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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 bee

The survival rates for pediatric patients with primary refractory or high-risk relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL), treated with chemotherapy-based protocols and followed by allogeneic hematopoietic cell transplantation (HCT), range from 15% to 30%.¹ These outcomes are even more unfavorable in countries with evolving healthcare insurance systems due to treatment-related mortality and financial toxicity.² The long-term event-free survival for such high-risk relapse of B-ALL is dependent on achieving minimal residual disease (MRD) negativity prior to HCT.³

In the past decade, there have been significant advancements in targeted antibody-based immunotherapies for managing r/r B-ALL.^4-11 Blinatumomab (Blina) is a T-cell engager that provides an antileukemic effect by targeting cytotoxic T cells to CD19-expressing cancer cells. Several studies have revealed the excellent efficacy of Blina in low-burden disease.^4-8 However, recipients of Blina with high tumor burden have low response rates and are at risk of severe cytokine release syndrome (CRS).⁹ Whereas, Inotuzumab ozogamicin (InO) targets CD22, which is conjugated to calicheamicin, a potent cytotoxic agent and works well even for high-burden disease with response rates as high as 80%.^{10, 11}

To optimize the use of these novel immunotherapies in r/r B-cell ALL, we designed a disease-burden-adapted protocol of InO followed by Blina for high-burden (minimal residual disease (MRD) > 5%) CD22+ CD19+ disease and Blina only for low-burden (MRD ≤ 5%) CD19+ disease.

This is a retrospective analysis of 39 patients with r/r B-cell ALL patients aged 1–18 years treated in three centers from January 2018 to August 2023. Patients were treated with a chemotherapy-based protocol from January 2018 to April 2021 and on a disease-burden-adapted immunotherapy protocol from May 2021 to August 2023.

End-of-induction (EOI) MRD of >5% with high-risk cytogenetics or age >16 years and all patients with end-of-consolidation (EOC) MRD > 0.1% irrespective of age or cytogenetics were considered primary refractory. Very early relapse (<18 months from diagnosis; marrow or isolated extramedullary), early relapse (18–36 months from diagnosis or until 6 months off therapy; marrow or isolated extramedullary), and late relapse (≥36 months from diagnosis or >6 months off therapy; marrow or isolated extramedullary) with postrelapse induction MRD of ≥0.1% and second relapse with any level of disease were considered as high-risk.

A fractionated dose of InO as 1.8 mg/m² per course was administered intravenously over 1 h on Days 1, 8, and 15 of 28-day cycle as previously described.^{10, 11} Blina was given as a 28-day continuous intravenous infusion. The first 7 days of the f

A second autologous stem-cell transplantation (ASCT2) is considered for relapsed multiple myeloma (RMM) patients showing prolonged response after a first ASCT. However, given breakthrough treatments like anti-CD38 and immunotherapy, its role remains debated. We conducted a real-life study in 10 French centers (1996–2017) involving 267 RMM patients receiving ASCT2. The median age was 61 years, with 49% females. Most patients received melphalan 200 mg/m² before ASCT2, with low early mortality (1%). Very good partial response or better (VGPR+) rate post ASCT2 was 78%. Post ASCT2, 48% received consolidation therapy and 40% maintenance therapy. Median event-free survival (EFS) after ASCT2 was 2.6 years (95% confidence interval [CI]: 2.3–2.8), and 2-year EFS estimate was 63% (95% CI: 57–70). Median overall survival (OS) was 8.1 years (95% CI: 5.9–NA), and 2-year OS estimate was 92% (95% CI: 88–95). Multivariate analysis revealed that VGPR+ status and maintenance therapy post ASCT2 were associated with better EFS (hazard ratio [HR]: 0.6; 95% CI: 0.3–0.9, p = 0.012 and HR: 0.4; 95% CI: 0.3–0.6, p < 0.001, respectively) and OS (HR: 0.4; 95% CI: 0.2–0.9, p = 0.017 and HR: 0.2; 95% CI: 0.1–0.4, p < 0.001, respectively), while male sex correlated with poorer outcomes for EFS (HR: 2.5; 95% CI: 1.7–3.7, p < 0.001) and OS (HR: 2.7; 95% CI: 1.4–4.9, p = 0.002). Overall, ASCT2 appeared efficient with low toxicity in RMM. Maintenance therapy was associated with extended EFS and OS, particularly in patients with VGPR+ status post ASCT2. These findings underscore ASCT2's potential in RMM when coupled with maintenance therapy in selected patients.

