126 reads in the past 30 days
Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous diseaseMay 2024
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205 Reads
Published by Wiley and British Society for Haematology
Online ISSN: 1365-2141
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Print ISSN: 0007-1048
Disciplines: Hematology
126 reads in the past 30 days
Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous diseaseMay 2024
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205 Reads
48 reads in the past 30 days
Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I‐BFM Study GroupMay 2024
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48 Reads
41 reads in the past 30 days
Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c geneMay 2024
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43 Reads
32 reads in the past 30 days
Pyruvate kinase deficiency in 29 Turkish patients with two novel intronic variantsMay 2024
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32 Reads
30 reads in the past 30 days
Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3August 2023
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91 Reads
An official journal of the British Society for Haematology, the British Journal of Haematology offers your research high visibility, receiving nearly 5 million article downloads annually. Content is delivered through a range of article types, including Original Papers, Reviews, BSH Guidelines, Images, and Wider Perspectives and Global View papers. The journal covers every specialism within haematology and welcomes high quality papers not just in clinical practice, but in the fields of basic science, translational research, and developments in haematology science. With fast turnaround times and personalized feedback from experts in the field, we provide a friendly submissions process that works collaboratively across haematology so every submitted paper has a home.
June 2024
June 2024
Maria Eva Mingot‐Castellano
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Jose Maria Bastida
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Waleed Ghanima
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[...]
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Mariana Canaro
Immune thrombocytopenia (ITP) refractory to multiple therapies may require a combination of drugs targeting different mechanisms and targets. In this retrospective, multicentre, international study, we report the safety and effectiveness of avatrombopag and fostamatininb in combination administered to 18 patients with multirefractory ITP. Overall, the combination response was achieved in 15 patients (83.3%), with a median time from combination start to best response of 15 days (IQR: 8–35 days). After a median follow‐up of 256 days (IQR: 142.8–319), 5 patients relapsed (26.7%), all during tapering or stopping one drug. Adverse events were described in 6 of 18 patients (33%).
June 2024
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2 Reads
Ibrahim N. Muhsen
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Helen E. Heslop
Immune response to vaccinations is dampened in patients with indolent lymphomas due to disease and treatment‐related factors. The study by Lim et al. demonstrated impaired humoral response but intact cellular response to the SARS‐CoV2 vaccine in patients with follicular lymphoma receiving front‐line therapy. The results highlight the importance of several factors in predicting immune response to vaccination and provide estimates of immune response for different clinical scenarios and treatment points. Commentary on: Lim et al. Immunogenicity of COVID‐19 vaccines in patients with follicular lymphoma receiving frontline chemoimmunotherapy. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19562.
June 2024
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2 Reads
M. Nelson
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L. Noisette
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N. Pugh
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[...]
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J. Kanter
Sickle cell disease (SCD) includes a group of heterogenous disorders that result in significant morbidities. HbSS is the most common type of SCD and HbSC is the second most common type of SCD. The prevalence of HbSC disease in the United States and United Kingdom is ~1 in 7174 births and 1 in 6174 births respectively. Despite its frequency, however, HbSC disease has been insufficiently studied and was historically categorized as a more ‘mild’ form of SCD. We conducted this study of HbSC disease as part of the NHLBI funded Sickle Cell Disease Implementation Consortium (SCDIC). The SCDIC registry included 2282 individuals with SCD, ages 15–45 years of whom 502 (22%) had HbSC disease. Compared with people with sickle cell anaemia (SCA), the study found that people with HbSC disease had a higher frequency of splenomegaly (n (%) = 169 (33.7) vs. 392 (22.1)) and retinopathy (n (%) = 116 (23.1) vs. 189 (10.6)). A Many people with HbSC also had avascular necrosis (n (%) = 112 (22.3)), pulmonary embolism (n (%) = 43 (8.6)) and acute chest syndrome (n (%) = 228 (45.4)) demonstrating significant disease severity. HbSC disease is more clinically severe than was previously recognized and deserves additional evaluation and targeted treatments.
June 2024
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3 Reads
Iñaki Ortiz de Landazuri
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Aina Oliver‐Caldés
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Marta Español‐Rego
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[...]
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Carlos Fernández de Larrea
Chimeric antigen receptor (CAR) T‐cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M‐protein. Quantitative immunoprecipitation mass spectrometry (QIP‐MS) can accurately measure serum M‐protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP‐MS in 33 patients treated with the academic BCMA‐directed CAR T‐cell ARI0002h (Cesnicabtagene Autoleucel). QIP‐MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M‐proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP‐MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)‐based next‐generation flow cytometry (NGF). Furthermore, QIP‐MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP‐MS(+)/BM‐based NGF(−) showed a non‐significant shorter median progression free survival than those with QIP‐MS(−)/BM‐based NGF(−). In summary, we show the first experience to our knowledge demonstrating that QIP‐MS could be particularly useful as a non‐invasive technique when evaluating response after CAR T‐cell treatment in MM.
