Long-term genetic and clinical remissions after cessation of azacitidine treatment in patients with VEXAS syndrome

IF 7.6 2区 医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2024-07-30 DOI:10.1002/hem3.129
Anna M. Aalbers, Paul L. A. van Daele, Virgil A. S. H. Dalm, Peter J. M. Valk, Marc H. G. P. Raaijmakers
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Raaijmakers","doi":"10.1002/hem3.129","DOIUrl":null,"url":null,"abstract":"<p>VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an inflammatory syndrome caused by acquired mutations in the gene encoding ubiquitin like modifier activating enzyme 1 (<i>UBA1</i>) that is often fatal.<span><sup>1, 2</sup></span> Allogeneic hematopoietic stem cell transplantation is currently considered the only curative treatment modality.<span><sup>3-6</sup></span> We were the first to report eradication of virtually all <i>UBA1</i>-mutated cells by the hypomethylating agent azacitidine, reflected in clinical and genetic remissions,<span><sup>7</sup></span> a finding confirmed in a recent phase II clinical trial.<span><sup>8</sup></span></p><p>Here, we report persistent, long-term (11–84 months) genetic and clinical remissions in VEXAS patients responding to treatment with the hypomethylating agent azacitidine, after cessation of therapy. The data indicate that azacitidine treatment may be an attractive alternative to stem cell transplant for disease eradication in VEXAS syndrome patients and reveal long-term clonal stability of <i>UBA1</i>-mutated cells under homeostatic and inflammatory conditions.</p><p>Since its first description in December 2020,<span><sup>1</sup></span> a <i>UBA1</i> variant-confirmed diagnosis of VEXAS syndrome was made in 11 patients at our institution until February 2024 (all male, median age at diagnosis 67 years, range 57–77 years). <i>UBA1</i> mutation detection and panel-based sequencing in these patients was performed as previously reported<span><sup>7</sup></span> and as described in the Supporting Information Methods section. Of these 11 patients, eight have been exposed to azacitidine (administered at a dose of 75 mg/m<sup>2</sup> subcutaneously once daily for 7 days in a 4-weekly schedule). Of the three patients that were not exposed to azacitidine, two patients were treated with corticosteroids and deceased due to infectious complications, and one patient was considered not a candidate for azacitidine treatment due to psychosocial circumstances. In two patients, azacitidine was used as a last resort on an in-house basis, after failure of multiple other lines of treatment, at the time that patients were critically ill (WHO performance status 4) due to VEXAS-related (respiratory) pathology. Both patients died shortly after administration of the first cycle of azacitidine with clinically active disease, and before genetic assessment of response after the first cycle. Six patients received multiple cycles of azacitidine (range, 3–8 cycles) on an out-patient basis with genetic monitoring of disease response. The characteristics of these six patients are listed in Table 1. Patients 1 and 2 carried a concurrent <i>DNMT3A</i> mutation at diagnosis with a variant allele frequency (VAF) of 59% and 30%, respectively, and patient 3 carried a <i>TET2</i> mutation with a VAF of 4%. In patients 4, 5, and 6 no other mutations were detected by panel-based sequencing. Three of these six patients have been described by us before, including one patient in whom the diagnosis of VEXAS syndrome was made in retrospect, that is, after treatment with azacitidine.<span><sup>7</sup></span> Long-term follow-up of patients with an initial response to azacitidine is reported here. The study was performed in compliance with the Declaration of Helsinki, and reported patients gave informed consent for study participation.