EJHaem最新文献

To the Editor,

Inhibitors of Bruton's tyrosine kinase (BTK) in chronic lymphocytic leukemia (CLL) result in durable responses in nearly all patients [1]. In contrast, in more aggressive B-cell malignancies, including diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), responses to single agent BTK inhibitors (BTKi) occur only in subsets of patients and are mostly of brief duration. However, exceptional responses may occur [2-6].

In relapsed/refractory (R/R) MCL, median progression-free survival (PFS) with single-agent covalent BTKi range from 12 (ibrutinib) to 20 months (acalabrutinib ACE-LY-004 NCT02213926 study) (Table S1) [7-9]. Analysis of responding patients in ACE-LY-004 showed that 8/29 evaluable patients eradicated minimal residual disease (MRD) using the quantitative ClonoSEQ next-generation sequencing assay of cellular peripheral blood DNA [10]. However, molecular determinants of responsiveness to BTKi in MCL, and clinical significance of attaining MRD negativity in this setting remain unknown.

Like acalabrutinib, tirabrutinib is a highly selective BTKi, binding covalently to BTKC481 via a reactive acyl alkyne group. Although only 16 MCL patients were treated with single-agent tirabrutinib within the POE001 phase 1 trial (NCT01659255), extended follow-up showed an estimated median PFS of 25.8 months at 3 years [11]. Three patients from this cohort, described below, attained complete responses lasting over 72 months, despite adverse prognostic features at diagnosis including TP53 mutations, blastoid morphology, and refractoriness to immunochemotherapy. In these exceptional responders [12], we sought to determine common features or a tumoral mutational signature that might predict exceptional responsiveness. Secondly, we determined the depth of response using digital droplet PCR (ddPCR) in both plasma and cellular DNA samples and whether serial assessment of levels of cellular and plasma circulating tumor (ct) DNA samples might presage relapse.

Clinical and laboratory details of the three cases are given in Table 1. A schema of the treatment timelines is shown in Figure 1. Full materials and methods are found in the Supporting Information. The three patients (201-139, 201-162, and 201-170) were all treated at our center and received either 480 or 600 mg of tirabrutinib once per day. All entered a clinical and radiological remission. One patient (patient 201-162) with primary immunochemotherapy-refractory disease remains in complete remission (CR) > 108 months from trial initiation. However, in 2020, they developed estrogen receptor positive grade 2 invasive ductal breast cancer, necessitating temporary discontinuation of tirabrutinib for 4 months. The breast cancer was treated radically with surgical resection, post operative radiotherapy and tamoxifen. There remains no clinical or radiological evidence of r

Andexanet alfa is a recombinant, modified factor Xa (FXa) molecule that is used for the reversal of the anticoagulant effect of oral anti-FXa anticoagulants in patients with major haemorrhage. Here, we present a case of an 85-year-old man taking rivaroxaban for atrial fibrillation, who presented with an acute, upper gastrointestinal bleed. He was stabilised with red cell transfusion and then received a 400 mg bolus of andexanet alfa. Within minutes of this, he developed chest tightness, shortness of breath, ischaemic electrocardiographic changes and then cardiac arrest from which he could not be resuscitated. The onset of symptoms was clearly temporally related to andexanet alfa administration and the differential diagnosis includes anaphylaxis with Kounis syndrome, or myocardial infarction. Although infusion site reactions have been reported and are relatively common, this is to date the first case of a fatal drug reaction andexanet alfa. This knowledge can be factored into physicians’ risk–benefit decisions when treating patients with oral anti-FXa anticoagulant-associated major haemorrhage.

Immune thrombocytopenic purpura (ITP) is an immune disorder characterized by thrombocytopenia. Fostamatinib is an orally administered spleen tyrosine kinase inhibitor intended to treat refractory ITP. To evaluate the efficacy and safety of fostamatinib as a subsequent-line therapy for ITP in adults. We searched four electronic databases for primary studies of any design. Primary efficacy outcomes included proportions of patients achieving overall (≥30 × 10⁹ cells/L), partial (≥50 × 10⁹ cells/L), and stable (as defined in original studies) platelet response. Safety outcomes included rescue medication use and other adverse events. We used narrative synthesis and Mantel–Haenszel random effect meta-analysis to summarize results. Our systematic review included 11 studies for analyses (n = 722). Weighted mean proportions of patients achieving overall, partial, and stable responses with fostamatinib treatment were 0.70 [0.62, 0.76], 0.48 [0.36, 0.61], and 0.28 [0.16, 0.44], respectively. Fostamatinib was favored over placebo for partial (relative risk [RR] = 3.04, 95% confidence interval [CI] [1.53, 6.06]) and stable (RR = 6.43, 95% CI [1.58, 26.23]) responses. Patients on fostamatinib required less rescue medication and were more likely to experience hypertension. Fostamatinib is a viable subsequent-line therapy option for refractory ITP. Given the heterogeneous data and large number of small studies, these results should be interpreted cautiously.

