<p>A recent study—ASC4FIRST<span><sup>1</sup></span>—builds the case that the novel drug, asciminib, a BCR::ABL1 inhibitor, is superior to current tyrosine kinase inhibitors (TKIs) for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). Some have even taken to social media to announce a post-imatinib era.</p><p>As the first TKI to be approved in oncology, imatinib has been a transformative oral anti-cancer drug, improving survival for patients with CP CML. Imatinib, and subsequent drugs—dasatinib, bosutinib, and nilotinib—have increased the life expectancy of patients diagnosed with CML to essentially the same length as the general population without CML.<span><sup>2</sup></span></p><p>Will asciminib further improve upon existing TKIs? We consider this alongside three questions raised by the ASC4FIRST trial: does it establish superiority over second-generation TKIs (dasatinib, bosutinib, and nilotinib), does the improvement in major molecular milestones mean the drug will improve survival or quality of life, and what can we conclude about adverse effects in this open-label study?</p><p>A primary concern with the ASC4FIRST trial is its approach to comparing asciminib with other TKIs, as a combined entity. The trial's design included two primary comparisons: asciminib versus all TKIs (a combined group of imatinib and second-generation TKIs) and asciminib versus imatinib alone. However, a direct comparison between asciminib and second-generation TKIs was relegated to a “secondary objective” and “not compared […] as a primary objective.” This design choice raises critical questions about the validity and clinical relevance of the findings.</p><p>Combining imatinib and second-generation TKIs into a single control group undermines the distinct therapeutic profiles and efficacy of these drugs. It is well-established that second-generation TKIs, such as dasatinib and nilotinib, outperform imatinib in achieving significant molecular responses in CML patients.<span><sup>3</sup></span> By lumping these agents together, the trial essentially sets up a comparison that is guaranteed to favor asciminib. This strategy, which we have called the use of “nested groups” as opposed to “adjacent groups,” is a common tactic in clinical trials which creates confusion about precisely which groups benefit or which comparisons are significant.<span><sup>4, 5</sup></span> In this case it lacks clinical justification and can mislead stakeholders about the true efficacy of the investigational drug.</p><p>In the ASC4FIRST trial, the difference in the 48-week major molecular response (MMR) between asciminib and the combined TKI group (a nested group) was significant. Yet, the more relevant comparison—asciminib versus second-generation TKIs (omitting imatinib, an adjacent subgroup)—revealed no significant difference (66.0% vs. 57.8%, respectively).<span><sup>1</sup></span> This finding is crucial because it highlights that asciminib may not offer a substantial im
{"title":"Imatinib remains the best frontline therapy in patients with chronic myeloid leukemia: Critical analysis of the ASC4FIRST trial","authors":"Nethra Srinivasan, Timothée Olivier, Alyson Haslam, Vinay Prasad","doi":"10.1002/ajh.27477","DOIUrl":"10.1002/ajh.27477","url":null,"abstract":"<p>A recent study—ASC4FIRST<span><sup>1</sup></span>—builds the case that the novel drug, asciminib, a BCR::ABL1 inhibitor, is superior to current tyrosine kinase inhibitors (TKIs) for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). Some have even taken to social media to announce a post-imatinib era.</p><p>As the first TKI to be approved in oncology, imatinib has been a transformative oral anti-cancer drug, improving survival for patients with CP CML. Imatinib, and subsequent drugs—dasatinib, bosutinib, and nilotinib—have increased the life expectancy of patients diagnosed with CML to essentially the same length as the general population without CML.<span><sup>2</sup></span></p><p>Will asciminib further improve upon existing TKIs? We consider this alongside three questions raised by the ASC4FIRST trial: does it establish superiority over second-generation TKIs (dasatinib, bosutinib, and nilotinib), does the improvement in major molecular milestones mean the drug will improve survival or quality of life, and what can we conclude about adverse effects in this open-label study?