Haematologica

Anti-CD19 chimeric antigen receptor T-cell therapy for B-cell acute lymphoid leukemia

Aaron P. Rapoport — Mon, 01 Apr 2024 00:00:00 +0000

Eligibility criteria: too big, too small or just right?

Ehab Atallah — Thu, 12 Oct 2023 00:00:00 +0000

More than a lonca-shot: beating the odds in relapsed/ refractory diffuse large B-cell lymphoma

Carrie Ho, Stephen D. Smith — Thu, 05 Oct 2023 00:00:00 +0000

Using machine learning to unravel the intricacy of acute myeloid leukemia

Luca Guarnera, Valeria Visconte — Thu, 12 Oct 2023 00:00:00 +0000

MYC overexpression: adding another piece to the puzzle of high-risk mantle cell lymphoma

Anita Kumar — Thu, 19 Oct 2023 00:00:00 +0000

First-line MAPK inhibition in pediatric histiocytosis: are we ready?

Oussama Abla — Thu, 16 Nov 2023 00:00:00 +0000

A key to engineering natural killer cells to attack acute myeloid leukemia

Yosuke Masamoto, Mineo Kurokawa — Thu, 02 Nov 2023 00:00:00 +0000

How we manage a high D-dimer

Thu, 26 Oct 2023 00:00:00 +0000

D-dimer, a soluble fibrin degradation product that originates from plasmin-induced degradation of cross-linked fibrin, is an important biomarker of coagulation activation and secondary fibrinolysis that is routinely used to rule out venous thromboembolism (VTE), and to evaluate the risk of VTE recurrence, as well as the optimal duration of anticoagulant therapy. Besides VTE, D-dimer may be high due to physiologic conditions, including aging, pregnancy, and strenuous physical activity. In addition, several disorders have been associated with increased D-dimer levels, ranging from disseminated intravascular coagulation to infectious diseases and cancers. Thus, it is far from unusual for hematologists to have to deal with ambulatory individuals with increased D-dimer without signs or symptoms of thrombus formation. This narrative review is dedicated to the management of these cases by the hematologist.

Use, variability, and justification of eligibility criteria for phase II and III clinical trials in acute leukemia

Thu, 10 Aug 2023 00:00:00 +0000

Clinical trial eligibility criteria can unfairly exclude patients or unnecessarily expose them to known risks if criteria are not concordant with drug safety. There are few data evaluating the extent to which acute leukemia eligibility criteria are justified. We analyzed criteria and drug safety data for front-line phase II and/or III acute leukemia trials with start dates 1/1/2010-12/31/2019 registered on clinicaltrials.gov. Multivariable analyses assessed concordance between criteria use and safety data (presence of criteria with a safety signal, or absence of criteria without a signal), and differences between criteria and safety-based limits. Of 250 eligible trials, concordant use of ejection fraction criteria was seen in 34.8%, corrected QT level (QTc) in 22.4%, bilirubin in 68.4%, aspartate transaminase/alanine aminotransferase (AST/ALT) in 58.8%, renal function in 68.4%, human immunodeficiency virus (HIV) in 54.8%, and hepatitis B and C in 42.0% and 41.2%. HIV and hepatitis B and C criteria use was concordant with safety data (adjusted Odds Ratios 2.04 [95%CI: 1.13, 3.66], 2.64 [95%CI: 1.38, 5.04], 2.27 [95%CI: 1.20, 4.32]) but organ function criteria were not (all P>0.05); phase III trials were not more concordant. Bilirubin criteria limits were the same as safety-based limits in 16.0% of trials, AST/ALT in 18.1%, and renal function in 13.9%; in 75.7%, 51.4%, and 56.5% of trials, criteria were more restrictive, respectively, by median differences of 0.2, 0.5, and 0.5 times the upper limits of normal. We found limited drug safety justifications for acute leukemia eligibility criteria. These data define criteria use and limits that can be rationally modified to increase patient inclusion and welfare.

