range 0.7-2.3) g/dL. Ontx increase in Hb >1g/dL was achieved in 11 (73%) pts, for whom the mean maximal Hb increase was 1.8 (1.2-2.3) g/dL. Absolute reticulocytes, indirect bilirubin and lactate dehydrogenase significantly decreased from BL and were sustained over the 12wk period (all P<0.05), indicative of increased RBC lifespan and decreased hemolysis. Several markers of disease activity significantly decreased from BL during daily etavopivat tx, including the inflammatory marker tumor necrosis factor-α , which decreased by 35% (P<0.001). Based on preliminary exploratory analysis with an aggregate duration of etavopivat exposure of 3.32 pt-yrs in the OL cohort, a decrease in the trend for VOC Hospitalizations was observed: annualized historical and on-tx VOC Hospitalization rates were 0.93 and 0.30, respectively;the 1 on-tx VOC Hospitalization was COVID-related. Summary/Conclusion: Etavopivat 400 mg once daily for up to 12 wks demonstrated a tolerable safety profile and showed improvements in various markers of RBC health in pts with SCD. Rapid and sustained increases in Hb were associated with decreases in reticulocyte counts and markers of hemolysis, supporting increased sickle RBC lifespan and improved anemia. Together, these results support further evaluation of etavopivat in the Phase 2/3 Hibiscus Study (NCT04624659) currently enrolling pts. (Figure Presented).

18.
HemaSphere ; 6:1910-1911, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032154

RESUMO

Background: Rituximab-based chemoimmunotherapy regimens are backbone treatment (Tmt) for both indolent (follicular [FL], marginal zone [MZL]) and aggressive (diffuse large B-cell [DLBCL], mantle cell [MCL]) B-cell lymphomas. Standard of care (SoC) for relapsed or refractory (R/R) disease includes anti-CD20 in combination with chemotherapy and targeted therapies, such as Bruton's tyrosine kinase inhibitors (eg, ibrutinib) and phosphoinositide 3-kinase (PI3K) inhibitors. Parsaclisib is a potent and highly selective next generation PI3Kδ inhibitor that is currently being investigated in hematological malignancies. Aims: CITADEL-112 (NCT03424122) is an open-label phase 1 study evaluating the safety and tolerability of adding parsaclisib to investigator choice SoC Tmt rituximab (RIT), RIT + bendamustine (BEN), or ibrutinib (IBR) in patients (pts) with R/R B-cell lymphoma. Methods: Enrolled pts were ≥18 years and had histologically confirmed DLBCL, FL, MCL, or MZL, ECOG PS 0-2, were R/R to ≥1 (≥2 for FL) prior systemic therapy, and ineligible for stem cell transplant. Pts received parsaclisib 20 mg orally once daily (QD) for 8 weeks then 20 mg once weekly (QW) in combination with either: RIT 375 mg/m2 IV QW for 4 doses in cycle 1 (± cycle 2) (Tmt A);RIT 375 mg/m2 IV on day 1 + BEN 90 mg/m2 on day 1 and day 2 of each 28-day cycle for ≤6 cycles (Tmt B);or IBR 560 mg QD (Tmt C). Pts received treatment until disease progression, unacceptable toxicity, or withdrawal. Results: At data cutoff (May 14, 2021), 50 pts were treated (16 pts each in Tmt A and C, 18 pts in Tmt B) and 13 pts were ongoing treatment (3 pts in Tmt A, 8 pts in Tmt B, 2 pts in Tmt C). Most pts had received ≥2 prior systemic treatments (81.3%, 61.1%, and 68.8% in Tmt A [range 1-4], B [range 1-4], and C [range 1-7], respectively). The most common reasons for discontinuation were progressive disease (56.3%, 38.9%, and 50.0%) and adverse events (AEs) (12.5%, 11.1%, and 6.3% in Tmt A, B, and C, respectively). One pt in Tmt B experienced a dose-limiting toxicity of grade 4 neutropenia for >14 days. All pts experienced at least 1 treatment-emergent AE (TEAE);in Tmt A, 75.0% had grade ≥3 and 37.5% had serious TEAEs;Tmt B, 83.3% had grade ≥3 and 27.8% had serious TEAEs;and Tmt C, 62.5% had grade ≥3 and 43.8% had serious TEAEs. Common any-grade TEAEs (≥30%) included neutropenia (62.5%), diarrhea (37.5%), and anemia (31.3%) in Tmt A;neutropenia (50.0%), abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Tmt B;neutropenia (50.0%) and increased ALT and increased AST (each 37.5%) in Tmt C. Most common grade ≥3 TEAEs (≥15%) were neutropenia (50.0%) and diarrhea (18.8%) in Tmt A, and neutropenia (38.9% and 25.0%) in Tmt B and Tmt C, respectively. Serious TEAEs occurring in >1 pt were COVID-19, diarrhea, and pneumonia (n = 2 each) in Tmt A, and atrial fibrillation (n = 2) in Tmt C. TEAEs with fatal outcome were reported in 2 pts in Tmt A (COVID-19 and COVID-19 pneumonia [n = 1], interstitial lung disease [n = 1]) and 1 pt in Tmt C (COVID-19, acute kidney injury). Parsaclisib dose interruption or dose reduction due to TEAEs occurred in 75.0% and 18.8% of pts, respectively, in Tmt A;66.7% and 27.8% of pts, respectively, in Tmt B;and 56.3% and 18.8% of pts, respectively, in Tmt C. Summary/Conclusion: Parsaclisib 20 mg QD for 8 weeks followed by 20 mg QW can be safely combined with RIT, RIT + BEN, or IBR in pts with R/R B-cell lymphomas. The tolerability profile of the combination regimens was manageable, with no unexpected safety concerns.