</p><p>A primary concern with the ASC4FIRST trial is its approach to comparing asciminib with other TKIs, as a combined entity. The trial's design included two primary comparisons: asciminib versus all TKIs (a combined group of imatinib and second-generation TKIs) and asciminib versus imatinib alone. However, a direct comparison between asciminib and second-generation TKIs was relegated to a “secondary objective” and “not compared […] as a primary objective.” This design choice raises critical questions about the validity and clinical relevance of the findings.</p><p>Combining imatinib and second-generation TKIs into a single control group undermines the distinct therapeutic profiles and efficacy of these drugs. It is well-established that second-generation TKIs, such as dasatinib and nilotinib, outperform imatinib in achieving significant molecular responses in CML patients.<span><sup>3</sup></span> By lumping these agents together, the trial essentially sets up a comparison that is guaranteed to favor asciminib. This strategy, which we have called the use of “nested groups” as opposed to “adjacent groups,” is a common tactic in clinical trials which creates confusion about precisely which groups benefit or which comparisons are significant.<span><sup>4, 5</sup></span> In this case it lacks clinical justification and can mislead stakeholders about the true efficacy of the investigational drug.</p><p>In the ASC4FIRST trial, the difference in the 48-week major molecular response (MMR) between asciminib and the combined TKI group (a nested group) was significant. Yet, the more relevant comparison—asciminib versus second-generation TKIs (omitting imatinib, an adjacent subgroup)—revealed no significant difference (66.0% vs. 57.8%, respectively).<span><sup>1</sup></span> This finding is crucial because it highlights that asciminib may not offer a substantial im","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 12","pages":"2392-2394"},"PeriodicalIF":10.1,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27477","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Peripheral blood smear reveals human granulocytic anaplasmosis, a rare cause of hemophagocytic lymphohistiocytosis","authors":"Charlotte M. Story, Shruti Chaturvedi","doi":"10.1002/ajh.27485","DOIUrl":"https://doi.org/10.1002/ajh.27485","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"46 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ayalew Tefferi, Saubia Fathima, Ali Khalid A. Alsugair, Fnu Aperna, Anuya Natu, Maymona G. Abdelmagid, Clifford M. Csizmar, Mark Gurney, Terra L. Lasho, Christy M. Finke, Abhishek A. Mangaonkar, Aref Al-Kali, Animesh Pardanani, Kaaren K. Reichard, Rong He, Naseema Gangat, Mrinal M. Patnaik
The current study was inspired by observations from exploratory analyses of an institutional cohort with chronic myelomonocytic leukemia (CMML; N = 398) that revealed no instances of blast transformation in the seven patients with plant homeodomain finger protein 6 (PHF6) mutation (PHF6MUT). A subsequent Mayo Clinic enterprise-wide database search identified 28 more cases with PHF6MUT. Compared with their wild-type PHF6 counterparts (PHF6WT; N = 391), PHF6MUT cases (N = 35) were more likely to co-express TET2 (89% vs. 45%; p < .01), RUNX1 (29% vs. 14%; p = .03), CBL (14% vs. 2%; p < .01), and U2AF1 (17% vs. 6%; p = .04) and less likely SRSF2 (23% vs. 45%; p < .01) mutation. They were also more likely to display loss of Y chromosome (LoY; 21% vs. 2%; p < .01) and platelets <100 × 109/L (83% vs. 51%; p < .01). Multivariable analysis identified PHF6MUT (HR 0.28, 95% CI 0.15–0.50) and DNMT3AMUT (HR 5.8, 95% CI 3.3–10.5) as the strongest molecular predictors of overall survival. The same was true for blast transformation-free survival with corresponding HR (95% CI) of 0.08 (0.01–0.6) and 9.5 (3.8–23.5). At median 20 months follow-up, blast transformation was documented in none of the 33 patients with PHF6MUT/DNMT3AWT but in 6 (32%) of 19 with DNMT3AMUT and 74 (20%) of 374 with PHF6WT/DNMT3AWT (p < .01). The specific molecular signatures sustained their significant predictive performance in the context of the CMML-specific molecular prognostic model (CPSS-mol). PHF6MUT identifies a unique subset of patients with CMML characterized by thrombocytopenia, higher prevalence of LoY, and superior prognosis.
