The magnitude of the natural killer (NK) cell response contributes to the achievement of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) and is regulated by the interaction between killer immunoglobulin-like receptors (KIRs) on NK cells and human leukocyte antigen (HLA) class I molecules on target cells. The abundant combination between KIR and HLA through genetic polymorphisms determines the functional diversity of NK cells. We previously reported that KIR3DL1-HLA-Bw status is associated with achievement of TFR by reflecting NK cell potential. Patients with strong interaction between KIR3DL1/HLA-Bw were identified as having a higher molecular relapse risk, based on the “missing self” hypothesis which suggests that the lack of cognate ligands for KIRs may induce target cell lysis. However, all the patients with strong interaction between KIR3DL1/HLA-Bw who received prior IFN-α therapy achieved TFR (p = 0.007), explained by the “NK cell licensing” concept, whereby NK cells become more functional through the recognition “self” HLA class I molecules by KIRs. NK cell licensing may contribute to the potential efficacy of IFN-α treatment in patients with CML. We defined high-risk molecular relapse patients and suggest that KIR3DL1/HLA-Bw status may help detect patients who could benefit from IFN-α for maintaining TFR.
{"title":"IFN-α treatment may enable discontinuation of TKIs in NK cell-licensed patients with CML-CP","authors":"Hiroshi Ureshino, Kazuharu Kamachi, Keisuke Kidoguchi, Shinya Kimura","doi":"10.1002/jha2.1053","DOIUrl":"10.1002/jha2.1053","url":null,"abstract":"<p>The magnitude of the natural killer (NK) cell response contributes to the achievement of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) and is regulated by the interaction between killer immunoglobulin-like receptors (KIRs) on NK cells and human leukocyte antigen (HLA) class I molecules on target cells. The abundant combination between <i>KIR</i> and <i>HLA</i> through genetic polymorphisms determines the functional diversity of NK cells. We previously reported that <i>KIR3DL1-HLA-Bw</i> status is associated with achievement of TFR by reflecting NK cell potential. Patients with strong interaction between <i>KIR3DL1/HLA-Bw</i> were identified as having a higher molecular relapse risk, based on the “missing self” hypothesis which suggests that the lack of cognate ligands for KIRs may induce target cell lysis. However, all the patients with strong interaction between <i>KIR3DL1/HLA-Bw</i> who received prior IFN-α therapy achieved TFR (<i>p</i> = 0.007), explained by the “NK cell licensing” concept, whereby NK cells become more functional through the recognition “self” HLA class I molecules by KIRs. NK cell licensing may contribute to the potential efficacy of IFN-α treatment in patients with CML. We defined high-risk molecular relapse patients and suggest that <i>KIR3DL1/HLA-Bw</i> status may help detect patients who could benefit from IFN-α for maintaining TFR.</p>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1278-1282"},"PeriodicalIF":0.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura Danhardt, Arnaud Wiedemann, Gerard Michel, Jean-Hugues Dalle, Fanny Rialland, Cécile Renard, Charlotte Jubert, Johan Maertens, Anne Sirvent, Nimrod Buchbinder, Christine Devalck, Bénédicte Brichard, Catherine Paillard, Stephanie Nguyen, Angelo Paci, David Combarel, Martin Castelle, Simona Pagliuca, Cecile Pochon
Context
Mucopolysaccharidosis (MPS) requires urgent treatment to prevent neurological damage. While gene therapy holds promise for effectively treating these diseases with minimal toxicity, access remains limited for most patients. Consequently, advancing allogeneic hematopoietic stem cell transplantation (HSCT) for young children is crucial. Since the 2010s, cord blood (CB) transplants with reduced-toxicity conditioning (RTC) have become the standard of care.
Patients and methods
Recent reports in France indicate a significant incidence of graft failures (GF), prompting a large-scale retrospective study from the French-speaking bone marrow transplantation society's registry, to understand GF risks, guide clinicians in selecting transplant platforms, and describe outcomes of second HSCT in young patients.
Results
This report analyses 93 children who underwent HSCT for MPS between 2000 and 2020. The GF rate was notably high (22.6% at day 100), primarily associated with the donor's HLA compatibility and the recipient's age. Well-matched CB and RTC were not found to be risk factors for GF. This study also details the procedures for second and third transplants in patients who rejected their first HSCT.
