Therapeutic Advances in Hematology最新文献

{"title":"Survival outcomes in patients with relapsed/refractory or MRD-positive B-cell acute lymphoblastic leukemia treated with blinatumomab.","authors":"Hagop M Kantarjian,&nbsp;Aaron C Logan,&nbsp;Faraz Zaman,&nbsp;Nicola Gökbuget,&nbsp;Ralf C Bargou,&nbsp;Yi Zeng,&nbsp;Gerhard Zugmaier,&nbsp;Franco Locatelli","doi":"10.1177/20406207231201454","DOIUrl":"10.1177/20406207231201454","url":null,"abstract":"<p><p>Blinatumomab has demonstrated significant efficacy in adult and pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-cell ALL) and patients with measurable residual disease (MRD). This review aimed to compare median relapse-free survival (RFS) and median overall survival (OS) in adult and pediatric patients with R/R or MRD-positive B-cell ALL from pivotal studies [MT-103-211 and TOWER for adults with Philadelphia chromosome (Ph)-negative R/R B-cell ALL, ALCANTARA for adults with Ph-positive R/R B-cell ALL, MT-103-203 for adults with MRD-positive B-cell ALL, and MT-103-205 for pediatric patients with R/R B-cell ALL], with the median RFS and OS from retrospective analyses, country or ethnicity-specific studies, and studies based on real-world evidence (RWE) identified from a literature search. Adults with Ph-negative R/R B-cell ALL who received blinatumomab as first salvage demonstrated a numerically longer median OS compared with that in patients from pivotal studies (MT-103-211 and TOWER) without additional safety concerns. In pediatric patients with R/R B-cell ALL treated with blinatumomab, the median RFS and OS from retrospective analyses and country/ethnicity-specific studies were comparable with the median RFS and OS from the pivotal study MT-103-205. The median RFS and OS from RWE studies in adults with R/R B-cell ALL were numerically longer than the median RFS and OS from pivotal studies (MT-103-211, TOWER, and ALCANTARA); however, this trend was not observed in pediatric patients with R/R B-cell ALL. In conclusion, this analysis identified first salvage adults with Ph-negative R/R B-cell ALL as particularly well-suited for treatment with blinatumomab since survival outcomes from retrospective analyses reported in this patient subgroup were numerically better compared with those from pivotal studies without additional safety signals.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231201454"},"PeriodicalIF":3.4,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10563488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41213714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term outcome of progressive multifocal leukoencephalopathy with recombinant interleukin-2 treatment and an associated increase in the number of HPyV-2-specific T-cells: a case report.","authors":"Fieke W Hoff,&nbsp;John Rolwes,&nbsp;Paula A Hardeman,&nbsp;Molly Perkins,&nbsp;Eugene O Major,&nbsp;Daniel Douek,&nbsp;Robert H Collins,&nbsp;Benjamin M Greenberg","doi":"10.1177/20406207231201721","DOIUrl":"https://doi.org/10.1177/20406207231201721","url":null,"abstract":"<p><p>Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by reactivation of the human polyomavirus 2 (HPyV-2). PML is associated with a high morbidity and mortality rate and there is currently no standard curative therapy. We report short-term immunologic response and long-term clinical outcomes in a patient diagnosed with follicular lymphoma (FL) who developed PML. Diagnosis of PML was established conclusively based on findings from a brain biopsy. The patient was treated with recombinant interleukin 2 (IL-2) and showed rapid clinical improvement. HPyV-2-specific T-cells were tracked longitudinally and correlation with clinical status, viral load, and radiographic imaging was documented. After the progression of the patient's FL, which required an allogeneic bone marrow transplant, the patient prophylactically received human leukocyte antigen-matched donor-derived HPyV-2 T-cells to prevent the recurrence of the PML as part of a clinical trial. Twelve years after the initial diagnosis of PML, he did not develop a relapse of his PML, supporting data that therapies that increase HPyV-2-specific T-cells, including IL-2, may be effective in the management of PML.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231201721"},"PeriodicalIF":3.4,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10563476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41213713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of erythropoiesis in Covid-19 patients: prevalence of positive Coombs tests and iron metabolism.","authors":"Léa Schmitz,&nbsp;Michelle Pirotte,&nbsp;Alizée Lebeau,&nbsp;Marie Ernst,&nbsp;Marianne Fillet,&nbsp;Anais Devey,&nbsp;Justine Schmitt,&nbsp;Gaël Cobraiville,&nbsp;Marilène Binsfeld,&nbsp;Stéphanie Gofflot,&nbsp;Yves Beguin,&nbsp;Gaëlle Vertenoeil","doi":"10.1177/20406207231199837","DOIUrl":"https://doi.org/10.1177/20406207231199837","url":null,"abstract":"<p><strong>Background: </strong>For more than 2 years medical practice has been dealing with the Covid-19 pandemic. Atypical symptoms, such as frostbites and acrosyndromes, have appeared, and autoimmune anemias (some of which with cold agglutinins) have been described.</p><p><strong>Objectives: </strong>We planned to study the prevalence of positive direct Coombs tests (DCTs) and hemolytic autoimmune anemia in patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its correlation with complications, and then investigate the impact of the infection on iron metabolism.