Pub Date : 2024-06-01DOI: 10.1016/j.bneo.2024.100013
Alexander Pemov , Jung Kim , Wen Luo , Jia Liu , Cole Graham , Kristine Jones , Delphine DeMangel , Neal D. Freedman , Charles Dumontet , Bin Zhu , Mary L. McMaster , Douglas R. Stewart
Abstract
Waldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P/LP variants in TREX1 and SAMHD1 (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, POT1, RECQL4, PTPN11, PMS2). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.
{"title":"The landscape of rare genetic variants in familial Waldenström macroglobulinemia","authors":"Alexander Pemov , Jung Kim , Wen Luo , Jia Liu , Cole Graham , Kristine Jones , Delphine DeMangel , Neal D. Freedman , Charles Dumontet , Bin Zhu , Mary L. McMaster , Douglas R. Stewart","doi":"10.1016/j.bneo.2024.100013","DOIUrl":"10.1016/j.bneo.2024.100013","url":null,"abstract":"<div><h3>Abstract</h3><p>Waldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P/LP variants in <em>TREX1</em> and <em>SAMHD1</em> (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, <em>POT1, RECQL4, PTPN11, PMS2</em>). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S295032802400013X/pdfft?md5=7d264d4490d9a6245a10e30efcc10a9c&pid=1-s2.0-S295032802400013X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140784350","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}
Pub Date : 2024-06-01DOI: 10.1016/j.bneo.2024.100014
Chung Hoow Kok , Yazad Irani , Jade Clarson , Verity Saunders , Phuong Dang , Naranie Shanmuganathan , Susan Branford , David Yeung , Agnes S. M. Yong , Timothy P. Hughes
Abstract
Achieving a deep molecular response (DMR) is a prerequisite for treatment-free remission in chronic myeloid leukemia (CML) and a key milestone for patients with CML. This study identified patients unlikely to achieve a 5-year DMR through differential expression of cluster of differentiation (CD) genes, and clinical variables at diagnosis. Peripheral blood samples (n = 131) from patients treated with imatinib or nilotinib underwent transcriptomic microarray profiling. The decision-tree analysis delineated 2 distinct poor-risk (PR) cohorts, distinguished by high 3-month BCR::ABL1% (PR-1), or high CD302 expression (PR-2). The 5-years DMR achievement rate was significantly lower in both PR groups than in the good-risk (GR) group in patients treated frontline with imatinib (0% vs 27% vs 83%; P < .0001) or nilotinib (PR-2 vs GR, 17% vs 83%; P = .02). Gene-set enrichment analysis revealed reduced expression of cell cycle–related genes in PR-2, as well as increased metabolism and STAT3 pathway genes, which has previously been linked to leukemic cell persistence and resistance to tyrosine kinase inhibitors. Moreover, PR-2 had a higher frequency of CD34+CD302+ and CD14+CD302+ cells than GR samples. Strategies aimed at targeting STAT3 and/or metabolic pathways associated with high CD302 may provide novel therapeutic approaches that could help improve treatment outcomes and eradicate residual disease.
摘要获得深度分子反应（DMR）是慢性粒细胞白血病（CML）无治疗缓解的先决条件，也是CML患者的一个重要里程碑。本研究通过分化簇（CD）基因的差异表达和诊断时的临床变量来确定不太可能实现5年DMR的患者。对接受伊马替尼或尼洛替尼治疗的患者的外周血样本（n = 131）进行了转录组芯片分析。决策树分析划分出了2个不同的低风险（PR）队列，分别是3个月BCR::ABL1%高表达（PR-1）或CD302高表达（PR-2）。在接受伊马替尼（0% vs 27% vs 83%; P <.0001）或尼洛替尼（PR-2 vs GR, 17% vs 83%; P = .02）一线治疗的患者中，两个PR组的5年DMR达标率均显著低于良险（GR）组。基因集富集分析显示，PR-2 中细胞周期相关基因的表达减少，代谢和 STAT3 通路基因的表达增加，而 STAT3 通路基因以前曾与白血病细胞的持久性和对酪氨酸激酶抑制剂的耐药性有关。此外，与GR样本相比，PR-2样本中CD34+CD302+和CD14+CD302+细胞的频率更高。针对STAT3和/或与高CD302相关的代谢途径的策略可能会提供新的治疗方法，有助于改善治疗效果和根除残留疾病。