</p><p>All six VEXAS patients were treated with azacitidine because they suffered from frequent (life-threatening) inflammatory flares of disease and (in all but patients 4 and 5 transfusion-dependent) anemia, insufficiently responding to treatment with corticosteroids and disease-modifying antirheumatic drugs (DMARDs) and/or biologicals (specified in Table 1) and/or requiring long-term corticosteroid treatment with concomitant adverse events. Of note, four of six VEXAS patients formally fulfilled MDS criteria according to the WHO 2016 classification, based on the presence of cytopenia (anemia Hb &lt;10 g/dL) and dysplasia (≥10% in any lineage), with clonality demonstrated by mutational analyses in three of these four patients.</p><p>Five (5/6) patients achieved a clinical and genetic response to azacitidine. In these patients, the VAF of the causative <i>UBA1</i> variant decreased from a median of 67% (range 56%–86%) in bone marrow or peripheral blood at start of treatment with azacitidine (indicating that the majority of cells in the bone marrow carried the mutation) to ≤1% in bone marrow and/or peripheral blood (range 0%–1%), which was documented after five cycles in four out of five patients (in patient 1, retrospective response assessment was performed firstly after eight cycles). <i>DNMT3A</i> VAF in patient 1 decreased from 59% to 1% and in patient 2 from 30% to 2%, consistent with the notion that azacitidine treatment resulted in the eradication of cells carrying both <i>DNMT3A</i> and <i>UBA1</i> variants in these patients. Genetic remissions, indicative of a dramatic reduction in the number of <i>UBA1</i>-mutated cells, were associated with complete clinical remissions, defined as complete absence of inflammatory flares of disease, as reflected by long-term normalization of C-reactive protein (CRP) in the blood plasma in these patients, and an increase in hemoglobin levels in all patients (Figure 1). All other immuno-modulatory drugs (e.g., corticosteroids, DMARDs and/or tocilizumab) could be weaned in all responding patients. In the three patients in whom a bone marrow evaluation was performed after achieving a clinical and genetic response, characteristic vacuolisation of erythroid and myeloid precursor cells, and dysplasia of erythroid, myeloid and/or megakaryocytic lineages, disappeared. The patient that was considered a nonresponder to azacitidine (patient 3) received a total of three cycles of azacitidine, after which the mutant <i>UBA1</i> VAF in bone marrow remained high (VAF 84%). <i>TET2</i> VAF remained similar before and after treatment (4% and 3%, respectively). Quality of life and anemia had not improved. Clinical symptoms of VEXAS were relatively mild at that time and treatment was stopped, which in retrospect might have been too early to achieve a genetic remission.</p><p>In the five responding patients, azacitidine treatment was stopped after achieving a genetic response, arbitrarily defined as mutant <i>UBA1</i> VAF &lt; 5%. In patient 1 this was done after eight cycles because of treatment for a colon carcinoma, in two other patients the decision to interrupt/stop treatment upon achieving a response after four cycles was based on grade 2–3 adverse effects (fatigue and neutropenia) and the observation in patient 1 that genetic remissions may be maintained after drug cessation. The remaining two responding patients achieved a clinical and genetically-defined response (VAF of mutant <i>UBA1</i> from 75% to 0% in patient 5, and from 56% to 0% in patient 6) after five cycles recently (at submission of this manuscript, May 2024) and treatment with azacitidine was discontinued after this fifth cycle based on the clinical and genetic response and previous experience with cessation of azacitidine in the other patients. All other immunomodulatory treatment (as specified in Table 1) could be completely stopped in all responding patients, except for patient 1 who continues on prednisolone 5 mg daily for VEXAS-unrelated reasons.