June 2024
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2 Reads
The transcription factor GATA2 has a pivotal role in haematopoiesis. Heterozygous germline GATA2 mutations result in a syndrome characterized by immunodeficiency, bone marrow failure and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukaemia. Clinical symptoms in these patients are diverse and mechanisms driving GATA2‐related phenotypes are largely unknown. To explore the impact of GATA2 haploinsufficiency on haematopoiesis, we generated a zebrafish model carrying a heterozygous mutation of gata2b (gata2b+/−), an orthologue of GATA2. Morphological analysis revealed myeloid and erythroid dysplasia in gata2b+/− kidney marrow. Because Gata2b could affect both transcription and chromatin accessibility during lineage differentiation, this was assessed by single‐cell (sc) RNA‐seq and single‐nucleus (sn) ATAC‐seq. Sn‐ATAC‐seq showed that the co‐accessibility between the transcription start site (TSS) and a −3.5–4.1 kb putative enhancer was more robust in gata2b+/− zebrafish HSPCs compared to wild type, increasing gata2b expression and resulting in higher genome‐wide Gata2b motif use in HSPCs. As a result of increased accessibility of the gata2b locus, gata2b+/− chromatin was also more accessible during lineage differentiation. scRNA‐seq data revealed myeloid differentiation defects, that is, impaired cell cycle progression, reduced expression of cebpa and cebpb and increased signatures of ribosome biogenesis. These data also revealed a differentiation delay in erythroid progenitors, aberrant proliferative signatures and down‐regulation of Gata1a, a master regulator of erythropoiesis, which worsened with age. These findings suggest that cell‐intrinsic compensatory mechanisms, needed to obtain normal levels of Gata2b in heterozygous HSPCs to maintain their integrity, result in aberrant lineage differentiation, thereby representing a critical step in the predisposition to MDS.
June 2024
Ezer Moysis
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Biobele J. Brown
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Wuraola Shokunbi
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[...]
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Delmiro Fernandez‐Reyes
In sub‐Saharan Africa, acute‐onset severe malaria anaemia (SMA) is a life‐threatening condition, particularly affecting children under five, requiring immediate blood transfusion followed by the administration of antimalarial treatment. The WHO defines SMA as a haemoglobin (Hb) concentration lower than 0.5 g/dL (or a haematocrit <16.0%) in the presence of any parasite density. The acute drop in haematocrit in SMA is thought to be driven by an increased phagocytotic pathological process in the spleen, leading to the presence of distinct red blood cells (RBCs) with altered morphological characteristics. While point‐of‐care diagnosis is based on clinical presentation at admission, assessment of haematocrit and the analysis of a peripheral thick blood film to detect the presence of malaria parasites, SMA is challenging to diagnose in patients presenting with very low parasitaemia. In this study, we develop and validate a novel deep learning tool (Multiple Instance Learning framework, to Identify SMA [MILISMA]) designed to complement existing SMA diagnostic frameworks by identifying subtle, morphological changes in RBCs that potentially signal the onset of SMA prior to the manifestation of clinical symptoms as defined by current WHO criteria. Our model can systematically and at scale discern these early RBC morphological signals, thereby offering a valuable resource for closely monitoring patients at risk of SMA. The presence of such abnormal RBCs in high numbers could be a clinical indicator that a patient is developing SMA, and it is especially useful in very low parasitaemia cases. Such predictive capability is particularly crucial in facilitating timely interventions, potentially preventing the progression to severe anaemia and thus improving patient outcomes. image
June 2024
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2 Reads
Chimeric antigen receptor (CAR)‐T‐cell therapy has demonstrated considerable efficacy and safety in the treatment of patients with relapsed/refractory haematological malignancies. Owing to significant advances, CAR‐T‐cell therapeutic modality has undergone substantial shifts in its clinical application. Coagulation abnormalities, which are prevalent complications in CAR‐T‐cell therapy, can range in severity from simple abnormalities in coagulation parameters to serious haemorrhage or disseminated intravascular coagulation associated with life‐threatening multiorgan dysfunction. Nonetheless, there is a lack of a comprehensive overview concerning the coagulation abnormalities associated with CAR‐T‐cell therapy. With an aim to attract heightened clinical focus and to enhance the safety of CAR‐T‐cell therapy, this review presents the characteristics of the coagulation abnormalities associated with CAR‐T‐cell therapy, including clinical manifestations, coagulation parameters, pathogenesis, risk factors and their influence on treatment efficacy in patients receiving CAR‐T‐cell infusion. Due to limited data, these conclusions may undergo changes as more experience accumulates.