{"title":"CD302 predicts achievement of deep molecular response in patients with chronic myeloid leukemia treated with imatinib","authors":"Chung Hoow Kok , Yazad Irani , Jade Clarson , Verity Saunders , Phuong Dang , Naranie Shanmuganathan , Susan Branford , David Yeung , Agnes S. M. Yong , Timothy P. Hughes","doi":"10.1016/j.bneo.2024.100014","DOIUrl":"https://doi.org/10.1016/j.bneo.2024.100014","url":null,"abstract":"<div><h3>Abstract</h3><p>Achieving a deep molecular response (DMR) is a prerequisite for treatment-free remission in chronic myeloid leukemia (CML) and a key milestone for patients with CML. This study identified patients unlikely to achieve a 5-year DMR through differential expression of cluster of differentiation (CD) genes, and clinical variables at diagnosis. Peripheral blood samples (n = 131) from patients treated with imatinib or nilotinib underwent transcriptomic microarray profiling. The decision-tree analysis delineated 2 distinct poor-risk (PR) cohorts, distinguished by high 3-month <em>BCR</em>::<em>ABL1</em>% (PR-1), or high <em>CD302</em> expression (PR-2). The 5-years DMR achievement rate was significantly lower in both PR groups than in the good-risk (GR) group in patients treated frontline with imatinib (0% vs 27% vs 83%; <em>P</em> < .0001) or nilotinib (PR-2 vs GR, 17% vs 83%; <em>P</em> = .02). Gene-set enrichment analysis revealed reduced expression of cell cycle–related genes in PR-2, as well as increased metabolism and STAT3 pathway genes, which has previously been linked to leukemic cell persistence and resistance to tyrosine kinase inhibitors. Moreover, PR-2 had a higher frequency of CD34<sup>+</sup>CD302<sup>+</sup> and CD14<sup>+</sup>CD302<sup>+</sup> cells than GR samples. Strategies aimed at targeting STAT3 and/or metabolic pathways associated with high CD302 may provide novel therapeutic approaches that could help improve treatment outcomes and eradicate residual disease.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000141/pdfft?md5=203d3abae466c2edbbfccec17f07d8a0&pid=1-s2.0-S2950328024000141-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141240049","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}
Pub Date : 2024-05-23DOI: 10.1016/j.bneo.2024.100017
Jad Othman , Ho Pui Jeff Lam , Sarah Leong , Faisal Basheer , Islam Abdallah , Kathryn Fleming , Priyanka Mehta , Heba Yassin , John Laurie , Michael Austin , Paolo Gallipoli , Tom Taylor , Mike Dennis , Johnathon Elliot , Georgina Clarke , Raymond Dang , Jennifer Vidler , Pramila Krishnamurthy , Anne-Louise Latif , Pallavi Kalkur , Richard Dillon
Abstract
Venetoclax with azacitidine is the standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy; however, uncertainties remain regarding the treatment schedule, accurate prognostication, and outcomes for patients treated outside clinical trials. The option of venetoclax with low-dose cytarabine (LDAC) is also available; however, it is not clear for which patients it may be a useful alternative. Here, we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n = 587) or LDAC (n = 67). The median age was 73 years, and 59% had de novo AML. Most patients received 100 mg of venetoclax with an azole antifungal. In cycle 1, patients spent a median of 14 days in the hospital, and 85% required red cell transfusion, 59% platelet transfusion, and 63% required IV antibiotics. Supportive care requirements significantly reduced after the first cycle. Patients receiving venetoclax-azacitidine had a complete remission (CR)/CR with incomplete hematological recovery rate of 67%, day 30 and day 60 mortality of 5% and 8%, respectively, and median overall survival of 13.6 months. Mutations in NPM1, RUNX1, STAG2, and IDH2 were associated with improved survival, whereas age, secondary and therapy-related AML, +8, MECOM rearrangements, complex karyotype, ASXL1, and KIT mutations were associated with poorer survival. Prognostic systems derived specifically for patients treated with venetoclax-azacitidine performed better than the European LeukemiaNet and Medical Research Council classifications; however, improved risk classifications are still required. In the 149 patients with NPM1 mutated AML, outcomes were similar for those treated with venetoclax-azacitidine and venetoclax-LDAC.