</p><p>After cessation of azacitidine treatment, the first three responding patients (in whom follow-up after cessation of treatment is present) remained in a clinical and genetic remission with a current median follow up of 31 months (range 11–84 months) after the last cycle of azacitidine (Figure 1). Patients remain free of any VEXAS-related inflammatory manifestations and maintain stable normalized blood levels. The mutant <i>UBA1</i> VAF in the blood remained relatively stable (range 0%–7%) in all patients during this median follow up of multiple years. We did observe a very gradual increase of the mutant <i>UBA1</i> VAF (from 1% to 7%) in patient 1 over the course of 7 years. Of further interest, mutant <i>UBA1</i> VAF was not notably affected by inflammatory episodes caused by a Campylobacter jejuni PCR-positive gastro-enteritis requiring hospitalization (patient 1) and an episode of crystal proven gout requiring hospitalization (patient 2) (Figure 1).</p><p>Collectively, these findings confirm relatively high rates of response to azacitidine treatment in VEXAS syndrome, as previously reported by us and others,<span><sup>7-10</sup></span> and, more importantly, indicate that azacitidine may be safely stopped upon achievement of a genetic response, resulting in long-term genetic and clinical remissions. This is of significant clinical relevance because it would position azacitidine treatment as an attractive alternative to stem cell transplant as the only currently available long-term disease eradicating therapeutic approach in VEXAS syndrome patients. Furthermore, cessation of azacitidine treatment would safeguard patients from frequently occurring adverse effects of the drug, including fatigue, myelosuppression and infectious complications, affecting quality of life. The data warrant incorporation of drug interruption (“holiday”) designs in future prospective clinical trials investigating the value of azacitidine treatment for VEXAS syndrome. The mechanism by which azacitidine eradicates <i>UBA1</i>-mutated cells is not known to date, but it may be hypothesized that a defect in the ubiquitin-proteasome system sensitizes cells to this agent.</p><p>Finally, findings might shed new light on the biology of disease and long-term kinetics of mutant <i>UBA1</i> clones, demonstrating that they can remain stable for many years, even in elderly patients. Although the number of documented infectious or inflammatory episodes is too small to draw conclusions, the data suggest that mutant <i>UBA1</i> clones may remain stable not only under “homeostatic” conditions but also in the event of “inflammatory stress” caused by infectious or inflammatory conditions. It may be speculated that clonal evolution of <i>UBA1</i> mutant cells takes many years and, ultimately, clones may be maintained by mutant <i>UBA1</i>-driven bone marrow inflammation, above a critical threshold, in a feed-forward manner. Breaking this feed-forward loop (with azacitidine) may thus result in long-term genetic and clinical remission in these patients, a notion that awaits experimental support and/or further long-term observation of VEXAS patients.</p><p>Marc H. G. P. Raaijmakers conceived and supervised the study. Marc H. G. P. Raaijmakers and Anna M. Aalbers were responsible for the clinical care of patients, collected data, and wrote the manuscript. Paul L. A. van Daele and Virgil A. S. H. Dalm were responsible for the clinical care of patients, collected data and edited the manuscript. Peter J. M. Valk coordinated genetic analyses and edited the manuscript.</p><p>The authors declare no conflict of interest.</p><p>This research received no funding.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287193/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"HemaSphere","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/hem3.129","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an inflammatory syndrome caused by acquired mutations in the gene encoding ubiquitin like modifier activating enzyme 1 (UBA1) that is often fatal.1, 2 Allogeneic hematopoietic stem cell transplantation is currently considered the only curative treatment modality.3-6 We were the first to report eradication of virtually all UBA1-mutated cells by the hypomethylating agent azacitidine, reflected in clinical and genetic remissions,7 a finding confirmed in a recent phase II clinical trial.8