Sickle cell disease (SCD) results from mutations in the β-globin gene, producing abnormal hemoglobin S (HbS) and leading to complications causing significant morbidity and mortality.¹ One of the hallmark consequences of SCD is the occurrence of vaso-occlusive crises (VOCs), which arise from the interplay of factors in the disease's pathophysiology, involving abnormal hemoglobin polymerization, inflammation, endothelial dysfunction, and activation of the immune system, culminating in the painful obstruction of blood vessels by sickled red blood cells, that tend to obstruct blood vessels, leading to reduced blood flow and oxygen supply. This vicious cycle of ischemia followed by reperfusion constitutes the ischemia-reperfusion model.²

The complement system, a complex defense mechanism, is implicated in various diseases through unregulated activation.³ However, diagnostic challenges hinder patient selection for complement inhibition.⁴ Preliminary data from our group using novel assays indicate complement activation even at a steady state in a limited patient population.⁵

Limited information exists on additional markers in the complement activation and endothelial dysfunction cycle in SCD. Neutrophil extracellular traps (NETs), indicative of thromboinflammation, are elevated in SCD patients, even during steady state.⁶ ADAMTS13 (A Disintegrin and Metalloproteinase with Thrombospondin motifs), studied for its role in SCD vasculopathy, shows conflicting results as a potential biomarker.^{7, 8} Genetic variants and autoantibodies leading to unregulated complement activation are implicated in the pathogenesis of various human diseases.⁹

Despite the lack of specific biomarkers or targeted treatments for crises, our hypothesis posits the presence of complement activation and thromboinflammation in SCD, particularly during complications, with distinct yet unexplored clinical or genetic features in these patients.

Our study's methods regarding patient population, observation period, functional assays, and genetic, bioinformatic, and statistical analysis are demonstrated in supplementary materials. Our study included 81 adult SCD patients who are treated in different Hemoglobinopathies Units across Northern Greece. Their median age was 41 years, and 50 were female (61.7%). As expected in our population, the majority had the S/beta genotype (62), while 19 patients had the S/S genotype. Twenty-three presented SCD complications during the observation period (17 vaso-occlusive crises and six proteinuria/nephropathy) and were studied during this complication. Importantly, none of the patients that presented with renal damage, was on deferasirox, or other iron chelation therapy. The remaining 58 patients were studied at the end of the observation period.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two BCMA-directed CAR T-cells approved for the treatment of relapsed or refractory multiple myeloma. Similar to CD19-directed CAR T-cells, acute adverse events may occur after BCMA-directed CAR T-cells, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). However, a new type of neurotoxicity has been recently reported in patients treated with BCMA-directed CAR T-cells, the so-called movement and neurocognitive toxicity (MNT). Common features include late onset of Parkinson-like symptoms such as tremor, bradykinesia, and neurocognitive disorder. Only 10 cases of MNT occurring after BCMA-directed CAR T-cells have been reported so far (Table 1). The symptoms appeared with a median time of 36 days (range, 14–914 days). Interestingly, all cases occurred in male patients and after cilta-cel except for one patient who had been treated with ide-cel.⁴ MNT has been associated with high expansion and persistence of circulating CAR T-cells, cerebrospinal fluid infiltration by CAR T-cells, and no clear response to levodopa. Autopsy report from a patient who died shortly after presenting with MNT showed a T-cell infiltrate in the periventricular region of the basal ganglia as well as BCMA expression in the basal ganglia, suggesting an on-target off-tumor toxicity.¹ BCMA expression was also found on basal ganglia cells of healthy subjects.¹ Potential risk factors of MNT include high tumor burden at baseline before the start of lymphodepletion, grade ≥2 CRS, occurrence of ICANS, high CAR T-cell expansion, and prolonged persistence.¹ Management of this new and rare toxicity remains poorly defined. Corticosteroids, systemic chemotherapy, anakinra, intrathecal injections of cytarabine and steroids, IV Ig, and plasmaspharesis have been tested without clear benefit. Most patients experience mild or no improvement of their symptoms. In some patients, symptoms worsen and may lead to death.

Here, we report the case of two female patients who developed parkinsonism after ide-cel infusion.

Patient 1 is a 74-year-old woman who had been diagnosed with monoclonal gammopathy of unknown significance in 2003, which progressed to multiple myeloma in 2009. Before undergoing CAR T-cell therapy, she had received 11 prior lines of therapy including chemotherapy, IMIDs, proteasome inhibitors, daratumumab, and lastly talquetamab, a CD3/GPRC5D bispecific antibody. She was offered CAR T-cell therapy after developing lytic bone lesions while being treated with talquetamab. She received bridging therapy with Selinexor, which allowed partial metabolic response. After ide-cel infusion, she developed grade 1 CRS on Day 2 and no ICANS. She did not require treatment with tocilizumab nor dexamethasone. She was discharged on Day 10 postinfusion.