{"title":"Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS","authors":"Jad Othman , Ho Pui Jeff Lam , Sarah Leong , Faisal Basheer , Islam Abdallah , Kathryn Fleming , Priyanka Mehta , Heba Yassin , John Laurie , Michael Austin , Paolo Gallipoli , Tom Taylor , Mike Dennis , Johnathon Elliot , Georgina Clarke , Raymond Dang , Jennifer Vidler , Pramila Krishnamurthy , Anne-Louise Latif , Pallavi Kalkur , Richard Dillon","doi":"10.1016/j.bneo.2024.100017","DOIUrl":"10.1016/j.bneo.2024.100017","url":null,"abstract":"<div><h3>Abstract</h3><p>Venetoclax with azacitidine is the standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy; however, uncertainties remain regarding the treatment schedule, accurate prognostication, and outcomes for patients treated outside clinical trials. The option of venetoclax with low-dose cytarabine (LDAC) is also available; however, it is not clear for which patients it may be a useful alternative. Here, we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n = 587) or LDAC (n = 67). The median age was 73 years, and 59% had de novo AML. Most patients received 100 mg of venetoclax with an azole antifungal. In cycle 1, patients spent a median of 14 days in the hospital, and 85% required red cell transfusion, 59% platelet transfusion, and 63% required IV antibiotics. Supportive care requirements significantly reduced after the first cycle. Patients receiving venetoclax-azacitidine had a complete remission (CR)/CR with incomplete hematological recovery rate of 67%, day 30 and day 60 mortality of 5% and 8%, respectively, and median overall survival of 13.6 months. Mutations in <em>NPM1</em>, <em>RUNX1</em>, <em>STAG2</em>, and <em>IDH2</em> were associated with improved survival, whereas age, secondary and therapy-related AML, +8, <em>MECOM</em> rearrangements, complex karyotype, <em>ASXL1</em>, and <em>KIT</em> mutations were associated with poorer survival. Prognostic systems derived specifically for patients treated with venetoclax-azacitidine performed better than the European LeukemiaNet and Medical Research Council classifications; however, improved risk classifications are still required. In the 149 patients with <em>NPM1</em> mutated AML, outcomes were similar for those treated with venetoclax-azacitidine and venetoclax-LDAC.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000177/pdfft?md5=1de290f83adace13a5f6e05842b39ad6&pid=1-s2.0-S2950328024000177-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141136394","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}
Pub Date : 2024-05-21DOI: 10.1016/j.bneo.2024.100021
Johann-Christoph Jann ∗ , Nanni Schmitt ∗ , Alexander Streuer , Qingyu Xu , Vladimir Riabov , Eva Altrock , Nadine Weimer , Verena Nowak , Julia Obländer , Iris Palme , Melda Göl , Marie Demmerle , Felicitas Rapp , Fabian Siegel , Laurenz Steiner , Mahmoud Ghazal , Angelika Duda , Verena Haselmann , Ali Darwich , Ahmed Jawhar , Daniel Nowak
Abstract
Myelodysplastic neoplasms (MDS) are hypothesized to remodel their bone marrow (BM) microenvironment to reinforce conditions for their propagation. In this study, we investigated interactions between MDS cells and the BM niche at single-cell level. In a patient-derived xenograft (PDX) model, we analyzed 13 000 cells from different murine niche cell populations after long-term (>24 weeks) exposure to MDS vs healthy human grafts. Subsequently, we analyzed over 24 000 primary human BM cells enriched for the nonhematopoietic compartment by using whole bone fragments from n = 8 patients with MDS and n = 7 healthy, age-matched donors. In PDX who received MDS transplantation, mesenchymal cell (MSC) subpopulations were forced to overexpress hematopoietic factors such as Cxcl12 and Il7 upon contact with hematopoietic MDS cells as compared with healthy grafts. Single-cell analyses of primary in situ BM cells from patients with MDS showed highly heterogeneous MSC subpopulations on a patient-individual level. We identified inflammatory gene expression profiles as well as overexpression of C-X-C Motif Chemokine Ligand 12, KIT ligand, and Interleukin 7 in MDS MSCs and endothelial cells. In conclusion, we demonstrate reprogramming of the BM microenvironment by MDS cells, pointing to altered MSC subpopulations with increased growth factor expression profiles in a subgroup of patients with MDS.