Here, we report persistent, long-term (11–84 months) genetic and clinical remissions in VEXAS patients responding to treatment with the hypomethylating agent azacitidine, after cessation of therapy. The data indicate that azacitidine treatment may be an attractive alternative to stem cell transplant for disease eradication in VEXAS syndrome patients and reveal long-term clonal stability of UBA1-mutated cells under homeostatic and inflammatory conditions.

Since its first description in December 2020,1 a UBA1 variant-confirmed diagnosis of VEXAS syndrome was made in 11 patients at our institution until February 2024 (all male, median age at diagnosis 67 years, range 57–77 years). UBA1 mutation detection and panel-based sequencing in these patients was performed as previously reported7 and as described in the Supporting Information Methods section. Of these 11 patients, eight have been exposed to azacitidine (administered at a dose of 75 mg/m2 subcutaneously once daily for 7 days in a 4-weekly schedule). Of the three patients that were not exposed to azacitidine, two patients were treated with corticosteroids and deceased due to infectious complications, and one patient was considered not a candidate for azacitidine treatment due to psychosocial circumstances. In two patients, azacitidine was used as a last resort on an in-house basis, after failure of multiple other lines of treatment, at the time that patients were critically ill (WHO performance status 4) due to VEXAS-related (respiratory) pathology. Both patients died shortly after administration of the first cycle of azacitidine with clinically active disease, and before genetic assessment of response after the first cycle. Six patients received multiple cycles of azacitidine (range, 3–8 cycles) on an out-patient basis with genetic monitoring of disease response. The characteristics of these six patients are listed in Table 1. Patients 1 and 2 carried a concurrent DNMT3A mutation at diagnosis with a variant allele frequency (VAF) of 59% and 30%, respectively, and patient 3 carried a TET2 mutation with a VAF of 4%. In patients 4, 5, and 6 no other mutations were detected by panel-based sequencing. Three of these six patients have been described by us before, including one patient in whom the diagnosis of VEXAS syndrome was made in retrospect, that is, after treatment with azacitidine.7 Long-term follow-up of patients with an initial response to azacitidine is reported here. The study was performed in compliance with the Declaration of Helsinki, and reported patients gave informed consent for study participation.

All six VEXAS patients were treated with azacitidine because they suffered from frequent (life-threatening) inflammatory flares of disease and (in all but patients 4 and 5 transfusion-dependent) anemia, insufficiently responding to treatment with corticosteroids and disease-modifying antirheumatic drugs (DMARDs) and/or biologicals (specified in Table 1) and/or requiring long-term corticosteroid treatment with concomitant adverse events. Of note, four of six VEXAS patients formally fulfilled MDS criteria according to the WHO 2016 classification, based on the presence of cytopenia (anemia Hb <10 g/dL) and dysplasia (≥10% in any lineage), with clonality demonstrated by mutational analyses in three of these four patients.

Five (5/6) patients achieved a clinical and genetic response to azacitidine. In these patients, the VAF of the causative UBA1 variant decreased from a median of 67% (range 56%–86%) in bone marrow or peripheral blood at start of treatment with azacitidine (indicating that the majority of cells in the bone marrow carried the mutation) to ≤1% in bone marrow and/or peripheral blood (range 0%–1%), which was documented after five cycles in four out of five patients (in patient 1, retrospective response assessment was performed firstly after eight cycles). DNMT3A VAF in patient 1 decreased from 59% to 1% and in patient 2 from 30% to 2%, consistent with the notion that azacitidine treatment resulted in the eradication of cells carrying both DNMT3A and UBA1 variants in these patients. Genetic remissions, indicative of a dramatic reduction in the number of UBA1-mutated cells, were associated with complete clinical remissions, defined as complete absence of inflammatory flares of disease, as reflected by long-term normalization of C-reactive protein (CRP) in the blood plasma in these patients, and an increase in hemoglobin levels in all patients (Figure 1). All other immuno-modulatory drugs (e.g., corticosteroids, DMARDs and/or tocilizumab) could be weaned in all responding patients. In the three patients in whom a bone marrow evaluation was performed after achieving a clinical and genetic response, characteristic vacuolisation of erythroid and myeloid precursor cells, and dysplasia of erythroid, myeloid and/or megakaryocytic lineages, disappeared. The patient that was considered a nonresponder to azacitidine (patient 3) received a total of three cycles of azacitidine, after which the mutant UBA1 VAF in bone marrow remained high (VAF 84%). TET2 VAF remained similar before and after treatment (4% and 3%, respectively). Quality of life and anemia had not improved. Clinical symptoms of VEXAS were relatively mild at that time and treatment was stopped, which in retrospect might have been too early to achieve a genetic remission.