{"title":"PHF6 mutations in chronic myelomonocytic leukemia identify a unique subset of patients with distinct phenotype and superior prognosis","authors":"Ayalew Tefferi, Saubia Fathima, Ali Khalid A. Alsugair, Fnu Aperna, Anuya Natu, Maymona G. Abdelmagid, Clifford M. Csizmar, Mark Gurney, Terra L. Lasho, Christy M. Finke, Abhishek A. Mangaonkar, Aref Al-Kali, Animesh Pardanani, Kaaren K. Reichard, Rong He, Naseema Gangat, Mrinal M. Patnaik","doi":"10.1002/ajh.27492","DOIUrl":"10.1002/ajh.27492","url":null,"abstract":"<p>The current study was inspired by observations from exploratory analyses of an institutional cohort with chronic myelomonocytic leukemia (CMML; <i>N</i> = 398) that revealed no instances of blast transformation in the seven patients with plant homeodomain finger protein 6 (<i>PHF6</i>) mutation (<i>PHF6</i><sup>MUT</sup>). A subsequent Mayo Clinic enterprise-wide database search identified 28 more cases with <i>PHF6</i><sup>MUT</sup>. Compared with their wild-type <i>PHF6</i> counterparts (<i>PHF6</i><sup>WT</sup>; <i>N</i> = 391), <i>PHF6</i><sup>MUT</sup> cases (<i>N</i> = 35) were more likely to co-express <i>TET2</i> (89% vs. 45%; <i>p</i> < .01), <i>RUNX1</i> (29% vs. 14%; <i>p</i> = .03), <i>CBL</i> (14% vs. 2%; <i>p</i> < .01), and <i>U2AF1</i> (17% vs. 6%; <i>p</i> = .04) and less likely <i>SRSF2</i> (23% vs. 45%; <i>p</i> < .01) mutation. They were also more likely to display loss of Y chromosome (LoY; 21% vs. 2%; <i>p</i> < .01) and platelets <100 × 10<sup>9</sup>/L (83% vs. 51%; <i>p</i> < .01). Multivariable analysis identified <i>PHF6</i><sup>MUT</sup> (HR 0.28, 95% CI 0.15–0.50) and <i>DNMT3A</i><sup>MUT</sup> (HR 5.8, 95% CI 3.3–10.5) as the strongest molecular predictors of overall survival. The same was true for blast transformation-free survival with corresponding HR (95% CI) of 0.08 (0.01–0.6) and 9.5 (3.8–23.5). At median 20 months follow-up, blast transformation was documented in none of the 33 patients with <i>PHF6</i><sup>MUT</sup>/<i>DNMT3A</i><sup>WT</sup> but in 6 (32%) of 19 with <i>DNMT3A</i><sup>MUT</sup> and 74 (20%) of 374 with <i>PHF6</i><sup>WT</sup>/<i>DNMT3A</i><sup>WT</sup> (<i>p</i> < .01). The specific molecular signatures sustained their significant predictive performance in the context of the CMML-specific molecular prognostic model (CPSS-mol). <i>PHF6</i><sup>MUT</sup> identifies a unique subset of patients with CMML characterized by thrombocytopenia, higher prevalence of LoY, and superior prognosis.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 12","pages":"2321-2327"},"PeriodicalIF":10.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27492","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexander A. Boucher, Vanessa J. Dayton, Annaliisa R. Pratt, Nicolas N. Nassar, Yasmin Elgammal, Theodosia A. Kalfa
CONFLICT OF INTEREST STATEMENT
The authors have no competing conflicts of interests to declare.