Conclusion
In the era of RTC, CB remains a viable and expedient option for MPS transplantation.
{"title":"Incidence and risk factors of graft failure in allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis in a nationwide pediatric cohort. A study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy","authors":"Laura Danhardt, Arnaud Wiedemann, Gerard Michel, Jean-Hugues Dalle, Fanny Rialland, Cécile Renard, Charlotte Jubert, Johan Maertens, Anne Sirvent, Nimrod Buchbinder, Christine Devalck, Bénédicte Brichard, Catherine Paillard, Stephanie Nguyen, Angelo Paci, David Combarel, Martin Castelle, Simona Pagliuca, Cecile Pochon","doi":"10.1002/jha2.1056","DOIUrl":"10.1002/jha2.1056","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Context</h3>\u0000 \u0000 <p>Mucopolysaccharidosis (MPS) requires urgent treatment to prevent neurological damage. While gene therapy holds promise for effectively treating these diseases with minimal toxicity, access remains limited for most patients. Consequently, advancing allogeneic hematopoietic stem cell transplantation (HSCT) for young children is crucial. Since the 2010s, cord blood (CB) transplants with reduced-toxicity conditioning (RTC) have become the standard of care.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Patients and methods</h3>\u0000 \u0000 <p>Recent reports in France indicate a significant incidence of graft failures (GF), prompting a large-scale retrospective study from the French-speaking bone marrow transplantation society's registry, to understand GF risks, guide clinicians in selecting transplant platforms, and describe outcomes of second HSCT in young patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This report analyses 93 children who underwent HSCT for MPS between 2000 and 2020. The GF rate was notably high (22.6% at day 100), primarily associated with the donor's HLA compatibility and the recipient's age. Well-matched CB and RTC were not found to be risk factors for GF. This study also details the procedures for second and third transplants in patients who rejected their first HSCT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In the era of RTC, CB remains a viable and expedient option for MPS transplantation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1295-1300"},"PeriodicalIF":0.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandrina Balanean, Samuel Baird, Brooke Dulka, Luke Jennings-Zhang, Robert N. Bone, Yolaine Jeune-Smith, Bruce Feinberg, Muhamed Baljevic
Introduction
Initially approved for the fifth-line or later therapeutic setting, the chimeric antigen receptor (CAR) T-cell regimen ciltacabtagene autoleucel (cilta-cel) was recently approved for second-line (2L) treatment in relapsed/refractory multiple myeloma (RRMM). Oncology practitioners use clinical trials to inform treatment, but real-world impressions and impact on practice are lacking. We aimed to determine whether presenting CARTITUDE-4 clinical trial data would impact real-world preferences/perceptions around CAR T-cell therapy.
Methods
Recruiting from the Cardinal Health Oncology Provider Extended Network (OPEN), we surveyed hematologists/oncologists to investigate fourth-line (4L) preferences in a hypothetical patient with triple-class–refractory MM. We posed the same questions and answers before and after the trial presentation and compared pre-/post-preferences toward cilta-cel and sequencing relative to bispecific antibodies (BsAbs). Using the same methodology as described above, we also performed a secondary analysis comparing pre-/post-perceptions on the use of CAR T-cell therapy in earlier lines for patients with triple-class–refractory MM.
Results
Among 50 respondents, decision-making factors before the trial presentation included CAR T-cell center availability (58%), comorbidities (52%), and center locations (34%). Additionally, 48% of 46 respondents chose 4L cilta-cel. Among 47, 40% wanted more real-world/long-term CAR T-cell therapy outcomes in any line, 38% wanted more 2L data, and 34% favored 2L/third-line (3L) use. After the presentation, the preference for cilta-cel doubled from 48% to 88% (p < 0.001) among 50 respondents and rose from 34% to 55% (p = 0.001) for earlier-line CAR T-cell therapy among 49. Moreover, 55% of 49 respondents preferred CAR T-cell therapy prior to BsAbs.
Discussion
We have shown that making oncology practitioners aware of trials precipitated decision-making factors and led to notable, significant shifts in future intended practice patterns. Being aware of trial data enables practitioners to make more informed decisions, tailor therapies to individual patients, and ultimately improve outcomes.