In the five responding patients, azacitidine treatment was stopped after achieving a genetic response, arbitrarily defined as mutant UBA1 VAF < 5%. In patient 1 this was done after eight cycles because of treatment for a colon carcinoma, in two other patients the decision to interrupt/stop treatment upon achieving a response after four cycles was based on grade 2–3 adverse effects (fatigue and neutropenia) and the observation in patient 1 that genetic remissions may be maintained after drug cessation. The remaining two responding patients achieved a clinical and genetically-defined response (VAF of mutant UBA1 from 75% to 0% in patient 5, and from 56% to 0% in patient 6) after five cycles recently (at submission of this manuscript, May 2024) and treatment with azacitidine was discontinued after this fifth cycle based on the clinical and genetic response and previous experience with cessation of azacitidine in the other patients. All other immunomodulatory treatment (as specified in Table 1) could be completely stopped in all responding patients, except for patient 1 who continues on prednisolone 5 mg daily for VEXAS-unrelated reasons.

After cessation of azacitidine treatment, the first three responding patients (in whom follow-up after cessation of treatment is present) remained in a clinical and genetic remission with a current median follow up of 31 months (range 11–84 months) after the last cycle of azacitidine (Figure 1). Patients remain free of any VEXAS-related inflammatory manifestations and maintain stable normalized blood levels. The mutant UBA1 VAF in the blood remained relatively stable (range 0%–7%) in all patients during this median follow up of multiple years. We did observe a very gradual increase of the mutant UBA1 VAF (from 1% to 7%) in patient 1 over the course of 7 years. Of further interest, mutant UBA1 VAF was not notably affected by inflammatory episodes caused by a Campylobacter jejuni PCR-positive gastro-enteritis requiring hospitalization (patient 1) and an episode of crystal proven gout requiring hospitalization (patient 2) (Figure 1).

Collectively, these findings confirm relatively high rates of response to azacitidine treatment in VEXAS syndrome, as previously reported by us and others,7-10 and, more importantly, indicate that azacitidine may be safely stopped upon achievement of a genetic response, resulting in long-term genetic and clinical remissions. This is of significant clinical relevance because it would position azacitidine treatment as an attractive alternative to stem cell transplant as the only currently available long-term disease eradicating therapeutic approach in VEXAS syndrome patients. Furthermore, cessation of azacitidine treatment would safeguard patients from frequently occurring adverse effects of the drug, including fatigue, myelosuppression and infectious complications, affecting quality of life. The data warrant incorporation of drug interruption (“holiday”) designs in future prospective clinical trials investigating the value of azacitidine treatment for VEXAS syndrome. The mechanism by which azacitidine eradicates UBA1-mutated cells is not known to date, but it may be hypothesized that a defect in the ubiquitin-proteasome system sensitizes cells to this agent.

Finally, findings might shed new light on the biology of disease and long-term kinetics of mutant UBA1 clones, demonstrating that they can remain stable for many years, even in elderly patients. Although the number of documented infectious or inflammatory episodes is too small to draw conclusions, the data suggest that mutant UBA1 clones may remain stable not only under “homeostatic” conditions but also in the event of “inflammatory stress” caused by infectious or inflammatory conditions. It may be speculated that clonal evolution of UBA1 mutant cells takes many years and, ultimately, clones may be maintained by mutant UBA1-driven bone marrow inflammation, above a critical threshold, in a feed-forward manner. Breaking this feed-forward loop (with azacitidine) may thus result in long-term genetic and clinical remission in these patients, a notion that awaits experimental support and/or further long-term observation of VEXAS patients.

Marc H. G. P. Raaijmakers conceived and supervised the study. Marc H. G. P. Raaijmakers and Anna M. Aalbers were responsible for the clinical care of patients, collected data, and wrote the manuscript. Paul L. A. van Daele and Virgil A. S. H. Dalm were responsible for the clinical care of patients, collected data and edited the manuscript. Peter J. M. Valk coordinated genetic analyses and edited the manuscript.

The authors declare no conflict of interest.

This research received no funding.