June 2024
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1 Read
MLL‐rearranged (MLL‐r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL‐r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI‐503, a potent menin‐MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34⁺ cells. In vivo treatment with SD70 and MI‐503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA‐seq following combined pharmacological inhibition of SD70 and MI‐503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI‐503 is a potential dual‐targeted therapy for MLL::AF9 AML.
June 2024
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9 Reads
Chronic myeloid leukaemia (CML) management is complicated by treatment‐emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management.
June 2024
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19 Reads
Secondary primary malignancies (SPM) have been reported after anti‐BCMA or anti‐CD19 chimeric antigen receptor (CAR)‐T‐cell therapies. While the cytotoxic effect of antecedent therapies, including chemotherapy and radiotherapy, has been well established, few data are available on risk related to CAR‐T immunotherapies. The study aimed to analyse the incidence of SPM in 651 patients enrolled in the Italian prospective observational CART‐SIE study. SPMs were documented in 4.3% (28/651), and the most frequent SPMs were haematological malignancies. In conclusion, the frequency of SPMs in our cohort of heavily pretreated patients receiving CAR‐T was relatively low and consistent with previous studies.
June 2024
June 2024
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8 Reads
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1 Citation
Immune responses to primary COVID‐19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016–004010‐10). COVID‐19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4⁺ T cells) or cyclophosphamide‐based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS‐CoV‐2 spike protein using the Abbott Architect and interferon‐gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T‐cell responses. Within the FL cohort, multivariable analysis identified low pre‐treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T‐cell responses, and bendamustine and high/intermediate FLIPI‐2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID‐19 vaccines in FL patients is influenced by multiple disease‐ and treatment‐related factors, among which B‐cell depletion showed differential effects on antibody and T‐cell responses.
June 2024
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31 Reads
Patients with sickle cell disease (SCD) often experience painful vaso‐occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso‐occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility.
June 2024
Upregulation of the Wilms' tumour 1 (WT1) gene is common in acute myeloid leukaemia (AML) and is associated with poor prognosis. WT1 generates 12 primary transcripts through different translation initiation sites and alternative splicing. The short WT1 transcripts express abundantly in primary leukaemia samples. We observed that overexpression of short WT1 transcripts lacking exon 5 with and without the KTS motif (sWT1+/− and sWT1−/−) led to reduced cell growth. However, only sWT1+/− overexpression resulted in decreased CD71 expression, G1 arrest, and cytarabine resistance. Primary AML patient cells with low CD71 expression exhibit resistance to cytarabine, suggesting that CD71 may serve as a potential biomarker for chemotherapy. RNAseq differential expressed gene analysis identified two transcription factors, HOXA3 and GATA2, that are specifically upregulated in sWT1+/− cells, whereas CDKN1A is upregulated in sWT1−/− cells. Overexpression of either HOXA3 or GATA2 reproduced the effects of sWT1+/−, including decreased cell growth, G1 arrest, reduced CD71 expression and cytarabine resistance. HOXA3 expression correlates with chemotherapy response and overall survival in NPM1 mutation‐negative leukaemia specimens. Overexpression of HOXA3 leads to drug resistance against a broad spectrum of chemotherapeutic agents. Our results suggest that WT1 regulates cell proliferation and drug sensitivity in an isoform‐specific manner.
June 2024
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4 Reads
The documented treatment‐induced excess mortality in Hodgkin lymphoma (HL) has spurred important treatment changes over recent decades. This study aimed to examine mortality among young HL patients treated with contemporary strategies, including historical data comparison. This nationwide study included 1348 HL patients, diagnosed in 1995–2015 and aged 15–40 at diagnosis. Among the patients, 66.5% had Ann Arbor stage I–II and 33.5% had stage III–IV disease. With a median follow‐up of 14.76 years, 139 deaths occurred, yielding a 5‐year overall survival of 94.6%. Older age, advanced disease, earlier treatment periods and extensive regimens were associated with higher overall mortality risk. The cumulative risk of HL‐related death showed an initial sharp rise, with a plateau at 5.3% 10‐year post‐diagnosis. Deaths due to cardiovascular or pulmonary diseases and second cancers initially had minimal risk, gradually reaching 1.2% and 2.0% at the 20‐year mark respectively. HL cases had a 7.5‐fold higher mortality hazard than the background population. This study suggests that contemporary HL treatment still poses excess mortality risk, but recent changes have notably reduced overall and cause‐specific mortality compared to earlier eras. Balancing treatment efficacy and toxicity remains crucial, but our findings highlight improved outcomes with modern treatment approaches.
June 2024
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29 Reads
Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR‐ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well‐tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts.