</p><p><strong>Design: </strong>This is an observational, cross-sectional, single-center, exploratory study.</p><p><strong>Methods: </strong>We obtained Coombs tests in a population of 179 infected patients at the CHU of Liège. We then studied iron metabolism in some of these patients, by measuring serum ferritin, erythropoietin (EPO), erythroferrone and hepcidin.</p><p><strong>Results: </strong>We did not identify any case of autoimmune hemolysis. However, there was a 20.3% prevalence of positive DCT, mainly with IgG (91.7%). These patients, compared to DCT-negative patients, were not only more anemic and transfused, but also required more transfers to intensive care units and had longer hospital stays and mechanical ventilation. The pattern of anemia was consistent with the anemia of inflammation, showing elevated hepcidin and ferritin levels, while EPO and erythroferrone values were lower than expected at this degree of anemia. Erythroferrone was higher and Hb was lower in DCT-positive patients. Finally, we identified a correlation between iron parameters and complicated forms of infection.</p><p><strong>Conclusion: </strong>Covid-19 patients suffered from inflammatory anemia with more severe forms of infection correlated to positive DCT status. This could potentially be of interest for future clinical practice.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231199837"},"PeriodicalIF":3.4,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b7/e5/10.1177_20406207231199837.PMC10540584.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41148394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of eltrombopag and avatrombopag in the treatment of refractory/relapsed aplastic anemia: a single-center retrospective study in China.","authors":"Zhuxin Zhang, Qinglin Hu, Chen Yang, Miao Chen, Bing Han","doi":"10.1177/20406207231191310","DOIUrl":"10.1177/20406207231191310","url":null,"abstract":"<p><strong>Background: </strong>Eltrombopag (ELT), a thrombopoietin receptor agonist (TPO-RA), has been approved for relapsed/refractory aplastic anemia (AA). However, data on avatrombopag (AVA), another TPO-RA, are limited, and the comparisons between the two TPO-RAs are lacking.</p><p><strong>Objectives: </strong>We aimed to compare the efficacy and safety between ELT and AVA in relapsed/refractory AA patients.</p><p><strong>Design: </strong>In this retrospective study, patients with relapsed/refractory AA who had been treated with ELT (<i>N</i> = 45) or AVA (<i>N</i> = 30) alone and had compatible baseline hematological parameters were compared.</p><p><strong>Methods: </strong>Data from patients diagnosed with acquired AA were retrospectively collected. All patients were refractory/relapsed to standard immunosuppressive therapy (IST) for at least 6 months before ELT or AVA. Patients had to be treated with ELT or AVA alone for at least 6 months before evaluation if they did not respond. Baseline characteristics, overall response (OR), complete response (CR), relapse, adverse events, and factors that may affect efficacy were analyzed.</p><p><strong>Results: </strong>Of the 75 patients enrolled, 45 received ELT and 30 received AVA. Patients with AVA had a higher percentage of abnormal liver or renal function than those with ELT (<i>p =</i> 0.036). No significant difference was found in the OR/CR rate in the first/second/third/sixth month between the two cohorts (<i>p ></i> 0.05). Patients treated with AVA had a shorter median time to response than those treated with ELT (<i>p =</i> 0.012) and had a higher platelet level in the second month (<i>p =</i> 0.041). AVA had fewer adverse events than ELT (<i>p =</i> 0.046). Under compatible follow-up time (<i>p =</i> 0.463), no difference was found between the ELT and AVA cohorts in relapse (<i>p =</i> 1.000) or clone evolution (<i>p =</i> 0.637). No predictive factors for OR and CR in the sixth month were found for either ELT or AVA.</p><p><strong>Conclusion: </strong>With worse liver or renal function, AVA had a similar OR/CR rate but a shorter median time to response and fewer adverse events for patients with relapsed/refractory AA.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231191310"},"PeriodicalIF":3.4,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/65/49/10.1177_20406207231191310.PMC10503291.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10672041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies.","authors":"Luis Carlos Saiz, Leire Leache, Marta Gutiérrez-Valencia, Juan Erviti, María Ximena Rojas Reyes","doi":"10.1177/20406207231168211","DOIUrl":"10.1177/20406207231168211","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;This living systematic review aims to provide a timely, rigorous, and continuously updated synthesis of the evidence available on the role of CAR-T therapy for the treatment of patients with hematologic malignancies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;A systematic review with meta-analysis of randomized controlled trials (RCTs) and comparative non-randomized studies of interventions (NRSI), evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, standard of care (SoC) or any other intervention, was performed in patients with hematologic malignancies. The primary outcome is overall survival (OS). Certainty of the evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Data sources and methods: &lt;/strong&gt;Searches were performed in the Epistemonikos database, which collates information from multiple sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library. A manual search was also carried out. We included the evidence published up to 1 July 2022.