Association of NUDT15 gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

Thu, 05 Oct 2023 00:00:00 +0000

6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction

Thu, 05 Oct 2023 00:00:00 +0000

Advances in the clinical management of pediatric B-cell acute lymphoblastic leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1⁺ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/ MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL.

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase

Thu, 09 Nov 2023 00:00:00 +0000

Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.

Prognostic value of European LeukemiaNet 2022 criteria and genomic clusters using machine learning in older adults with acute myeloid leukemia

Thu, 14 Sep 2023 00:00:00 +0000

This study aimed to validate the new European Leukemia Net (ELN) 2022 criteria for genetic risk stratification in older adults with acute myeloid leukemia (AML) and to determine the most likely set of clusters of similar cytogenetic and mutation properties correlated with survival outcomes in three treatment groups: intensive chemotherapy (IC), hypomethylating agents (HMA) alone, and HMA plus venetoclax (HMA/VEN). The study included 279 patients (aged ≥60 years) who received IC (N=131), HMA (N=76), and HMA/VEN (N=72) between July 2017 and October 2021. No significant differences were observed in survival among the groups according to ELN 2022 risk stratification. Unsupervised hierarchical clustering analysis identified nine genomic clusters (C1-9) with varying survival outcomes depending on treatment type. For example, C4 (predominant for core binding factor-AML) displayed a favorable prognosis in the IC group, but not in the HMA or HMA/VEN groups. The HMA/VEN group had better outcomes than the HMA group in many clusters (C1, 2, 3, and 5); however, the addition of VEN to HMA or IC did not improve the survival outcomes compared with those of HMA alone in C7 and C9 (predominant for -5, del(5q), -7, -17/abn(17p), complex karyotypes, and mutated TP53). The study highlights the limitations of ELN genetic risk stratification in older adults with AML. It emphasizes the need for a more comprehensive approach that considers co-occurring somatic mutations to guide treatment selection in older adults with AML.

Immune checkpoint molecule DNAM-1/CD112 axis is a novel target for natural killer-cell therapy in acute myeloid leukemia

Thu, 21 Sep 2023 00:00:00 +0000

Acute myeloid leukemia (AML) is a hematologic malignancy that frequently relapses, even if remission can be achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic cells from immune surveillance. Currently, there is no effective immunotherapy for AML because of the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and determine the therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 cases of AML indicated that the survival of patients with high expression of CD112 was shorter than that of patients with low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhanced the expression of cytotoxicity-related genes, thus overcoming the inhibitory activity of TIGIT. Between CD155 and CD112, CD112 is an especially important target for natural killer (NK)-cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also discovered that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, our findings suggest that the levels of expression of these molecules are potential prognostic markers in AML.

HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation

Thu, 28 Sep 2023 00:00:00 +0000

The null allele HLA-C*04:09N differs from HLA-C*04:01 in a frameshift mutation within its cytoplasmic domain, resulting in translation of 32 additional amino acids that are assumed to prevent cell surface expression. However, we recently identified a multiple myeloma-reactive T-cell receptor (TCR) that appeared to recognize antigen presented on HLA-C*04:09N and encouraged us to ask whether HLA-C*04:09N, albeit not easily detectable at the cell surface, can present antigen sufficient for T-cell activation. We generated two HLA-class I-deficient cell lines, re-expressed HLAC* 04:09N, detected HLA expression by flow cytometry, and tested for T-cell activation using a cytomegalovirus peptide- specific HLA-C*04:01-restricted TCR. In both cell lines, HLA-C*04:09N expression was detectable at the cell surface and could be enhanced by IFN-γ exposure. Recombinant HLA-C*04:09N expression was sufficient for T-cell activation in vitro, which could be blocked by an HLA-class I-specific antibody, suggesting HLA-TCR interaction at the cell surface. Peripheral blood mononuclear cells isolated from an individual who physiologically expressed HLA-C*04:09N triggered peptide-specific T-cell activation, confirming our results with cells with natural HLA expression levels. In conclusion, we present peptide-specific HLA-C*04:09N-restricted T-cell activation and suggest consideration of this allele in the appropriate clinical context, such as allogeneic stem cell transplantation, or in the setting of cellular therapy.