利益冲突声明作者没有需要声明的利益冲突。
{"title":"Three-generation female cohort with macrocytic anemia and iron overload","authors":"Alexander A. Boucher, Vanessa J. Dayton, Annaliisa R. Pratt, Nicolas N. Nassar, Yasmin Elgammal, Theodosia A. Kalfa","doi":"10.1002/ajh.27489","DOIUrl":"https://doi.org/10.1002/ajh.27489","url":null,"abstract":"<h2> CONFLICT OF INTEREST STATEMENT</h2>\u0000<p>The authors have no competing conflicts of interests to declare.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"35 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeremy W. Jacobs, Garrett S. Booth, Sheharyar Raza, Landon M. Clark, Ross M. Fasano, Eleni Gavriilaki, Elizabeth A. Abels, Thomas C. Binns, Miriam Andrea Duque, Zoe K. McQuilten, María Eva Mingot-Castellano, Bipin N. Savani, Deva Sharma, Minh-Ha Tran, Christopher A. Tormey, Kenneth J. Moise Jr, Evan M. Bloch, Brian D. Adkins
The neonatal fragment crystallizable (Fc) receptor (FcRn) transports IgG across mucosal surfaces and the placenta and protects IgG from degradation. Numerous clinical trials are investigating therapeutic FcRn inhibition for various immune-mediated neuromuscular and rheumatologic conditions; however, FcRn inhibition also represents a potential therapy for IgG-mediated hematologic conditions (e.g., immune thrombocytopenia, autoimmune hemolytic anemia, immune thrombotic thrombocytopenic purpura, acquired hemophilia, red blood cell/platelet alloimmunization). Current evidence derived from both in vitro and in vivo studies suggests that FcRn inhibitors effectively reduce total IgG levels without impacting its production or altering the levels of other immunoglobulin isotypes. Moreover, the risk of serious adverse events, including serious infections, appears to be lower than that seen with other commonly used immunomodulatory/immunosuppressive therapies, albeit in the setting of limited clinical trial data. Ultimately, additional clinical trials that include varied patient populations are required prior to incorporating these agents into standard treatment algorithms for most hematologic conditions. However, based on the pathophysiology of IgG-mediated hematologic disorders and the mechanism of action of FcRn inhibitors, these agents may represent a future novel therapeutic strategy for patients with hematologic conditions caused by IgG antibodies.
{"title":"Current state and potential applications of neonatal Fc receptor (FcRn) inhibitors in hematologic conditions","authors":"Jeremy W. Jacobs, Garrett S. Booth, Sheharyar Raza, Landon M. Clark, Ross M. Fasano, Eleni Gavriilaki, Elizabeth A. Abels, Thomas C. Binns, Miriam Andrea Duque, Zoe K. McQuilten, María Eva Mingot-Castellano, Bipin N. Savani, Deva Sharma, Minh-Ha Tran, Christopher A. Tormey, Kenneth J. Moise Jr, Evan M. Bloch, Brian D. Adkins","doi":"10.1002/ajh.27487","DOIUrl":"10.1002/ajh.27487","url":null,"abstract":"<p>The neonatal fragment crystallizable (Fc) receptor (FcRn) transports IgG across mucosal surfaces and the placenta and protects IgG from degradation. Numerous clinical trials are investigating therapeutic FcRn inhibition for various immune-mediated neuromuscular and rheumatologic conditions; however, FcRn inhibition also represents a potential therapy for IgG-mediated hematologic conditions (e.g., immune thrombocytopenia, autoimmune hemolytic anemia, immune thrombotic thrombocytopenic purpura, acquired hemophilia, red blood cell/platelet alloimmunization). Current evidence derived from both in vitro and in vivo studies suggests that FcRn inhibitors effectively reduce total IgG levels without impacting its production or altering the levels of other immunoglobulin isotypes. Moreover, the risk of serious adverse events, including serious infections, appears to be lower than that seen with other commonly used immunomodulatory/immunosuppressive therapies, albeit in the setting of limited clinical trial data. Ultimately, additional clinical trials that include varied patient populations are required prior to incorporating these agents into standard treatment algorithms for most hematologic conditions. However, based on the pathophysiology of IgG-mediated hematologic disorders and the mechanism of action of FcRn inhibitors, these agents may represent a future novel therapeutic strategy for patients with hematologic conditions caused by IgG antibodies.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 12","pages":"2351-2366"},"PeriodicalIF":10.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27487","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Measurable residual disease (MRD) is strongly associated with risk of relapse and long-term survival outcomes in patients with acute myeloid leukemia (AML). Apart from its clear prognostic impact, MRD information is also increasingly used to guide therapeutic decision-making, including selection of appropriate patients for stem cell transplant, use of post-transplant maintenance, and candidacy for non-transplant maintenance therapies or MRD-directed clinical trials. While much progress has been made in accurately assessing MRD and understanding its clinical importance, many questions remain about how to optimize MRD testing and guide treatment decisions for individual patients. In this review, we discuss the common methods to assess MRD in AML and the prognostic impact of MRD across common clinical scenarios. We also review emerging and investigational strategies to target MRD and discuss some of the important unanswered questions and challenges in the field.