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We included the evidence published up to 1 July 2022. We considered 139 RCTs and 1725 NRSI as potentially eligible. Two RCTs (&lt;i&gt;N&lt;/i&gt; = 681) comparing CAR-T therapy with SoC in patients with recurrent/relapsed (R/R) B-cell lymphoma were included. RCTs did not show statistical differences in OS, serious adverse events, or total adverse events with grade ⩾ 3. Higher complete response with substantial heterogeneity [risk ratio = 1.59; 95% confidence interval (CI) = (1.30-1.93); &lt;i&gt;I&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt; = 89%; 2 studies; 681 participants; very low certainty evidence] and higher progression-free survival [hazard ratio for progression or death = 0.49; 95% CI = (0.37-0.65); 1 study; 359 participants; moderate certainty evidence] were reported with CAR-T therapies. Nine NRSI (&lt;i&gt;N&lt;/i&gt; = 540) in patients with T or B-cell acute lymphoblastic leukemia or R/R B-cell lymphoma were also included, providing secondary data. In general, the GRADE certainty of the evidence for main outcomes was mostly low or very low.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;So far, assuming important limitations in the level of certainty due to scarce and heterogenous comparative studies, CAR-T therapies have shown some benefit in terms of progression-free ","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231168211"},"PeriodicalIF":3.4,"publicationDate":"2023-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5a/37/10.1177_20406207231168211.PMC10150428.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9779262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges in the treatment of melanoma with BRAF and MEK inhibitors in patients with sickle cell disease: case report and review of the literature.","authors":"Panagiotis T Diamantopoulos, Amalia Anastasopoulou, Maria Dimopoulou, Michalis Samarkos, Helen Gogas","doi":"10.1177/20406207231155991","DOIUrl":"10.1177/20406207231155991","url":null,"abstract":"<p><p>Patients with sickle cell disease (SCD) suffer from complications due to anemia, inflammation, and vaso-occlusion. Factors that trigger sickling and/or inflammation may initiate such complications, while treatment with hydroxyurea (HU) reduces their emergence and prolongs survival. On the contrary, inhibition of the BRAF-MEK-ERK pathway with BRAF and MEK inhibitors (BRAF/MEKi) has revolutionized treatment of melanoma but their use has been correlated with inflammatory adverse events. Thus, treatment of patients with SCD with BRAF/MEKi may be quite challenging and pyrexia in those patients should be managed as a medical emergency. In this article, intrigued by the case of a 36-year-old female patient with S/β-thal under HU who was treated with dabrafenib and trametinib for melanoma, we analyze the mechanisms underlying inflammation and vaso-occlusion in SCD, the mechanisms of pyrexia and inflammation induced by BRAF/MEKi, their potential interconnections, the shared role of the inflammasome in these two entities, and the protective effect of HU in SCD. Since SCD is the most common inheritable blood disorder, the administration of BRAF/MEKi for melanoma in patients with SCD may be a rather common challenge. Thus, proper treatment with HU may pave the way for an uneventful management of such patients.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231155991"},"PeriodicalIF":3.4,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ed/8d/10.1177_20406207231155991.PMC10021083.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9145886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use and positioning of fostamatinib in the management of primary chronic immune thrombocytopenia: an Italian expert opinion.","authors":"Alessandro Lucchesi, Bruno Fattizzo, Valerio De Stefano, Marco Ruggeri, Sergio Siragusa, Nicola Vianelli, Francesco Zaja, Francesco Rodeghiero","doi":"10.1177/20406207221147777","DOIUrl":"10.1177/20406207221147777","url":null,"abstract":"<p><p>Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, represents a new therapeutic opportunity for patients with immune thrombocytopenia (ITP) in Europe and Italy. However, the positioning of this drug in patient's therapeutic sequence is undefined within the most recent international guidelines. The conclusions from a consensus meeting between Italian experts, whose task was to outline the profile of the ideal candidate to receive fostamatinib, are reported here. A modified Delphi methodology was used to achieve shared statements, which were reported in a narrative form. In particular, the panelists examined the strengths and weaknesses of the registration studies in terms of clinical outcomes, the safety profile of fostamatinib, the drug's impact on the quality of life of patients with chronic ITP, and the potential benefits of its use in the pandemic era. Although the experience with thrombopoietin receptor agonists (TPO-RAs) and the amount of data from real-world studies suggest the preferential use of these drugs as a second-line treatment in most patients, the absence of an increased thrombotic risk in the clinical trials could make fostamatinib a reasonable choice in patients with an increased risk of vascular events. An unstable platelet count during TPO-RAs might also justify a switch to the Syk inhibitor, which is more likely to stabilize the platelet count in responders. Fostamatinib may be preferred to immunosuppressors during the SARS-CoV-2 pandemic, in patients at infectious risk, or in case of contraindication to splenectomy. Finally, the novel mechanism of action makes it an attractive drug in multi-refractory patient.