{"title":"Instructive interaction between myelodysplastic hematopoiesis and the bone marrow microenvironment at the single-cell level","authors":"Johann-Christoph Jann ∗ , Nanni Schmitt ∗ , Alexander Streuer , Qingyu Xu , Vladimir Riabov , Eva Altrock , Nadine Weimer , Verena Nowak , Julia Obländer , Iris Palme , Melda Göl , Marie Demmerle , Felicitas Rapp , Fabian Siegel , Laurenz Steiner , Mahmoud Ghazal , Angelika Duda , Verena Haselmann , Ali Darwich , Ahmed Jawhar , Daniel Nowak","doi":"10.1016/j.bneo.2024.100021","DOIUrl":"10.1016/j.bneo.2024.100021","url":null,"abstract":"<div><h3>Abstract</h3><p>Myelodysplastic neoplasms (MDS) are hypothesized to remodel their bone marrow (BM) microenvironment to reinforce conditions for their propagation. In this study, we investigated interactions between MDS cells and the BM niche at single-cell level. In a patient-derived xenograft (PDX) model, we analyzed 13 000 cells from different murine niche cell populations after long-term (>24 weeks) exposure to MDS vs healthy human grafts. Subsequently, we analyzed over 24 000 primary human BM cells enriched for the nonhematopoietic compartment by using whole bone fragments from n = 8 patients with MDS and n = 7 healthy, age-matched donors. In PDX who received MDS transplantation, mesenchymal cell (MSC) subpopulations were forced to overexpress hematopoietic factors such as Cxcl12 and Il7 upon contact with hematopoietic MDS cells as compared with healthy grafts. Single-cell analyses of primary in situ BM cells from patients with MDS showed highly heterogeneous MSC subpopulations on a patient-individual level. We identified inflammatory gene expression profiles as well as overexpression of C-X-C Motif Chemokine Ligand 12, KIT ligand, and Interleukin 7 in MDS MSCs and endothelial cells. In conclusion, we demonstrate reprogramming of the BM microenvironment by MDS cells, pointing to altered MSC subpopulations with increased growth factor expression profiles in a subgroup of patients with MDS.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000219/pdfft?md5=7e40a71e101380a24de189eb79bb44c9&pid=1-s2.0-S2950328024000219-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131243","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}
Pub Date : 2024-05-21DOI: 10.1016/j.bneo.2024.100018
Ulrich Dührsen , Andreas Bockisch , Bernd Hertenstein , Imke E. Karsten , Frank Kroschinsky , Michael Heuser , Andreas Hochhaus , Heinz-Gert Höffkes , Dirk Behringer , Gabriele Prange-Krex , Mareike Tometten , Martin Grieshammer , Götz U. Grigoleit , Oliver Schmalz , Karin Jordan , Helga Bernhard , Tobias Gaska , Aristoteles Giagounidis , Roland Schroers , Uwe M. Martens , M. Neuhäuser
Abstract
The PETAL (Positron Emission Tomography–Guided Therapy of Aggressive Non-Hodgkin Lymphomas) trial investigated whether treatment intensification after 2 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; plus rituximab [R] for CD20+ lymphomas) improved survival in aggressive non-Hodgkin lymphoma. A total of 754 patients (87.5%) had a negative and 108 (12.5%) had a positive interim positron emission tomography (iPET) scan. iPET-positive patients were randomly assigned to receive another 6 (R-)CHOP cycles or 6 blocks of a more intensive protocol. Interim PET-negative patients received another 4 cycles of R-CHOP with or without 2 additional doses of R. After a median follow-up of 4 years, treatment intensification had not improved outcome. These results were confirmed after 10.3 years of follow-up. The present analysis also describes the management of relapse that was part of the study. Among 240 relapsing patients, 94 of 133 autologous transplantation–eligible patients (70.7%) and 16 of 107 ineligible patients (15.0%) received the salvage treatments recommended in the study protocol. Adherence to recommendations had no impact on outcome. Best results were seen after allogeneic transplantation, followed by autologous transplantation and treatment without transplantation (5-year overall survival rate, 64.3% vs 45.5% vs 22.6%), but patients undergoing allogeneic transplantation were significantly younger and their disease was well controlled at the time of transplantation. Early outcome prediction by iPET, alone or in combination with other methods, is a powerful tool to investigate the value of immunological treatment options for patients with a poor response to chemotherapy. This trial was registered at ClinicalTrials.gov as #NCT00554164.