{"title":"Real-world practitioner perceptions of CARTITUDE-4 results for patients with previously treated multiple myeloma","authors":"Alexandrina Balanean, Samuel Baird, Brooke Dulka, Luke Jennings-Zhang, Robert N. Bone, Yolaine Jeune-Smith, Bruce Feinberg, Muhamed Baljevic","doi":"10.1002/jha2.1047","DOIUrl":"10.1002/jha2.1047","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Initially approved for the fifth-line or later therapeutic setting, the chimeric antigen receptor (CAR) T-cell regimen ciltacabtagene autoleucel (cilta-cel) was recently approved for second-line (2L) treatment in relapsed/refractory multiple myeloma (RRMM). Oncology practitioners use clinical trials to inform treatment, but real-world impressions and impact on practice are lacking. We aimed to determine whether presenting CARTITUDE-4 clinical trial data would impact real-world preferences/perceptions around CAR T-cell therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Recruiting from the Cardinal Health Oncology Provider Extended Network (OPEN), we surveyed hematologists/oncologists to investigate fourth-line (4L) preferences in a hypothetical patient with triple-class–refractory MM. We posed the same questions and answers before and after the trial presentation and compared pre-/post-preferences toward cilta-cel and sequencing relative to bispecific antibodies (BsAbs). Using the same methodology as described above, we also performed a secondary analysis comparing pre-/post-perceptions on the use of CAR T-cell therapy in earlier lines for patients with triple-class–refractory MM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 50 respondents, decision-making factors before the trial presentation included CAR T-cell center availability (58%), comorbidities (52%), and center locations (34%). Additionally, 48% of 46 respondents chose 4L cilta-cel. Among 47, 40% wanted more real-world/long-term CAR T-cell therapy outcomes in any line, 38% wanted more 2L data, and 34% favored 2L/third-line (3L) use. After the presentation, the preference for cilta-cel doubled from 48% to 88% (<i>p </i>< 0.001) among 50 respondents and rose from 34% to 55% (<i>p </i>= 0.001) for earlier-line CAR T-cell therapy among 49. Moreover, 55% of 49 respondents preferred CAR T-cell therapy prior to BsAbs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>We have shown that making oncology practitioners aware of trials precipitated decision-making factors and led to notable, significant shifts in future intended practice patterns. Being aware of trial data enables practitioners to make more informed decisions, tailor therapies to individual patients, and ultimately improve outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1154-1164"},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anemia is a major clinical manifestation seen in myelodysplastic syndromes (MDS). Treatment options for anemia in low-risk MDS are limited. Especially, oral medication which is uniformly effective for anemia in low-risk MDS is required. Hypoxia-inducible factor (HIF) prolyl hydroxylase (HIF-PH) inhibitors, such as daprodustat, are oral tablets effective for renal anemia. Pharmacological restoration of HIF activity by HIF-PH inhibitors may be beneficial for MDS-related anemia as well. Yet, their efficacy and safety against low-risk MDS are unclear. Here, we report two cases of low-risk MDS complicated with chronic kidney disease whose anemia responded to daprodustat treatment.
{"title":"Successful treatment of low-risk myelodysplastic syndrome-related anemia in patients with chronic kidney disease with daprodustat: A report of two cases","authors":"Hiroyoshi Kunimoto, Takayuki Sakuma, Takuma Ohashi, Mayoko Shirafuta, Hiroshi Teranaka, Hideaki Nakajima","doi":"10.1002/jha2.1057","DOIUrl":"10.1002/jha2.1057","url":null,"abstract":"<p>Anemia is a major clinical manifestation seen in myelodysplastic syndromes (MDS). Treatment options for anemia in low-risk MDS are limited. Especially, oral medication which is uniformly effective for anemia in low-risk MDS is required. Hypoxia-inducible factor (HIF) prolyl hydroxylase (HIF-PH) inhibitors, such as daprodustat, are oral tablets effective for renal anemia. Pharmacological restoration of HIF activity by HIF-PH inhibitors may be beneficial for MDS-related anemia as well. Yet, their efficacy and safety against low-risk MDS are unclear. Here, we report two cases of low-risk MDS complicated with chronic kidney disease whose anemia responded to daprodustat treatment.</p>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1335-1339"},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sickle cell disease (SCD) is characterized by acute episodes called vaso-occlusive crises (VOC). VOC is marked by severe pain due to blocked blood vessels by sickled cells. Ketamine has been reported to be effective and safe in managing VOC in SCD patients.