I

Teclistamab, a T-cell redirecting bispecific antibody (BsAb) targeting B-cell maturation antigen (BCMA), has marked activity in heavily pretreated multiple myeloma (MM) patients (overall response rate: 63.0%; at least very good partial response [≥VGPR]: 59.4%; median progression-free survival [PFS]: 11.3 months).^{1, 2} Teclistamab treatment induces T-cell activation and production of proinflammatory cytokines such as interleukin-6 (IL-6).³ This increase in cytokines frequently results in a systemic inflammatory response syndrome (cytokine-release syndrome [CRS]), characterized by fever, and in more severe cases also hypotension and hypoxia.^{1, 2, 4, 5} CRS mitigation strategies include step-up dosing and premedication with steroids and antihistamines. The incidence of CRS in teclistamab-treated patients was 72.1% (grade 2: 21.2%; grade ≥3: 0.6%) with most CRS events occurring during step-up dosing.^{1, 2, 4} Recurrent CRS occurred in 33.3% of the patients.⁴ Patients are generally hospitalized for the administration of the step-up doses and first full dose to adequately monitor for early signs and symptoms of CRS (median hospital stay in a real-world setting: 10 days).^{1, 6} Treatment of CRS with steroids or the IL-6 receptor-blocking antibody tocilizumab is effective with rapid resolution of symptoms.^{3, 4} Patients who received tocilizumab for their first CRS event were less likely to experience a subsequent CRS event compared to those who did not receive tocilizumab (20.0% vs. 62.2%).⁴ A single dose of tocilizumab blocks the IL-6 receptor for approximately 10 days and covers the full step-up dosing period.⁷ Based on these data, we aimed to evaluate the efficacy of tocilizumab administered prior to the first step-up dose to prevent the development of CRS following the initiation of teclistamab therapy in 29 patients treated in our hospital.

Teclistamab was administered according to the approved schedule with two step-up doses (0.06 and 0.3 mg/kg) followed by the full dose of 1.5 mg/kg every week (48–72 h between step-up doses and the first full dose). In patients undergoing hemodialysis, teclistamab was given directly after hemodialysis sessions. Prophylactic tocilizumab (8 mg/kg intravenously [IV]; maximum dose of 800 mg) was administered 1 h prior to the first step-up dose. Patients also received 16 mg dexamethasone, 2 mg clemastine, and 1000 mg acetaminophen 1 h prior to both step-up doses and the first full dose. All patients received herpes zoster (valacyclovir) and Pneumocystis jirovecii pneumonia prophylaxis (co-trimoxazole, or pentamidine in case of co-trimoxazole allergy). Granulocyte colony-stimulating factor was considered in cases of grade ≥3 neutropenia, and IgG replacement was given in cases with polyclonal IgG <

The advent of BCL-2 inhibitor-based time-limited therapies has currently replaced chemoimmunotherapy as one standard of care in chronic lymphocytic leukemia (CLL). Despite many differences in efficacy and safety profile, both treatment approaches achieve similarly high rates of undetectable measurable residual disease (U-MRD).^{1, 2} U-MRD has been shown to correlate with progression-free survival (PFS) and even with overall survival (OS) within the MURANO trial,³ as well as in the CLL14 trial.⁴ Currently, U-MRD is accepted by the European Medicines Agency (EMA) as intermediate endpoint within clinical trials.⁵

The iwCLL 2018 response criteria require a bone marrow (BM) aspirate and trephine biopsy for confirmation of complete remission, with immunohistochemistry (IHC) recommended as a tool to differentiate between CLL cells versus benign T- and B-cell infiltrates.⁶ While the prognostic value of measurable residual disease (MRD) in CLL has been extensively studied before,^7-11 the role of BM assessments by IHC on trephine biopsies has not yet been evaluated. As both BM aspirations and trephine biopsies are collected using an invasive procedure, their added valued remained a matter of debate. Therefore, prognostic value of BM IHC and flow cytometry-based BM MRD assessments is analyzed herein. Moreover, we investigated whether or not sensitive MRD assessments in the peripheral blood (PB) might be able to completely replace the need for BM assessments. Finally, the impact of central versus local pathology investigations are evaluated.

Patient data were derived from the prospective, randomized CLL10 trial of the GCLLSG, in which chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) was administered. BM aspiration and biopsy were performed at final staging 2 months (+28 days) after end of therapy. Central assessment of BM trephine biopsy material for IHC was performed by the hematopathology department in Kiel in conjunction with the prior local pathology. To this end, pathologists aim to identify lymphoid cells with a CLL phenotype in aggregates of lymphoid cells according to the current WHO classification¹² by superimposing B-cell distribution pattern detected by CD20, CD19, or CD79a with the staining for CD5 and CD23 on separate slides. B-cell markers were stained according to standard protocols on an automated stainer. MRD was assessed in the central laboratory in Kiel by four-color flow cytometry at a threshold of 10⁻⁴ as previously described.^{13, 14}