摘要PETAL（正电子发射断层扫描引导的侵袭性非霍奇金淋巴瘤治疗）试验研究了在环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP；CD20+淋巴瘤加利妥昔单抗[R]）治疗2个周期后加强治疗是否能提高侵袭性非霍奇金淋巴瘤患者的生存率。共有 754 名患者（87.5%）的中期正电子发射断层扫描（iPET）结果为阴性，108 名患者（12.5%）的中期正电子发射断层扫描（iPET）结果为阳性。中位随访 4 年后，强化治疗并未改善疗效。这些结果在随访 10.3 年后得到了证实。本分析报告还介绍了作为研究一部分的复发治疗情况。在240名复发患者中，133名符合自体移植条件的患者中有94名（70.7%）和107名不符合条件的患者中有16名（15.0%）接受了研究方案中建议的挽救治疗。遵守建议对结果没有影响。接受同种异体移植的疗效最好，其次是自体移植和不进行移植的治疗（5年总生存率分别为64.3% vs 45.5% vs 22.6%），但接受同种异体移植的患者明显更年轻，而且移植时病情控制良好。通过iPET单独或结合其他方法进行早期结果预测，是研究化疗反应不佳患者免疫治疗方案价值的有力工具。该试验已在 ClinicalTrials.gov 注册，编号为 #NCT00554164。
{"title":"Response-guided first-line therapy and treatment of relapse in aggressive lymphoma: 10-year follow-up of the PETAL trial","authors":"Ulrich Dührsen , Andreas Bockisch , Bernd Hertenstein , Imke E. Karsten , Frank Kroschinsky , Michael Heuser , Andreas Hochhaus , Heinz-Gert Höffkes , Dirk Behringer , Gabriele Prange-Krex , Mareike Tometten , Martin Grieshammer , Götz U. Grigoleit , Oliver Schmalz , Karin Jordan , Helga Bernhard , Tobias Gaska , Aristoteles Giagounidis , Roland Schroers , Uwe M. Martens , M. Neuhäuser","doi":"10.1016/j.bneo.2024.100018","DOIUrl":"10.1016/j.bneo.2024.100018","url":null,"abstract":"<div><h3>Abstract</h3><p>The PETAL (Positron Emission Tomography–Guided Therapy of Aggressive Non-Hodgkin Lymphomas) trial investigated whether treatment intensification after 2 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; plus rituximab [R] for CD20<sup>+</sup> lymphomas) improved survival in aggressive non-Hodgkin lymphoma. A total of 754 patients (87.5%) had a negative and 108 (12.5%) had a positive interim positron emission tomography (iPET) scan. iPET-positive patients were randomly assigned to receive another 6 (R-)CHOP cycles or 6 blocks of a more intensive protocol. Interim PET-negative patients received another 4 cycles of R-CHOP with or without 2 additional doses of R. After a median follow-up of 4 years, treatment intensification had not improved outcome. These results were confirmed after 10.3 years of follow-up. The present analysis also describes the management of relapse that was part of the study. Among 240 relapsing patients, 94 of 133 autologous transplantation–eligible patients (70.7%) and 16 of 107 ineligible patients (15.0%) received the salvage treatments recommended in the study protocol. Adherence to recommendations had no impact on outcome. Best results were seen after allogeneic transplantation, followed by autologous transplantation and treatment without transplantation (5-year overall survival rate, 64.3% vs 45.5% vs 22.6%), but patients undergoing allogeneic transplantation were significantly younger and their disease was well controlled at the time of transplantation. Early outcome prediction by iPET, alone or in combination with other methods, is a powerful tool to investigate the value of immunological treatment options for patients with a poor response to chemotherapy. This trial was registered at <span>ClinicalTrials.gov</span><svg><path></path></svg> as #NCT00554164.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000189/pdfft?md5=0e7371b07f0b752e8ed5c88b58052061&pid=1-s2.0-S2950328024000189-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141145706","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}
Pub Date : 2024-05-20DOI: 10.1016/j.bneo.2024.100019
Christopher S. Strouse , Vanessa E. Siebert , Bradley T. Loeffler , Bradley D. McDowell , Brian J. Smith , Brian K. Link
Abstract
Bendamustine is among the most commonly used chemoimmunotherapies for patients with follicular lymphoma (FL). It is typically delivered with a goal regimen consisting of 6 cycles, but it is possible that treatment goals could be achieved with fewer cycles, particularly in older patients. We used data from the National Cancer Institute (NCI) linkage between Surveillance, Epidemiology, and End Results program and Medicare claims to evaluate the overall survival of patients with FL receiving 3 to 4 vs 5 to 6 cycles of bendamustine. Patients receiving 1 to 2 cycles of bendamustine chemotherapy were not included. Patients receiving 5 to 6 cycles of bendamustine were significantly younger (mean age, 75.0 vs 76.2 years; P < .01) and had fewer comorbidities by the NCI comorbidity index (mean score, 1.7 vs 2.0; P = .05) than those receiving 3 to 4 cycles of bendamustine, and on univariate analysis exhibited significantly lower risk of death (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.57-0.98; P = .04). However, multivariate analysis controlling for age and comorbidity did not reveal a significant association between overall survival and number of cycles of bendamustine (HR, 0.87; 95% CI, 0.66-1.15; P = .33). Limitations inherent to use of data such as these for causal inference are acknowledged. Nonetheless, these analyses suggest some older patients with FL achieve satisfactory survival outcomes even with lesser bendamustine exposure, and future efforts to prospectively identify such patients are warranted.