June 2024
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6 Reads
June 2024
June 2024
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29 Reads
In Australia, bortezomib‐based induction (V‐IND) is used in >90% of newly diagnosed transplant‐eligible multiple myeloma (MM) patients. Four cycles of V‐IND with bortezomib–cyclophosphamide–dexamethasone or bortezomib–lenalidomide–dexamethasone are available via the Pharmaceutical Benefits Scheme prior to autologous stem cell transplantation (ASCT). Patients who demonstrate suboptimal response or who are refractory to V‐IND demonstrate inferior survival, representing a subgroup of MM where an unmet need persists. We evaluated an early, response‐adapted approach in these patients by switching to an intensive sequential therapeutic strategy incorporating daratumumab–lenalidomide–dexamethasone‐based (DRd) salvage, high‐dose melphalan ASCT followed by DRd consolidation and R maintenance. The overall response rate following four cycles of DRd salvage was 72% (95% credible interval: 57.9–82.4); prespecified, dual, Bayesian proof‐of‐concept criteria were met. Euro‐flow minimal residual disease (MRD) negativity was 46% in the intention‐to‐treat population and 79% in the evaluable population following 12 cycles of DRd consolidation. At the 24‐month follow‐up, median progression‐free survival and overall survival were not reached. DRd salvage was well tolerated with grade 3 and 4 events reported in 24% and 8% respectively. Response‐adapted DRd combined with ASCT achieves high rates of MRD negativity and durable disease control in this functional high‐risk group.
June 2024
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14 Reads
We compared serum anti‐Mullerian hormone (AMH) levels in women with sickle cell disease (SCD) (n = 152) to those of Black comparison women (n = 128) between the ages of 20 and 45 years and evaluated the impact of hydroxyurea (HU) and iron overload on ovarian reserve in those with SCD. SCD treatment was abstracted from medical records. Linear regression models were fit to examine the relationship between log(AMH) and SCD, adjusting for age. The analysis was repeated to account for HU use (current, previous, never) and iron overload (ferritin ≥1000 ng/mL vs. <1000 ng/mL). AMH estimates among women with SCD were lower than those among comparison women (2.23, 95% confidence interval [CI] 1.80–2.76 vs. 4.12, 95% CI 3.11–5.45, respectively). Women with SCD who were currently using HU had 63% lower (95% CI 43–76) AMH values than comparison women; those with SCD with prior or no HU use also had lower AMH estimates than comparison women, but the difference was less pronounced. There were no differences in predicted AMH values among women with SCD for those with and without iron overload. Women with SCD and low AMH may have a shorter reproductive window and may benefit from referral to a reproductive specialist.
June 2024
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10 Reads
Access to upfront daratumumab for AL amyloidosis is expanding, but it is not universal. Bomsztyk et al. show that patients who do not receive front‐line daratumumab can be effectively rescued with this agent, indicating that deep haematological response should be pursued tenaciously. Commentary on: Bomsztyk et al. Response rates to second‐line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain (AL) amyloidosis after initial bortezomib‐based regime. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19529.
June 2024
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5 Reads
June 2024
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19 Reads
Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second‐line daratumumab‐bortezomib‐dexamethasone (DVD) in AL amyloidosis in bortezomib‐exposed patients. A total of 116 patients treated with second‐line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second‐line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event‐free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2‐year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second‐line treatment in systemic AL amyloidosis in a bortezomib‐exposed population. However, the response to DVD is poorer in those with an inadequate response to first‐line bortezomib.
June 2024
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11 Reads
For patients with relapsed or refractory AML, sequential conditioning prior to allogeneic stem cell transplantation (alloSCT) is an established and potentially curative treatment option. Early response to treatment during conditioning indicates chemotherapy‐responsive disease and may have prognostic value. We retrospectively evaluated blast clearance on day 5 after melphalan, administered 11 days prior to alloSCT as part of a sequential conditioning in 176 patients with active AML. Overall survival (OS) was 52% (95% confidence interval [CI] 45%–60%), and relapse‐free survival (RFS) was 47% (95% CI 40%–55%) at 3 years. Patients who achieved early blast clearance did not show a significant improvement in OS and RFS (OS, hazard ratio [HR] HR 0.75, p 0.19; RFS, HR 0.71, p 0.09, respectively), but had a significantly lower non‐relapse mortality rate (HR 0.46, p 0.017). HLA‐mismatched donor, older age, adverse genetic risk and higher comorbidity scores were associated with inferior survival outcomes. A high initial blast count was only associated with inferior prognosis in patients receiving chemotherapy‐only compared to total body irradiation containing conditioning therapy. These results indicate that for patients transplanted with active AML, sensitivity to chemotherapy might be of less importance, compared to other disease‐ and transplant‐related factors.
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