{"title":"Measurable residual disease monitoring in AML: Prospects for therapeutic decision-making and new drug development","authors":"Nicholas J. Short, Richard Dillon","doi":"10.1002/ajh.27482","DOIUrl":"https://doi.org/10.1002/ajh.27482","url":null,"abstract":"Measurable residual disease (MRD) is strongly associated with risk of relapse and long-term survival outcomes in patients with acute myeloid leukemia (AML). Apart from its clear prognostic impact, MRD information is also increasingly used to guide therapeutic decision-making, including selection of appropriate patients for stem cell transplant, use of post-transplant maintenance, and candidacy for non-transplant maintenance therapies or MRD-directed clinical trials. While much progress has been made in accurately assessing MRD and understanding its clinical importance, many questions remain about how to optimize MRD testing and guide treatment decisions for individual patients. In this review, we discuss the common methods to assess MRD in AML and the prognostic impact of MRD across common clinical scenarios. We also review emerging and investigational strategies to target MRD and discuss some of the important unanswered questions and challenges in the field.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"31 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Delafoy, J. H. Dalle, C. Pondarre, G. P. Andrieu, M. Fahd, K. Yakouben, M. Castelle, B. Koehl, B. Neven, A. Grain, for the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire
<p>While emerging therapies such as gene therapy are being explored, allogenic hematopoietic stem cell transplantation (HSCT) remains the most established curative treatment for sickle cell anemia (SCA). Yet its application is limited by toxicity risks, donor availability, and socioeconomic factors. In pediatric cases, myeloablative HSCT from an HLA-matched related donor (HLA-MRD), following either Busulfan or Treosulfan-based conditioning regimen yields SCA-free survival rates surpassing 90%, along with minimal occurrences of graft-versus-host disease (GVHD).<span><sup>1-4</sup></span> However, the optimal timing of transplantation remains debated due to concerns about fertility impairment, incidence of GVHD and transplant-related mortality at older ages.<span><sup>2</sup></span> While current literature suggests that outcomes generally improve with younger age (10–16 years), extensive toxicities associated with HSCT in SCA are not well-characterized. This analysis, aims to address this gap by providing a comprehensive assessment of acute toxicities associated with pediatric HSCT from HLA-MRD in the treatment of SCA, with a comparison between two age groups.</p><p>This study included 97 SCA patients under 18 years of age who underwent HLA-MRD transplantation following myeloablative conditioning (MAC) regimen with antithymocyte globulin (ATG) between January 2005 and December 2019. Of these, 78 patients were under 13 years old, while 19 were aged 13–18 years. Median age at transplantation was 9 years [6; 12]. Patient and transplant characteristics are detailed in Table 1. The primary indications for HSCT were recurrent vaso-occlusive events, acute chest syndrome, and cerebral vasculopathy. Before transplantation, patients aged 13–18 years exhibited higher incidence of bacterial infections (68% vs. 35%, <i>p</i> = .01). All patients received a MAC regimen, based on IV busulfan (16 mg/kg, adjusted to drug monitoring when available with a targeted AUC of 900–1300 μmol min/L), combined with either cyclophosphamide (<i>n</i> = 91, total dose of 200 mg/kg) or fludarabine (<i>n</i> = 6, total dose of 160 mg/m<sup>2</sup>). In vivo T-cell depletion was achieved using rabbit ATG (total dose of 20 mg/kg). Cyclosporin A (CSA) was used for GVHD prophylaxis alone (<i>n</i> = 7), or combined with methotrexate (<i>n</i> = 58) or mycophenolate mofetil (<i>n</i> = 28) (conditioning regimens are detailed in Table S1). Bone marrow (BM) was the primary stem cell source (<i>n</i> = 84), while cord blood was exclusively used in patients below 13 years (<i>p</i> = .07), either as a unique source (<i>n</i> = 13, 17%) or in combination with BM (<i>n</i> = 7, 9%). The median infused CD34+ cell count was significantly higher in patients under 13 years (6.0 × 10<sup>6</sup> CD34<sup>+</sup>/kg [3; 8] vs. 4.5 × 10<sup>6</sup> CD34<sup>+</sup>/kg [3; 5], <i>p</i> = .034).