Objectives/methods
This review aims to determine ketamine's safety and efficacy through analysis of clinical trials and observational studies.
Methods
Adhering to PRISMA guidelines, this systematic review and meta-analysis systematically searched seven databases on May 20, 2024 for randomized control trials (RCT), cohorts, and case–control studies.
Results
Five studies with 689 participants met the inclusion criteria. A meta-analysis of two studies (518 observations) for the Numerical Rating Scale (NRS) pain score showed no significant difference, with a standardized mean difference (MD) of 0.23 (95% CI: −0.13 to 0.59, p = 0.21, I2 = 0%). For morphine milligram equivalent (MME), a meta-analysis of two studies (344 observations) resulted in an MD of −0.03 (95% CI: −0.09 to 0.04, p = 0.45, I2 = 97%). However, the side effects analysis from four studies (608 observations) showed a significantly higher relative risk (RR) of 5.74 (95% CI: 2.80–11.79, p < 0.0001, I2 = 0%) for mild side effects, including nausea, vomiting, and dizziness.
Conclusion
Ketamine qualitative synthesis shows potential for improving pain management in SCD patients during VOC, but without statistically significant differences in pain reduction. It is associated with increased mild side effects, though no severe adverse events were reported. Further research is needed to increase the sample size and power of the analysis to clarify optimal dosing and administration protocols for ketamine in this context.
{"title":"Safety and efficacy of ketamine use in patients with vaso-occlusive crisis: A systematic review and meta-analysis","authors":"Ernesto Calderon Martinez, Stephin Zachariah Saji, Thomas Campos Carmona, Vaidarshi Abbagoni, Mohammad Salman, Mishell Estefanía Llerena Vargas, Suchita Mylavarapu, Druvini Fernando, Lakshmi Sheethal Arvapalli, Nathalia Schettino Samad, Nithin Karnan, Camila Sanchez Cruz","doi":"10.1002/jha2.1050","DOIUrl":"10.1002/jha2.1050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Sickle cell disease (SCD) is characterized by acute episodes called vaso-occlusive crises (VOC). VOC is marked by severe pain due to blocked blood vessels by sickled cells. Ketamine has been reported to be effective and safe in managing VOC in SCD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives/methods</h3>\u0000 \u0000 <p>This review aims to determine ketamine's safety and efficacy through analysis of clinical trials and observational studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Adhering to PRISMA guidelines, this systematic review and meta-analysis systematically searched seven databases on May 20, 2024 for randomized control trials (RCT), cohorts, and case–control studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Five studies with 689 participants met the inclusion criteria. A meta-analysis of two studies (518 observations) for the Numerical Rating Scale (NRS) pain score showed no significant difference, with a standardized mean difference (MD) of 0.23 (95% CI: −0.13 to 0.59, <i>p</i> = 0.21, <i>I</i><sup>2</sup> = 0%). For morphine milligram equivalent (MME), a meta-analysis of two studies (344 observations) resulted in an MD of −0.03 (95% CI: −0.09 to 0.04, <i>p</i> = 0.45, <i>I</i><sup>2</sup> = 97%). However, the side effects analysis from four studies (608 observations) showed a significantly higher relative risk (RR) of 5.74 (95% CI: 2.80–11.79, <i>p</i> < 0.0001, <i>I</i><sup>2</sup> = 0%) for mild side effects, including nausea, vomiting, and dizziness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ketamine qualitative synthesis shows potential for improving pain management in SCD patients during VOC, but without statistically significant differences in pain reduction. It is associated with increased mild side effects, though no severe adverse events were reported. Further research is needed to increase the sample size and power of the analysis to clarify optimal dosing and administration protocols for ketamine in this context.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1312-1321"},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Monica Messina, Alfonso Piciocchi, Leonardo M. Siena, Stefano Soddu, Francesco Buccisano, Cristina Mecucci, Giovanni Martinelli, Antonio Curti, Roberto Cairoli, Paola Fazi, Marco Vignetti, Maria Teresa Voso, Adriano Venditti, Anna Candoni
Given the limited data on the real-life therapeutic use of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML) patients receiving FLT3 inhibitors and we collected data on the efficacy and safety of these agents. The survey results showed that in the real-life setting the response rate of the 3/7 + midostaurin regimen in newly diagnosed FLT3-mutated AML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. The discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases).