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VEXAS 综合征患者停止阿扎胞苷治疗后的长期遗传和临床缓解。
遗传学缓解表明 UBA1 突变细胞的数量急剧减少,与临床完全缓解有关,临床完全缓解的定义是疾病完全没有炎症复发,这体现在这些患者血浆中的 C 反应蛋白(CRP)长期恢复正常,以及所有患者的血红蛋白水平都有所提高(图 1)。所有应答患者均可停用所有其他免疫调节药物(如皮质类固醇、DMARDs 和/或托西珠单抗)。在临床和基因应答后进行骨髓评估的三名患者中,红细胞和髓系前体细胞的特征性空泡化以及红细胞、髓系和/或巨核细胞系的发育不良均已消失。被认为对阿扎胞苷无反应的患者(患者 3)共接受了三个周期的阿扎胞苷治疗,之后骨髓中的突变 UBA1 VAF 仍然很高(VAF 84%)。TET2 VAF 在治疗前后保持相似(分别为 4% 和 3%)。生活质量和贫血没有改善。当时,VEXAS 的临床症状相对较轻,因此停止了治疗,现在回想起来,这可能对实现基因缓解来说为时过早。在五名有应答的患者中,阿扎胞苷治疗在实现基因应答(任意定义为突变 UBA1 VAF &lt;5%)后停止。1号患者在8个周期后因结肠癌治疗而停止治疗,另外两名患者在4个周期后出现应答,决定中断/停止治疗的原因是2-3级不良反应(疲劳和中性粒细胞减少),以及在1号患者中观察到停药后基因缓解仍可维持。其余两名有反应的患者在最近(2024 年 5 月提交本稿件时)五个周期后获得了临床和基因定义的反应(患者 5 突变 UBA1 的 VAF 从 75% 降至 0%,患者 6 突变 UBA1 的 VAF 从 56% 降至 0%),根据临床和基因反应以及之前其他患者停用阿扎胞苷的经验,在第五个周期后停止了阿扎胞苷治疗。在停止阿扎胞苷治疗后,前三例应答患者(停止治疗后进行了随访)的临床和遗传学症状均得到缓解,目前的中位随访时间为阿扎胞苷治疗最后一个周期后的31个月(11-84个月)(图1)。患者仍无任何与 VEXAS 相关的炎症表现,血药浓度保持稳定正常。在多年的中位随访期间,所有患者血液中的突变 UBA1 VAF 均保持相对稳定(范围为 0%-7%)。在 7 年的随访过程中,我们确实观察到患者 1 的突变 UBA1 VAF 逐渐增加(从 1%增至 7%)。更令人感兴趣的是,突变型 UBA1 VAF 并没有受到炎症发作的明显影响,炎症发作包括空肠弯曲杆菌 PCR 阳性的胃肠炎(患者 1)和晶体证明的痛风发作(患者 2),前者需要住院治疗(图 1)。总之,这些研究结果证实,正如我们和其他人之前所报道的那样,VEXAS 综合征患者对阿扎胞苷治疗的反应率相对较高7-10 ,更重要的是,这些研究结果表明,在获得基因应答后,可以安全地停用阿扎胞苷,从而获得长期的基因和临床缓解。这具有重要的临床意义,因为这将使阿扎胞苷治疗成为干细胞移植的一种有吸引力的替代疗法,而干细胞移植是目前唯一可用于VEXAS综合征患者的长期根除疾病的治疗方法。此外,停止阿扎胞苷治疗将保护患者免受该药物经常出现的不良反应,包括疲劳、骨髓抑制和感染并发症,从而影响生活质量。这些数据表明,在今后研究阿扎胞苷治疗 VEXAS 综合征价值的前瞻性临床试验中,应采用药物中断("假日")设计。迄今为止,阿扎胞苷根除UBA1突变细胞的机制尚不清楚,但可以假设泛素蛋白酶体系统的缺陷使细胞对这种药物敏感。最后,研究结果可能会对疾病的生物学特性和突变UBA1克隆的长期动力学产生新的启示,证明它们可以保持稳定多年,甚至在老年患者中也是如此。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
HemaSphere
HemaSphere Medicine-Hematology
CiteScore
6.10
自引率
4.50%
发文量
2776
审稿时长
7 weeks
期刊介绍: HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.
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