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207221147777"},"PeriodicalIF":3.4,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/17/63/10.1177_20406207221147777.PMC10326469.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9811193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How to translate and implement the current science of gene therapy into haemophilia care?","authors":"Cedric Hermans, Yves Gruel, Laurent Frenzel, Evelien Krumb","doi":"10.1177/20406207221145627","DOIUrl":"10.1177/20406207221145627","url":null,"abstract":"<p><p>Gene-based therapy opens an entirely new paradigm in managing people with haemophilia (PWH), offering them the possibility of a functional cure by enabling continuous expression of factor VIII (FVIII) or factor IX (FIX) after transfer of a functional gene designed to replace the PWH's own defective gene. In recent years, significant advances in gene therapy have been made, resulting in clotting factor activity attaining near-normal levels, as reflected by 'zero bleeding rates' in previously severely inflicted patients following a single administration of adeno-associated viral (AAV) vectors. While this new approach represents a major advancement, there are still several issues that must be resolved before applying this technology in clinical practice. First, awareness, communication, and education about the therapeutic potential and modalities of gene therapy must be further strengthened. To this end, objective, unbiased, transparent, and regularly updated information must be shared, in an appropriate way and understandable language with the support of patients' organizations. Second, healthcare providers should adopt a patient-centred approach, as the 'one size fits all' approach is inappropriate when considering gene therapy. Instead, a holistic patient view taking into account their physical and mental dimensions, along with unexpressed expectations and preferences, is mandatory. Third, the consent procedure must be improved, ensuring that patients' interests are maximally protected. Finally, gene therapy is likely to be first delivered in a few centres, with the highest expertise and experience in this domain. Thus, patients should be managed based on a hub-and-spoke model, taking into account that the key to gene therapy's success lies in an optimal communication and collaboration both within and between haemophilia centres sharing their experiences in the frame of international registries. This review describes recent progress and explains outstanding hurdles that must be tackled to ease the implementation of this paradigm-changing new therapy.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207221145627"},"PeriodicalIF":3.4,"publicationDate":"2023-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/25/1c/10.1177_20406207221145627.PMC9841832.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10541926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luspatercept for transfusion-dependent β-thalassemia: time to get real.","authors":"Khaled M Musallam,&nbsp;Sujit Sheth,&nbsp;Maria Domenica Cappellini,&nbsp;Antonis Kattamis,&nbsp;Kevin H M Kuo,&nbsp;Ali T Taher","doi":"10.1177/20406207231195594","DOIUrl":"https://doi.org/10.1177/20406207231195594","url":null,"abstract":"Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the Sage and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). TherapeuTic advances in hematology","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231195594"},"PeriodicalIF":3.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a9/85/10.1177_20406207231195594.PMC10460678.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10111519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia.","authors":"Wojciech Jurczak,&nbsp;Nagah Elmusharaf,&nbsp;Christopher P Fox,&nbsp;William Townsend,&nbsp;Amanda G Paulovich,&nbsp;Jeffrey R Whiteaker,&nbsp;Fanny Krantz,&nbsp;Chuan-Chuan Wun,&nbsp;Graeme Parr,&nbsp;Shringi Sharma,&nbsp;Veerendra Munugalavadla,&nbsp;Richa Manwani,&nbsp;Emma Dean,&nbsp;Talha Munir","doi":"10.1177/20406207231173489","DOIUrl":"https://doi.org/10.1177/20406207231173489","url":null,"abstract":"<p><strong>Background: </strong>Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in <i>TP53</i>- and <i>ATM</i>-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL.</p><p><strong>Objectives: </strong>To evaluate ceralasertib ± acalabrutinib in R/R CLL.</p><p><strong>Design: </strong>Nonrandomized, open-label phase I/II study.</p><p><strong>Methods: </strong>In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective.</p><p><strong>Results: </strong>Eleven patients were treated [arm A, <i>n</i> = 8 (cohort 1, <i>n</i> = 5; cohort 2, <i>n</i> = 3); arm B, <i>n</i> = 3 (acalabrutinib plus ceralasertib, <i>n</i> = 2; acalabrutinib only, <i>n</i> = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached.</p><p><strong>Conclusion: </strong>Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size.</p><p><strong>Registration: </strong>NCT03328273.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":"14 ","pages":"20406207231173489"},"PeriodicalIF":3.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/dd/f3/10.1177_20406207231173489.PMC10233611.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10645893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}