</p><p>All patients achieved engraftment, and no cases of secondary rejection or recurrence of SCA symptom
{"title":"Assessing acute toxicity profiles of HLA-identical hematopoietic stem cell transplantation in pediatric patients with sickle cell anemia: A comprehensive analysis on behalf of the SFGM-TC","authors":"M. Delafoy, J. H. Dalle, C. Pondarre, G. P. Andrieu, M. Fahd, K. Yakouben, M. Castelle, B. Koehl, B. Neven, A. Grain, for the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire","doi":"10.1002/ajh.27486","DOIUrl":"10.1002/ajh.27486","url":null,"abstract":"<p>While emerging therapies such as gene therapy are being explored, allogenic hematopoietic stem cell transplantation (HSCT) remains the most established curative treatment for sickle cell anemia (SCA). Yet its application is limited by toxicity risks, donor availability, and socioeconomic factors. In pediatric cases, myeloablative HSCT from an HLA-matched related donor (HLA-MRD), following either Busulfan or Treosulfan-based conditioning regimen yields SCA-free survival rates surpassing 90%, along with minimal occurrences of graft-versus-host disease (GVHD).<span><sup>1-4</sup></span> However, the optimal timing of transplantation remains debated due to concerns about fertility impairment, incidence of GVHD and transplant-related mortality at older ages.<span><sup>2</sup></span> While current literature suggests that outcomes generally improve with younger age (10–16 years), extensive toxicities associated with HSCT in SCA are not well-characterized. This analysis, aims to address this gap by providing a comprehensive assessment of acute toxicities associated with pediatric HSCT from HLA-MRD in the treatment of SCA, with a comparison between two age groups.</p><p>This study included 97 SCA patients under 18 years of age who underwent HLA-MRD transplantation following myeloablative conditioning (MAC) regimen with antithymocyte globulin (ATG) between January 2005 and December 2019. Of these, 78 patients were under 13 years old, while 19 were aged 13–18 years. Median age at transplantation was 9 years [6; 12]. Patient and transplant characteristics are detailed in Table 1. The primary indications for HSCT were recurrent vaso-occlusive events, acute chest syndrome, and cerebral vasculopathy. Before transplantation, patients aged 13–18 years exhibited higher incidence of bacterial infections (68% vs. 35%, <i>p</i> = .01). All patients received a MAC regimen, based on IV busulfan (16 mg/kg, adjusted to drug monitoring when available with a targeted AUC of 900–1300 μmol min/L), combined with either cyclophosphamide (<i>n</i> = 91, total dose of 200 mg/kg) or fludarabine (<i>n</i> = 6, total dose of 160 mg/m<sup>2</sup>). In vivo T-cell depletion was achieved using rabbit ATG (total dose of 20 mg/kg). Cyclosporin A (CSA) was used for GVHD prophylaxis alone (<i>n</i> = 7), or combined with methotrexate (<i>n</i> = 58) or mycophenolate mofetil (<i>n</i> = 28) (conditioning regimens are detailed in Table S1). Bone marrow (BM) was the primary stem cell source (<i>n</i> = 84), while cord blood was exclusively used in patients below 13 years (<i>p</i> = .07), either as a unique source (<i>n</i> = 13, 17%) or in combination with BM (<i>n</i> = 7, 9%). The median infused CD34+ cell count was significantly higher in patients under 13 years (6.0 × 10<sup>6</sup> CD34<sup>+</sup>/kg [3; 8] vs. 4.5 × 10<sup>6</sup> CD34<sup>+</sup>/kg [3; 5], <i>p</i> = .034).