{"title":"A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real-world practice","authors":"Monica Messina, Alfonso Piciocchi, Leonardo M. Siena, Stefano Soddu, Francesco Buccisano, Cristina Mecucci, Giovanni Martinelli, Antonio Curti, Roberto Cairoli, Paola Fazi, Marco Vignetti, Maria Teresa Voso, Adriano Venditti, Anna Candoni","doi":"10.1002/jha2.1045","DOIUrl":"10.1002/jha2.1045","url":null,"abstract":"<p>Given the limited data on the real-life therapeutic use of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML) patients receiving FLT3 inhibitors and we collected data on the efficacy and safety of these agents. The survey results showed that in the real-life setting the response rate of the 3/7 + midostaurin regimen in newly diagnosed FLT3-mutated AML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. The discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases).</p>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1274-1277"},"PeriodicalIF":0.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Davidson Zhao, Musani Rumina, Mojgan Zarif, Cuihong Wei, Hong Chang
<p>To the Editor,</p><p>Secondary-type mutations (STM: <i>ASXL1</i>, <i>BCOR</i>, <i>EZH2</i>, <i>SF3B1</i>, <i>SRSF2</i>, <i>STAG2</i>, <i>U2AF1</i>, and <i>ZRSR2</i>) in acute myeloid leukemia (AML) were reported to be highly specific for secondary disease and associated with inferior event-free survival (EFS) [<span>1, 2</span>]. In light of these findings, the newly-revised 5th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5) includes STM in the criteria defining AML, myelodysplasia-related (AML-MR) [<span>3</span>]. In the newly-published International Consensus of Classification of myeloid neoplasms and acute leukemia (ICC), <i>RUNX1</i> mutation together with STM as described by WHO-HAEM5 define the entity of AML with myelodysplasia-related gene mutations [<span>4</span>]. To date, several studies have examined the impact of STM in other molecularly defined entities of AML such as <i>NPM1</i>+ AML [<span>5-9</span>]. However, the impact of STM in AML with <i>CEBPA</i> mutation has not been studied extensively and remains unclear. Thus, we sought to investigate the clinical impact of STM in AML with <i>CEBPA</i> mutation.</p><p>We conducted a retrospective analysis with a single center cohort of 38 cases of AML with <i>CEBPA</i> mutation diagnosed at our institution from 2015 to 2024. Patients were included if they met WHO-HAEM5 criteria of blasts ≥ 20% and either biallelic <i>CEBPA</i> mutation or single <i>CEBPA</i> mutation in the basic leucine zipper (bZIP) domain. Cytogenetic testing, molecular genetic testing, and variant calling in next-generation sequencing were performed according to previously described procedures [<span>10</span>]. Gene panel for targeted sequencing and exon coverage for hotspot genes are listed in Tables S1 and S2.</p><p>The baseline clinicopathological characteristics and co-mutation landscape of the study cohort are summarized in Table 1 and Figure 1A. Of the 38 patients with AML with <i>CEBPA</i> mutation, 11 (29%) had STM. <i>SRSF2</i> and <i>STAG2</i> were the most common STMs (both 8/38, 21%), followed by <i>ASXL1</i> (6/38, 16%), <i>BCOR</i> (2/38, 5%), and <i>U2AF1</i> (1/38, 3%). <i>RUNX1</i> mutations were found in two (5%) patients, both of whom had concurrent WHO-HAEM5-defined STMs. <i>EZH2</i>, <i>ZRSR2</i>, and <i>SF3B1</i> mutations were not detected. The most common recurrent (>10%) co-mutated genes in the cohort were <i>TET2</i> (10/38; 26%), <i>GATA2</i> (9/38, 24%), <i>WT1</i> (8/38, 21%), <i>NRAS</i> (6/38, 16%) and <i>FLT3</i>-ITD (4/38, 11%). Compared to patients without STM, patients with STM were older, had less proliferative disease, had lower hemoglobin levels, and had significantly lower variant allele frequency of mutant <i>CEBPA</i> and infrequent in-frame bZIP <i>CEBPA</i> mutation.</p><p>Consistent with the older age of the STM+ group, only five (46%) patients received intensive chemotherapy compared to all 27 (100%) patients in the STM-ve group. Of note,