{"title":"Optimal number of cycles of bendamustine as initial chemoimmunotherapy for older patients with follicular lymphoma","authors":"Christopher S. Strouse , Vanessa E. Siebert , Bradley T. Loeffler , Bradley D. McDowell , Brian J. Smith , Brian K. Link","doi":"10.1016/j.bneo.2024.100019","DOIUrl":"10.1016/j.bneo.2024.100019","url":null,"abstract":"<div><h3>Abstract</h3><p>Bendamustine is among the most commonly used chemoimmunotherapies for patients with follicular lymphoma (FL). It is typically delivered with a goal regimen consisting of 6 cycles, but it is possible that treatment goals could be achieved with fewer cycles, particularly in older patients. We used data from the National Cancer Institute (NCI) linkage between Surveillance, Epidemiology, and End Results program and Medicare claims to evaluate the overall survival of patients with FL receiving 3 to 4 vs 5 to 6 cycles of bendamustine. Patients receiving 1 to 2 cycles of bendamustine chemotherapy were not included. Patients receiving 5 to 6 cycles of bendamustine were significantly younger (mean age, 75.0 vs 76.2 years; <em>P</em> < .01) and had fewer comorbidities by the NCI comorbidity index (mean score, 1.7 vs 2.0; <em>P</em> = .05) than those receiving 3 to 4 cycles of bendamustine, and on univariate analysis exhibited significantly lower risk of death (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.57-0.98; <em>P</em> = .04). However, multivariate analysis controlling for age and comorbidity did not reveal a significant association between overall survival and number of cycles of bendamustine (HR, 0.87; 95% CI, 0.66-1.15; <em>P</em> = .33). Limitations inherent to use of data such as these for causal inference are acknowledged. Nonetheless, these analyses suggest some older patients with FL achieve satisfactory survival outcomes even with lesser bendamustine exposure, and future efforts to prospectively identify such patients are warranted.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000190/pdfft?md5=39bb4295030312550b540bb0e3d862e2&pid=1-s2.0-S2950328024000190-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141136987","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}
Pub Date : 2024-05-20DOI: 10.1016/j.bneo.2024.100020
Jun Y. Jiang , Chijioke Nze , Danielle Guffey , Rockbum Kim , Abiodun O. Oluyomi , Omar Rosales , Raka Bandyo , Courtney N. Miller-Chism , Mark M. Udden , Martha P. Mims , Hilary Ma , Gustavo A. Rivero , Akiva Diamond , Purnima S. Teegavarapu , Ang Li ∗ , Christopher R. Flowers ∗
Abstract
Real-world outcome data for patients with large B-cell lymphomas (LBCLs) who are uninsured or have socioeconomic barriers to care are limited. We performed a retrospective cohort study of patients with newly diagnosed LBCL treated in a large safety-net hospital system. Between January 2011 and June 2022, 496 patients aged >18 years were diagnosed with LBCL at Harris Health System, Houston, Texas. The median age was 53 years, 75% were uninsured, and 81% were in the most disadvantaged Area Deprivation Index national quartiles. Most (69%) had stage III/IV disease, 44% had poor-risk disease by the Revised International Prognostic Index (R-IPI), and 17% had a history of HIV infection. The median diagnosis-to-treatment interval was 17 days. The median follow-up time was 53.5 months. Among 464 evaluable patients, 66% achieved a complete response, and 11% had a partial response. Of 48 patients, 26 (54%) eligible for cell therapies received them. At 5 years, event-free and overall survival (OS) rates were 57% and 68%, respectively. Factors that affected OS included Hispanic ethnicity (hazard ratio [HR], 0.70; P = .027), R-IPI (HR, 4.67 for poor vs very good risk; P < .001), National Cancer Institute Comorbidity Index (HR, 1.53 per unit increment; P = .003), hemoglobin (HR, 0.89 per unit increment; P = .002), and International Normalized Ratio (HR, 2.17 per unit increment; P = .007). Insurance status was not associated with differences in OS. In our safety-net health system with robust financial assistance programs and limited access to cell therapies, uninsured status was not associated with inferior outcomes. Addressing barriers to care may improve outcomes in other settings.