19.
HemaSphere ; 6:1096-1097, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032152

RESUMO

Background: Infectious complications are a major cause of morbidity and mortality in Chronic Lymphocytic Leukaemia (CLL). Therapeutic approaches that deplete CLL cells also affect normal B-cells. Optimal treatment would result in eradication of CLL cells and recovery of normal immune function. FLAIR (ISRCTN01844152) is a phase III trial for previously untreated CLL comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR) and subsequently amended to also compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Measurable residual disease (MRD) and normal B-cell levels were assessed at multiple timepoints. Aims: To assess the depletion of normal B-cells during treatment and recovery after end of treatment. Methods: Participants aged under 75 years with <20% TP53-deleted cells were initially randomised to FCR or IR and subsequently to FCR, IR, I+V or I with the IR arm closed after randomisation of 771 participants to FCR/IR. FCR was given for 6 cycles, while treatment in the IR, I and I+V arms continued for up to 6 years except in participants attaining <0.01% MRD who continued treatment for the time taken to achieved MRD <0.01% and then stopped if MRD remained <0.01%. Month (M) 24 was earliest permitted stopping point. MRD flow cytometry was performed according to ERIC guidelines (panel: CD19/5/20/43/79/81+ROR1, acquisition of 0.5-2.2 million cells, BD Biosciences Lyric). Additional analysis of normal B-cell subsets was performed in a cohort of >500 patients (panel: CD19 to identify B-cells, CD20/5/79b+ROR1 and CD3 to exclude CLL & contaminating cells, with CD27/ 38/IgD/IgM to characterise normal B-cell subsets using a Coulter Cytoflex LX). Results: Normal B-cells were undetectable during FCR treatment and only rarely detectable until 12 months after last FCR cycle. Circulating normal B-cells were reduced in number or undetectable in participants receiving ibrutinibcontaining regimens with greater depletion in the I+V and IR arms relative to I monotherapy. B-progenitors persist through FCR treatment but were depleted during I, I+R or I+V treatment. Normal B-cell levels at 24 and 36 months after randomisation, with time off-treatment if applicable, are shown in Figure 1. In the ibrutinib-containing arms (IR, I, and I+V), there was a trend towards fewer COVID-associated SAE at any time point for participants with detectable B-cells at 24M (4/181, 2.2%) compared to those with no detectable B-cells (14/344, 4.1%) and COVID-associated SAEs were not observed in FCR-treated participants who had recovered any level of normal B-cells by 24M (0/215). However, the data on COVID infections are limited and there was no apparent association between normal B-cell levels at 24M with the proportion of participants experiencing an infectious SAE overall. Assessment of normal B-cell subsets during ibrutinib-based treatment demonstrated a mix of naïve and memory B-cells. Serological response to COVID infection/vaccination in this cohort is currently being performed. Participants stopping I+V treatment at 24-30 months post-randomisation due to MRD eradication showed rapid recovery of normal naive B-cells within 6-12 months after end of treatment in the vast majority (>95%) of evaluable cases. Summary/Conclusion: Normal circulating B-cells are depleted during treatment with rituximab but can persist at a low level during I, IR or I+V treatment. Most patients in remission after treatment with FCR or I+V show recovery of normal B-cells at 12 months of stopping treatment.