{"title":"Impact of secondary-type mutations in acute myeloid leukemia with CEBPA mutation","authors":"Davidson Zhao, Musani Rumina, Mojgan Zarif, Cuihong Wei, Hong Chang","doi":"10.1002/jha2.1055","DOIUrl":"10.1002/jha2.1055","url":null,"abstract":"<p>To the Editor,</p><p>Secondary-type mutations (STM: <i>ASXL1</i>, <i>BCOR</i>, <i>EZH2</i>, <i>SF3B1</i>, <i>SRSF2</i>, <i>STAG2</i>, <i>U2AF1</i>, and <i>ZRSR2</i>) in acute myeloid leukemia (AML) were reported to be highly specific for secondary disease and associated with inferior event-free survival (EFS) [<span>1, 2</span>]. In light of these findings, the newly-revised 5th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5) includes STM in the criteria defining AML, myelodysplasia-related (AML-MR) [<span>3</span>]. In the newly-published International Consensus of Classification of myeloid neoplasms and acute leukemia (ICC), <i>RUNX1</i> mutation together with STM as described by WHO-HAEM5 define the entity of AML with myelodysplasia-related gene mutations [<span>4</span>]. To date, several studies have examined the impact of STM in other molecularly defined entities of AML such as <i>NPM1</i>+ AML [<span>5-9</span>]. However, the impact of STM in AML with <i>CEBPA</i> mutation has not been studied extensively and remains unclear. Thus, we sought to investigate the clinical impact of STM in AML with <i>CEBPA</i> mutation.</p><p>We conducted a retrospective analysis with a single center cohort of 38 cases of AML with <i>CEBPA</i> mutation diagnosed at our institution from 2015 to 2024. Patients were included if they met WHO-HAEM5 criteria of blasts ≥ 20% and either biallelic <i>CEBPA</i> mutation or single <i>CEBPA</i> mutation in the basic leucine zipper (bZIP) domain. Cytogenetic testing, molecular genetic testing, and variant calling in next-generation sequencing were performed according to previously described procedures [<span>10</span>]. Gene panel for targeted sequencing and exon coverage for hotspot genes are listed in Tables S1 and S2.</p><p>The baseline clinicopathological characteristics and co-mutation landscape of the study cohort are summarized in Table 1 and Figure 1A. Of the 38 patients with AML with <i>CEBPA</i> mutation, 11 (29%) had STM. <i>SRSF2</i> and <i>STAG2</i> were the most common STMs (both 8/38, 21%), followed by <i>ASXL1</i> (6/38, 16%), <i>BCOR</i> (2/38, 5%), and <i>U2AF1</i> (1/38, 3%). <i>RUNX1</i> mutations were found in two (5%) patients, both of whom had concurrent WHO-HAEM5-defined STMs. <i>EZH2</i>, <i>ZRSR2</i>, and <i>SF3B1</i> mutations were not detected. The most common recurrent (>10%) co-mutated genes in the cohort were <i>TET2</i> (10/38; 26%), <i>GATA2</i> (9/38, 24%), <i>WT1</i> (8/38, 21%), <i>NRAS</i> (6/38, 16%) and <i>FLT3</i>-ITD (4/38, 11%). Compared to patients without STM, patients with STM were older, had less proliferative disease, had lower hemoglobin levels, and had significantly lower variant allele frequency of mutant <i>CEBPA</i> and infrequent in-frame bZIP <i>CEBPA</i> mutation.</p><p>Consistent with the older age of the STM+ group, only five (46%) patients received intensive chemotherapy compared to all 27 (100%) patients in the STM-ve group. Of note,","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1370-1372"},"PeriodicalIF":0.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kerrie Sweeney, Aaron Niblock, Diana Greenfield, John Snowden
Advances in myeloma have resulted in improved prognosis for patients. However complications of the disease and treatment, pose a risk of specific long-term consequences. An audit tool was adapted to assess adherence to the British Society for Haematology guidelines for screening and management of long-term myeloma consequences. Thereafter a screening checklist was developed to prompt the implementation of guideline recommendations, followed by a re-audit evaluating the effectiveness of the checklist.