{"title":"Clinical outcomes of patients with newly diagnosed large B-cell lymphoma in a safety-net hospital system","authors":"Jun Y. Jiang , Chijioke Nze , Danielle Guffey , Rockbum Kim , Abiodun O. Oluyomi , Omar Rosales , Raka Bandyo , Courtney N. Miller-Chism , Mark M. Udden , Martha P. Mims , Hilary Ma , Gustavo A. Rivero , Akiva Diamond , Purnima S. Teegavarapu , Ang Li ∗ , Christopher R. Flowers ∗","doi":"10.1016/j.bneo.2024.100020","DOIUrl":"10.1016/j.bneo.2024.100020","url":null,"abstract":"<div><h3>Abstract</h3><p>Real-world outcome data for patients with large B-cell lymphomas (LBCLs) who are uninsured or have socioeconomic barriers to care are limited. We performed a retrospective cohort study of patients with newly diagnosed LBCL treated in a large safety-net hospital system. Between January 2011 and June 2022, 496 patients aged >18 years were diagnosed with LBCL at Harris Health System, Houston, Texas. The median age was 53 years, 75% were uninsured, and 81% were in the most disadvantaged Area Deprivation Index national quartiles. Most (69%) had stage III/IV disease, 44% had poor-risk disease by the Revised International Prognostic Index (R-IPI), and 17% had a history of HIV infection. The median diagnosis-to-treatment interval was 17 days. The median follow-up time was 53.5 months. Among 464 evaluable patients, 66% achieved a complete response, and 11% had a partial response. Of 48 patients, 26 (54%) eligible for cell therapies received them. At 5 years, event-free and overall survival (OS) rates were 57% and 68%, respectively. Factors that affected OS included Hispanic ethnicity (hazard ratio [HR], 0.70; <em>P</em> = .027), R-IPI (HR, 4.67 for poor vs very good risk; <em>P</em> < .001), National Cancer Institute Comorbidity Index (HR, 1.53 per unit increment; <em>P</em> = .003), hemoglobin (HR, 0.89 per unit increment; <em>P</em> = .002), and International Normalized Ratio (HR, 2.17 per unit increment; <em>P</em> = .007). Insurance status was not associated with differences in OS. In our safety-net health system with robust financial assistance programs and limited access to cell therapies, uninsured status was not associated with inferior outcomes. Addressing barriers to care may improve outcomes in other settings.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000207/pdfft?md5=e382f0d8e27c903ab9a7be1a0e9c73ff&pid=1-s2.0-S2950328024000207-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141144995","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}
Glucocorticoids (GCs), such as dexamethasone and prednisone, are crucial components of B-cell precursor acute lymphoblastic leukemia (B-ALL) therapies. However, the molecular basis of GC-induced cell death remains elusive. Here, we show that GC suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling and that, conversely, oncogenic activation of mTORC1 confers resistance to GCs. Our genome-wide CRISPR/CRISPR-associated protein 9 (CRISPR/Cas9) dropout screens reveal that depletion of components of either the gap activity toward Rags 1 or tuberous sclerosis complexes, both negative regulators of mTORC1 signaling, significantly attenuates B-ALL cell sensitivity to dexamethasone. Dexamethasone primarily induces B-ALL cell death by downregulating mTORC1 activity, thus promoting autophagy and impairing protein synthesis. Dexamethasone treatment failed to suppress mTORC1 activity in B-ALL cells expressing mutant GC receptors lacking DNA-binding capacity, suggesting that dexamethasone transcriptionally represses mTORC1 activity. RNA-sequencing analysis identified multiple dexamethasone target genes that negatively regulate mTORC1 activity. Our findings suggest that GC sensitivity is significantly influenced by oncogenic stimuli and/or growth factors that activate the PI3K-AKT-mTORC1 pathway. This is consistent with the frequent GC resistance found in Ph and Ph-like ALLs.