We compared the impact of MRD and IHC using Kaplan–Meier landmark analyses of PFS and OS from the time point of sample assessment with log-rank tests and Cox proportional hazards regression modeling. Independent prognostic baseline

Targeting B-cell maturation antigen (BCMA) on myeloma cells has led to improved clinical benefit in heavily pretreated patients with relapsed or refractory multiple myeloma (RRMM), including those patients with triple-class exposed disease.¹ Elranatamab, a humanized BCMA-CD3 bispecific antibody, was approved for the treatment of patients with RRMM based on the results from the registrational MagnetisMM-3 study, which enrolled patients previously treated with at least one immunomodulatory drug, one proteasome inhibitor, and one anti-CD38 monoclonal antibody.^{2, 3} Among BCMA-naive patients (n = 123), treatment with elranatamab led to an objective response rate (ORR) of 61.0%, with 35.0% of patients achieving a complete response (CR) or better.⁴ After a descriptive median follow-up of 14.7 months (data cutoff approximately 14 months after the last patient's initial dose), the median progression-free survival (PFS) and overall survival (OS) had not been reached, making it difficult to contextualize the survival outcomes in the treatment landscape for RRMM.⁴ Here, we report updated results, including Kaplan–Meier estimates of PFS and OS after a longer follow-up.

As of the data cutoff of March 26, 2024 (approximately 26 months after the last patient's initial dose), with a median follow-up of 28.4 months (95% confidence interval [CI], 28.0–29.0; estimated by reverse Kaplan–Meier), the ORR was 61.0%, with 37.4% of patients achieving CR or better. Among responders, the median duration of response was not yet reached, and the probability of maintaining response at 24 months was 66.9% (95% CI, 54.4–76.7). The median PFS was 17.2 months (95% CI, 9.8–not-estimable [NE]) (Figure 1) and the median OS was 24.6 months (95% CI, 13.4–NE) (Figure 2).

No new safety signals emerged with longer follow-up. Hematologic adverse events in ≥25% (any grade, maximum grade 3/4) of the patient population included neutropenia (49.6%, 49.6%), anemia (48.8%, 37.4%), thrombocytopenia (31.7%, 23.6%), and lymphopenia (26.8%, 25.2%). Other adverse events of interest observed in patients included infections (70.7%; 42.3% maximum grade 3/4; 6.5% grade 5), cytokine release syndrome (57.7%; all grade ≤2), and immune effector cell–associated neurotoxicity (4.9%; all grade ≤2).

Elranatamab monotherapy continues to improve survival outcomes without new safety signals. Despite the refractory patient population with a high percentage of patients with poor prognostic features in MagnetisMM-3, the median PFS of 17.2 months and the median OS of 24.6 months observed with additional follow-up are promising among bispecific antibodies currently approved for RRMM. In an analysis of MajesTEC-1 with a median follow-up of 23 months, BCMA-naive patients treated with teclistamab had a median PFS of 11.3 months (95% CI, 8.8–16.4) and a median OS of 21.9 months (95% CI, 15.1–NE).

Ferreri AJM, Illerhaus G, Doorduijn JK, et al. Primary central nervous system lymphomas: EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. HemaSphere. 2024;8:e89.

In the author listing of this manuscript, the first name of the first author was misspelled. The correct spelling is Andrés JM Ferreri.

The original article has been corrected. We apologize for this error.

Patients with chronic lymphocytic leukemia (CLL) exhibit diverse clinical outcomes. An expanding array of genetic tests is now employed to facilitate the identification of patients with high-risk disease and inform treatment decisions. These tests encompass molecular cytogenetic analysis, focusing on recurrent chromosomal alterations, particularly del(17p). Additionally, sequencing is utilized to identify TP53 mutations and to determine the somatic hypermutation status of the immunoglobulin heavy variable gene. Concurrently, a swift advancement of targeted treatment has led to the implementation of novel strategies for patients with CLL, including kinase and BCL2 inhibitors. This review explores both current and emerging diagnostic tests aimed at identifying high-risk patients who should benefit from targeted therapies. We outline existing treatment paradigms, emphasizing the importance of matching the right treatment to the right patient beyond genetic stratification, considering the crucial balance between safety and efficacy. We also take into consideration the practical and logistical issues when choosing a management strategy for each individual patient. Furthermore, we delve into the mechanisms underlying therapy resistance and stress the relevance of monitoring measurable residual disease to guide treatment decisions. Finally, we underscore the necessity of aggregating real-world data, adopting a global perspective, and ensuring patient engagement. Taken together, we argue that precision medicine is not the mere application of precision diagnostics and accessibility of precision therapies in CLL but encompasses various aspects of the patient journey (e.g., lifestyle exposures and comorbidities) and their preferences toward achieving true personalized medicine for patients with CLL.