Good baseline practice was identified relating to vaccinations, herpes prophylaxis, dental assessment, bisphosphonates, calcium/ vitamin D supplementation and holistic needs assessments. However gaps in practice included monitoring of lipids, HBA1C, NT-pro-BNP/ BNP, BMI, calcium/ vitamin D and parathyroid hormone in kidney disease, endocrine screening and geriatric assessments. Re-audit demonstrated that geriatric assessment remains a gap in practice, however other standards now scored between 80 to 100% compliance, highlighting the benefits of a screening checklist, to increase adherence to recommendations.
{"title":"Immediate improvement in patient care: Auditing adherence to the British Society for Haematology guidelines on screening and management of the long-term consequences of multiple myeloma and treatment","authors":"Kerrie Sweeney, Aaron Niblock, Diana Greenfield, John Snowden","doi":"10.1002/jha2.999","DOIUrl":"10.1002/jha2.999","url":null,"abstract":"<p>Advances in myeloma have resulted in improved prognosis for patients. However complications of the disease and treatment, pose a risk of specific long-term consequences. An audit tool was adapted to assess adherence to the British Society for Haematology guidelines for screening and management of long-term myeloma consequences. Thereafter a screening checklist was developed to prompt the implementation of guideline recommendations, followed by a re-audit evaluating the effectiveness of the checklist.</p><p>Good baseline practice was identified relating to vaccinations, herpes prophylaxis, dental assessment, bisphosphonates, calcium/ vitamin D supplementation and holistic needs assessments. However gaps in practice included monitoring of lipids, HBA1C, NT-pro-BNP/ BNP, BMI, calcium/ vitamin D and parathyroid hormone in kidney disease, endocrine screening and geriatric assessments. Re-audit demonstrated that geriatric assessment remains a gap in practice, however other standards now scored between 80 to 100% compliance, highlighting the benefits of a screening checklist, to increase adherence to recommendations.</p>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1359-1362"},"PeriodicalIF":0.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients.
Methods
We analyzed expression levels of 770 neuroinflammation-related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the “recurrence group (RG)” or “non-recurrence group (NRG)” were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (n = 30).
Results
Forty-five of 770 NFR genes were highly expressed in the RG (3-year overall survival (OS, 22.2%), compared with the NRG group (3-year OS 66.7%). Signatures related to glial cells were enriched in the RG-associated gene set. Multivariate analysis revealed that high expressions of TUBB4A (p = 0.028, HR: 3.88), S100B (p = 0.046, HR: 3.093), and SLC6A1 (p = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells.
Conclusion
These data suggest that TME-related genes play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. TME targeting, especially glial cell-specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.