CD4+ chronic lymphocytic leukemia (CLL) represents an extremely rare example of phenotypic aberrancy within CLL. We present a case of an 86-year-old male veteran with a history of multiple comorbidities who was incidentally diagnosed with CD4+ CLL during a routine peripheral blood workup. This case highlights the diagnostic challenges and characteristic features of CD4+ CLL, including flow cytometric analysis, molecular, and fluorescence in situ hybridization findings. The patient was classified as asymptomatic CLL Rai stage 0, warranting regular monitoring without a need for treatment intervention.

We evaluated the clinical impacts of the concurrent modification of post-transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)-initiation timing in 61 patients with human leukocyte antigen-haploidentical transplantation. Reduced-dose PTCy (80 mg/kg) was associated with a higher incidence of moderate-to-severe chronic graft-versus-host disease (GVHD) than standard-dose PTCy (100 mg/kg) (35.0% vs. 26.6%, p = 0.053). Notably, early-initiation Tac (day -1) increased moderate-to-severe chronic GVHD than standard-initiation Tac (day 5) in the reduced-dose PTCy group (p = 0.032), whereas Tac-initiation timing did not impact chronic GVHD in the standard-dose PTCy group. These data indicate that the combination of reduced-dose PTCy and early-initiation Tac can amplify chronic GVHD.

Donor-specific anti-human leukocyte antigen (HLA) antibodies represent a main cause of primary graft failure specifically in the setting of haploidentical stem cell transplantation. Newer therapy strategies including daratumumab could overcome some of these limitations. We describe the case of a patient with refractory acute myeloid leukemia. A haploidentical allogeneic stem cell transplantation was therefore initiated. HLA-antibodies testing revealed a high titer of donor-specific antibodies. First desensitization therapy failed, resulting in primary graft failure. A second desensitization regimen including plasmapheresis, intravenous gammaglobulins, and daratumumab resulted in good engraftment. Daratumumab is a promising and effective desensitization option in high-risk allo-sensitized patients undergoing haploidentical stem cell transplantation.

Somatic hypermutations (SHMs) in the variable region (V_H) of the immunoglobulin heavy chain (IgH) gene are common in diffuse large B-cell lymphoma (DLBCL). Recently, IgH V_H SHMs have become known as immunogenic neoantigens, but few studies have evaluated the prognostic impact of the frequency of V_H SHMs in DLBCL. The BIOMED-2 protocol is the gold standard polymerase chain reaction (PCR) for clonality analysis in lymphoid malignancies, but can produce false negatives due to the presence of IgH V_H SHMs. To overcome this problem, three primer sets were designed for the three framework regions (FR1, FR2, and FR3). We evaluated the predictive value of this PCR pattern in patients with DLBCL. To evaluate the prognostic impact of complete detection of the clonal amplifications (V_HFR1–J_H, V_HFR2–J_H, and V_HFR3–J_H) in the BIOMED-2 protocol, we retrospectively analyzed 301 DLBCL patients who were initially treated with anthracycline-based immunochemotherapy. Complete detection of the FR1 to FR3 primer-based IgH V_H PCR patterns in the BIOMED-2 protocol was associated with low frequency of V_H SHMs (p < 0.001). Patients who were positive for all these three PCRs (n = 79) were significantly associated with shorter 5-year overall survival (OS; 54.2% vs. 73.2%; p = 0.002) and progression-free survival (PFS; 34.3% vs. 59.3%; p < 0.001) compared to patients with other PCR patterns (n = 202). Specifically, the successful FR3-J_H detection was associated with significantly worse OS (p < 0.001) and PFS (p < 0.001). PCR patterns of complete IgH rearrangement using the BIOMED-2 protocol are clinically meaningful indicators for prognostic stratification of DLBCL patients.

Monoclonal gammopathy-associated pure red cell aplasia (MG-PRCA) is characterized by the absence or pronounced hypoplasia of erythroid precursors in the bone marrow, causing reticulocytopenia and a normocytic, normochromic anaemia in a patient with a monoclonal plasma cell dyscrasia. We report here on the successful treatment of MG-PRCA with isatuximab, pomalidomide, and dexamethasone after multiple lines of immunosuppressive and anti-plasma cell-directed treatments.