</p><p>All patients achieved engraftment, and no cases of secondary rejection or recurrence of SCA symptom","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 12","pages":"2406-2410"},"PeriodicalIF":10.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27486","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dragan Jevremovic, Min Shi, Pedro Horna, Gregory E. Otteson, Michael M. Timm, Shannon A. Bennett, Linda B. Baughn, Patricia T. Greipp, Wilson I. Gonsalves, Prashant Kapoor, Morie A. Gertz, Moritz Binder, Francis K. Buadi, Angela Dispenzieri, Taxiarchis Kourelis, Eli Muchtar, Jiehao Zhou, S. Vincent Rajkumar, Shaji K. Kumar, Horatiu Olteanu
<p>Two recent decisions by the Food and Drug Administration will likely significantly impact testing for multiple myeloma (MM) minimal residual disease (MRD). First, on April 12, 2024, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted to approve the use of MRD as an end point for accelerated approval of new treatments for patients with MM.<span><sup>1</sup></span> This was a result of near 10 years effort by multiple institutions, professional societies, and patient's advocacy groups,<span><sup>2-6</sup></span> and reflects the current state of MM treatment in which new therapeutic options have dramatically improved progression-free and overall survival (PFS and OS),<span><sup>7</sup></span> making them impractical as the only clinical trial endpoints. Second, after many years of deliberations, FDA announced on April 29, 2024 that it will start overseeing laboratory developed tests (LDTs).<span><sup>8</sup></span> LDTs are in vitro diagnostic products (IVDs) intended for clinical use; they are designed and validated for use within individual laboratories certified for performing high complexity testing under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The FDA's decision is currently being challenged by the American Clinical Laboratory Association.</p><p>The most commonly used assays for MRD detection in plasma cell neoplasms are next-generation sequencing (NGS) of the rearranged variable immunoglobulin heavy chain<span><sup>9, 10</sup></span> and high sensitivity flow cytometry immunophenotyping (next-generation flow, NGF).<span><sup>11-14</sup></span> Each type of assay has its advantages and disadvantages. For example, NGS requires knowledge of the diagnostic specimen for sequence comparison, but that knowledge enables higher sensitivity (10<sup>−6</sup>). NGF, as developed by the Euroflow/Spanish flow cytometry experts and commercialized by Cytognos requires no prior diagnostic specimen and can provide information regarding quality of the specimen (hemodilution); the sensitivity of the NGF is between 10<sup>−5</sup> and 2 × 10<sup>−6</sup>, depending on the number of cells (events) collected. In 2016, the International Myeloma Working Group established the minimum sensitivity of 10<sup>−5</sup> for MM MRD testing.<span><sup>4</sup></span></p><p>Currently the only FDA-approved test for MM MRD is NGS-based clonoSEQ® by Adaptive Biotechnologies.<span><sup>9</sup></span> For the NGF method to be FDA-approved, it will require a comprehensive package submission to the FDA, either as Premarket Approval (PMA) application or a Premarket Notification 510(k). However, FDA has a category of investigational device exemption (IDE) which allows a test to be used in a clinical study to collect safety and effectiveness data. There is limited data available regarding the requirements for FDA IDE approval of a flow cytometry assay for MRD testing.</p><p>In our laboratory, we adopted and validated the NGF method as an LDT, and have, sin