{"title":"Association between microenvironment-related genes and prognosis of primary central nervous system lymphoma","authors":"Keiichiro Hattori, Kenichi Makishima, Sakurako Suma, Yoshiaki Abe, Yasuhito Suehara, Tatsuhiro Sakamoto, Naoki Kurita, Ryota Ishii, Ryota Matsuoka, Masahide Matsuda, Takao Tsurubuchi, Ryo Nishikawa, Shota Tanaka, Akitake Mukasa, Yoshitaka Narita, Koichi Ichimura, Motoo Nagane, Shingo Takano, Bryan J. Mathis, Eiichi Ishikawa, Daisuke Matsubara, Shigeru Chiba, Mamiko Sakata-Yanagimoto","doi":"10.1002/jha2.1046","DOIUrl":"10.1002/jha2.1046","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed expression levels of 770 neuroinflammation-related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the “recurrence group (RG)” or “non-recurrence group (NRG)” were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (<i>n</i> = 30).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Forty-five of 770 NFR genes were highly expressed in the RG (3-year overall survival (OS, 22.2%), compared with the NRG group (3-year OS 66.7%). Signatures related to glial cells were enriched in the RG-associated gene set. Multivariate analysis revealed that high expressions of <i>TUBB4A</i> (<i>p</i> = 0.028, HR: 3.88), <i>S100B</i> (<i>p</i> = 0.046, HR: 3.093), and <i>SLC6A1</i> (<i>p</i> = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data suggest that TME-related genes play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. TME targeting, especially glial cell-specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1201-1214"},"PeriodicalIF":0.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joachim Baech, Tarec Christoffer El-Galaly, Joshua P. Entrop, Ingrid Glimelius, Daniel Molin, Sissel Johanne Godtfredsen, Michael J. Crowther, Karin E. Smedby, Sandra Eloranta, Caroline E. Dietrich
Introduction
Congestive heart failure (CHF) is a known complication after anthracyclines and radiotherapy for classical Hodgkin lymphoma (cHL). Contemporary cHL treatment may be associated with less risk because radiotherapy use and techniques have changed substantially over time.
Methods
In this study, Swedish cHL patients diagnosed in 2000–2018, and treated with adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), were matched 1:10 to the general population on birth year and sex to investigate relative rates and cumulative risks of CHF.
Results
A total of 1994 cHL patients were included, with a median age of 34 years. The median follow-up was 8.1 years. The CHF rate was higher for patients versus comparators (adjusted hazard ratio [HR] = 3.02, 95% confidence interval [CI]: 2.26–4.02). Patients treated with ≤200 mg/m2 of anthracyclines had HR of 2.89 (95% CI: 1.51–3.47) versus 3.91 (95% CI: 2.72–5.60) for >200 mg/m2. Treatment with ABVD was associated with a significantly higher CHF rate (adjusted HR = 3.25, 95% CI: 2.31–4.23), while BEACOPP was not (adjusted HR = 1.95, 95% CI: 0.91–4.16). The increase in relative rates translated to the absolute scale, with an increased risk persisting up to 18 years for low cumulative doses.
Conclusion
These findings highlight that cHL survivors still face a substantial excess risk of CHF in the modern treatment era and that focus on cardiovascular health remains relevant.
{"title":"Congestive heart failure after anthracycline-containing treatment for Hodgkin lymphoma: A Swedish matched cohort study","authors":"Joachim Baech, Tarec Christoffer El-Galaly, Joshua P. Entrop, Ingrid Glimelius, Daniel Molin, Sissel Johanne Godtfredsen, Michael J. Crowther, Karin E. Smedby, Sandra Eloranta, Caroline E. Dietrich","doi":"10.1002/jha2.1048","DOIUrl":"10.1002/jha2.1048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Congestive heart failure (CHF) is a known complication after anthracyclines and radiotherapy for classical Hodgkin lymphoma (cHL). Contemporary cHL treatment may be associated with less risk because radiotherapy use and techniques have changed substantially over time.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, Swedish cHL patients diagnosed in 2000–2018, and treated with adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), were matched 1:10 to the general population on birth year and sex to investigate relative rates and cumulative risks of CHF.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 1994 cHL patients were included, with a median age of 34 years. The median follow-up was 8.1 years. The CHF rate was higher for patients versus comparators (adjusted hazard ratio [HR] = 3.02, 95% confidence interval [CI]: 2.26–4.02). Patients treated with ≤200 mg/m<sup>2</sup> of anthracyclines had HR of 2.89 (95% CI: 1.51–3.47) versus 3.91 (95% CI: 2.72–5.60) for >200 mg/m<sup>2</sup>. Treatment with ABVD was associated with a significantly higher CHF rate (adjusted HR = 3.25, 95% CI: 2.31–4.23), while BEACOPP was not (adjusted HR = 1.95, 95% CI: 0.91–4.16). The increase in relative rates translated to the absolute scale, with an increased risk persisting up to 18 years for low cumulative doses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings highlight that cHL survivors still face a substantial excess risk of CHF in the modern treatment era and that focus on cardiovascular health remains relevant.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1190-1200"},"PeriodicalIF":0.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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