{"title":"Central role of the mTORC1 pathway in glucocorticoid activity against B-ALL cells","authors":"Hiroshi Imanaga , Yuichiro Semba , Kensuke Sasaki , Kiyoko Setoguchi , Hillary Maniriho , Takuji Yamauchi , Tatsuya Terasaki , Shigeki Hirabayashi , Fumihiko Nakao , Jumpei Nogami , Shai Izraeli , Koichi Akashi , Takahiro Maeda","doi":"10.1016/j.bneo.2024.100015","DOIUrl":"https://doi.org/10.1016/j.bneo.2024.100015","url":null,"abstract":"<div><h3>Abstract</h3><p>Glucocorticoids (GCs), such as dexamethasone and prednisone, are crucial components of B-cell precursor acute lymphoblastic leukemia (B-ALL) therapies. However, the molecular basis of GC-induced cell death remains elusive. Here, we show that GC suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling and that, conversely, oncogenic activation of mTORC1 confers resistance to GCs. Our genome-wide CRISPR/CRISPR-associated protein 9 (CRISPR/Cas9) dropout screens reveal that depletion of components of either the gap activity toward Rags 1 or tuberous sclerosis complexes, both negative regulators of mTORC1 signaling, significantly attenuates B-ALL cell sensitivity to dexamethasone. Dexamethasone primarily induces B-ALL cell death by downregulating mTORC1 activity, thus promoting autophagy and impairing protein synthesis. Dexamethasone treatment failed to suppress mTORC1 activity in B-ALL cells expressing mutant GC receptors lacking DNA-binding capacity, suggesting that dexamethasone transcriptionally represses mTORC1 activity. RNA-sequencing analysis identified multiple dexamethasone target genes that negatively regulate mTORC1 activity. Our findings suggest that GC sensitivity is significantly influenced by oncogenic stimuli and/or growth factors that activate the PI3K-AKT-mTORC1 pathway. This is consistent with the frequent GC resistance found in Ph and Ph-like ALLs.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000153/pdfft?md5=ab04dd4c2a9ccc8ef49f43cf5cbbb31a&pid=1-s2.0-S2950328024000153-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141090068","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}
Pub Date : 2024-04-12DOI: 10.1016/j.bneo.2024.100010
Megan Metzger , Zachary M. Avigan , Pankit Vachhani , Julian Waksal , John Mascarenhas
Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by constitutional symptoms, progressive cytopenias, and splenomegaly. Activating mutations in the JAK/STAT pathway and cytokine dysregulation driving bone marrow fibrosis and extramedullary hematopoiesis underlie the pathobiology of MF. Although multiple JAK inhibitors are currently approved and provide significant symptom improvement, these agents do not possess disease course modifying potential. Additionally, outcomes are poor for patients who fail JAK inhibitors, highlighting the need for novel mechanism-based therapies and innovative combination strategies. Selinexor, a novel Exportin 1 (XPO1) inhibitor that blocks nuclear export, increases nuclear localization and activity of p53 and other tumor suppressor pathways and decreases cytoplasmic activation of multiple proliferative and profibrotic pathways. Selinexor currently has approved indications in multiple myeloma and lymphoma, with broad potential applications in other malignancies, although it can be limited by toxicity in some settings. Selinexor has shown clinical activity and tolerability in MF, both as monotherapy and, particularly, in combination with ruxolitinib. The collective, early phase trial data support a phase 3 randomized, registration study of selinexor and ruxolitinib in patients with MF naïve to JAK inhibitor therapy. Further work is needed to elucidate the role of XPO1 inhibition as a potential disease-modifying strategy to improve outcomes in MF.
{"title":"A novel application of XPO1 inhibition for the treatment of myelofibrosis","authors":"Megan Metzger , Zachary M. Avigan , Pankit Vachhani , Julian Waksal , John Mascarenhas","doi":"10.1016/j.bneo.2024.100010","DOIUrl":"10.1016/j.bneo.2024.100010","url":null,"abstract":"<div><h3>Abstract</h3><p>Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by constitutional symptoms, progressive cytopenias, and splenomegaly. Activating mutations in the JAK/STAT pathway and cytokine dysregulation driving bone marrow fibrosis and extramedullary hematopoiesis underlie the pathobiology of MF. Although multiple JAK inhibitors are currently approved and provide significant symptom improvement, these agents do not possess disease course modifying potential. Additionally, outcomes are poor for patients who fail JAK inhibitors, highlighting the need for novel mechanism-based therapies and innovative combination strategies. Selinexor, a novel Exportin 1 (XPO1) inhibitor that blocks nuclear export, increases nuclear localization and activity of p53 and other tumor suppressor pathways and decreases cytoplasmic activation of multiple proliferative and profibrotic pathways. Selinexor currently has approved indications in multiple myeloma and lymphoma, with broad potential applications in other malignancies, although it can be limited by toxicity in some settings. Selinexor has shown clinical activity and tolerability in MF, both as monotherapy and, particularly, in combination with ruxolitinib. The collective, early phase trial data support a phase 3 randomized, registration study of selinexor and ruxolitinib in patients with MF naïve to JAK inhibitor therapy. Further work is needed to elucidate the role of XPO1 inhibition as a potential disease-modifying strategy to improve outcomes in MF.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000104/pdfft?md5=ddc40a14d238e982837d9bb17da6c825&pid=1-s2.0-S2950328024000104-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140787629","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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