20.
HemaSphere ; 6:1059-1060, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2032148

RESUMO

Background: In the largest study of Baliakas et al. (2019) the presence of at least 5 abnormalities, was associated with dismal clinical outcome, independently of the somatic hypermutation status and TP53 status. The presence of 3 or 4 aberrations is defined as clinically relevant in the absence of TP53. Studies by Kittai (2021) and Al-Sawaf (2020) showed the impact of karyotypic complexity on survival in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib or venetoclax. The complex karyotype (CK) is a topic that is being intensively researched, both in the aspect of increasing karyotypic complexity stratification and clonal evolution. Optimal therapy for patients with CLL has not yet been developed. The combination therapy of ibrutinib and venetoclax was superior to chlorambucil and obinutuzumab in terms of undetectable minimal residual disease (MRD) responses according to data from the GLOW trial (Tunir, 2021). The importance of achieving a complete response with undetectable MRD as the goal of therapy in CLL was proposed (Montserrat, 2005). Aims: The aim of our study is to evaluate the effectiveness of therapy with ibrutinib and venetoclax in combination for the patients with CLL and CK. Methods: This ambilinear observational study included patients with CLL with high genetic complexity (high-CK), defined as >=5 aberrations or CK (>=3 aberrations) in combination with a 17p deletion (CK+del17p). The first retrospective cohort included patients treated with ibrutinib monotherapy (Imono) to progression or intolerable toxicity since May 2015. The second prospective cohort included patients receiving ibrutinib in combination with venetoclax (IVen) since July 2019. Venetoclax therapy was started at the 3rd month of ibrutinib (from the escalation phase). Combination therapy was continued until a complete response, defined as three consecutive PET-CT-negative and MRD-negative results 3 months apart. If this criterion was not achieved at 24th month of therapy, venetoclax was discontinued and ibrutinib continued indefinitely. Results: Seventy-nine patients are included in the study. Twenty-nine patients in the first cohort and 50 patients in the second cohort. The characteristic is presented in Table. At the current follow-up periods, there were no significant differences in PFS and OS regarding a follow-up period <= 24 months (with the exception of death from COVID-19, since patients were not observed at parallel time intervals). In the group of patients treated with Imono, the majority of patients achieved partial remission or partial remission with lymphocytosis by 12 months. In 21 patients from Iven group, with a median follow-up of 7.4 months, a complete remission was achieved (72.4%);of these, 8 had unmeasurable MRD. Four patients did not complete the escalation period. There was a significant difference in the median MRD response achieved between 3 (log10>10) and 12 (log10<0,1) months in IVen group (p=0,03). In 2 patient from the IVen group progression of the disease was noted. Summary/Conclusion: Combination therapy with ibrutinib and venetoclax is an effective oral regimen for high-risk patients with complex karyotype disorders. PFS in both groups is currently not significantly different, which is obviously due to the short follow-up period. Patients receiving the IVen regimen achieve a significantly better response, which paves the way for allogeneic transplantation in these patients.

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