{"title":"FDA IDE validation of multiple myeloma MRD test by flow cytometry","authors":"Dragan Jevremovic, Min Shi, Pedro Horna, Gregory E. Otteson, Michael M. Timm, Shannon A. Bennett, Linda B. Baughn, Patricia T. Greipp, Wilson I. Gonsalves, Prashant Kapoor, Morie A. Gertz, Moritz Binder, Francis K. Buadi, Angela Dispenzieri, Taxiarchis Kourelis, Eli Muchtar, Jiehao Zhou, S. Vincent Rajkumar, Shaji K. Kumar, Horatiu Olteanu","doi":"10.1002/ajh.27484","DOIUrl":"10.1002/ajh.27484","url":null,"abstract":"<p>Two recent decisions by the Food and Drug Administration will likely significantly impact testing for multiple myeloma (MM) minimal residual disease (MRD). First, on April 12, 2024, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted to approve the use of MRD as an end point for accelerated approval of new treatments for patients with MM.<span><sup>1</sup></span> This was a result of near 10 years effort by multiple institutions, professional societies, and patient's advocacy groups,<span><sup>2-6</sup></span> and reflects the current state of MM treatment in which new therapeutic options have dramatically improved progression-free and overall survival (PFS and OS),<span><sup>7</sup></span> making them impractical as the only clinical trial endpoints. Second, after many years of deliberations, FDA announced on April 29, 2024 that it will start overseeing laboratory developed tests (LDTs).<span><sup>8</sup></span> LDTs are in vitro diagnostic products (IVDs) intended for clinical use; they are designed and validated for use within individual laboratories certified for performing high complexity testing under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The FDA's decision is currently being challenged by the American Clinical Laboratory Association.</p><p>The most commonly used assays for MRD detection in plasma cell neoplasms are next-generation sequencing (NGS) of the rearranged variable immunoglobulin heavy chain<span><sup>9, 10</sup></span> and high sensitivity flow cytometry immunophenotyping (next-generation flow, NGF).<span><sup>11-14</sup></span> Each type of assay has its advantages and disadvantages. For example, NGS requires knowledge of the diagnostic specimen for sequence comparison, but that knowledge enables higher sensitivity (10<sup>−6</sup>). NGF, as developed by the Euroflow/Spanish flow cytometry experts and commercialized by Cytognos requires no prior diagnostic specimen and can provide information regarding quality of the specimen (hemodilution); the sensitivity of the NGF is between 10<sup>−5</sup> and 2 × 10<sup>−6</sup>, depending on the number of cells (events) collected. In 2016, the International Myeloma Working Group established the minimum sensitivity of 10<sup>−5</sup> for MM MRD testing.<span><sup>4</sup></span></p><p>Currently the only FDA-approved test for MM MRD is NGS-based clonoSEQ® by Adaptive Biotechnologies.<span><sup>9</sup></span> For the NGF method to be FDA-approved, it will require a comprehensive package submission to the FDA, either as Premarket Approval (PMA) application or a Premarket Notification 510(k). However, FDA has a category of investigational device exemption (IDE) which allows a test to be used in a clinical study to collect safety and effectiveness data. There is limited data available regarding the requirements for FDA IDE approval of a flow cytometry assay for MRD testing.</p><p>In our laboratory, we adopted and validated the NGF method as an LDT, and have, sin","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 12","pages":"2399-2401"},"PeriodicalIF":10.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The importance of autologous stem cell transplantation in improving outcomes in newly diagnosed patients with multiple myeloma","authors":"Morie A. Gertz","doi":"10.1002/ajh.27483","DOIUrl":"10.1002/ajh.27483","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 11","pages":"2060-2062"},"PeriodicalIF":10.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：