Tissue factor pathway inhibitor is associated with risk of venous thromboembolism and all-cause mortality in patients with cancer

Thu, 12 Oct 2023 00:00:00 +0000

Venous thromboembolism (VTE) is a common complication in patients with cancer. Data on the role of natural inhibitors of coagulation for occurrence of cancer-associated VTE are limited, thus, we investigated the association of tissue factor pathway inhibitor (TFPI) with risk of VTE and all-cause mortality in patients with cancer. Total TFPI antigen levels were measured with a commercially available enzyme-linked immunosorbant assay in patients included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study with the primary outcome VTE. Competing risk analysis and Cox regression analysis were performed to explore the association of TFPI levels with VTE and all-cause mortality. TFPI was analyzed in 898 patients (median age 62 years; interquartile range [IQR], 53-68; 407 (45%) women). Sixty-seven patients developed VTE and 387 died (24-month cumulative risk 7.5% and 42.1%, respectively). Patients had median TFPI levels at study inclusion of 56.4 ng/mL (IQR, 45.7-70.0), with highest levels in tumor types known to have a high risk of VTE (gastroesophageal, pancreatic and brain cancer: 62.0 ng/mL; IQR, 52.0-75.0). In multivariable analysis adjusting for age, sex, cancer type and stage, TFPI levels were associated with VTE risk (subdistribution hazard ratio per doubling =1.63, 95% confidence interval [CI]: 1.03-2.57). When patients with high and intermediate/low VTE risk were analyzed separately, the association remained independently associated in the high risk group only (subdistribution hazard ratio =2.63, 95% CI: 1.40-4.94). TFPI levels were independently associated with all-cause mortality (hazard ratio =2.36, 95% CI: 1.85-3.00). In cancer patients increased TFPI levels are associated with VTE risk, specifically in patients with high-risk tumor types, and with all-cause mortality.

Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders

Thu, 21 Sep 2023 00:00:00 +0000

The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.

Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation

Thu, 31 Aug 2023 00:00:00 +0000

Chemoimmunotherapy followed by consolidative high-dose therapy with autologous stem cell rescue was a standard upfront treatment for fit patients with mantle cell lymphoma (MCL) in first remission; however, treatment paradigms are evolving in the era of novel therapies. Lenalidomide is an immunomodulatory agent with known efficacy in treating MCL. We conducted a single-center, investigator-initiated, phase II study of immunochemotherapy incorporating lenalidomide, without autologous stem cell transplant consolidation, enriching for patients with high-risk MCL (clinicaltrials gov. Identifier: NCT02633137). Patients received four cycles of lenalidomide-R-CHOP, two cycles of R-HiDAC, and six cycles of R-lenalidomide. The primary endpoint was rate of 3-year progression-free survival. We measured measurable residual disease (MRD) using a next-generation sequencing-based assay after each phase of treatment and at 6 months following end-oftreatment. We enrolled 49 patients of which 47 were response evaluable. By intent-to-treat, rates of overall and complete response were equivalent at 88% (43/49), one patient with stable disease, and two patients had disease progression during study; 3-year progression-free survival was 63% (primary endpoint not met) and differed by TP53 status (78% wild-type vs. 38% ALT; P=0.043). MRD status was prognostic and predicted long-term outcomes following R-HiDAC and at 6 months following end-of-treatment. In a high-dose therapy-sparing, intensive approach, we achieved favorable outcomes in TP53- wild-type MCL, including high-risk cases. We confirmed that sequential MRD assessment is a powerful prognostic tool in patients with MCL.

Outcome of combined modality treatment in first-line for stage I(E) peripheral T-cell lymphoma; a nationwide population-based cohort study from the Netherlands

Thu, 05 Oct 2023 00:00:00 +0000

Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of mature T-cell neoplasms with an unfavorable prognosis; presentation with stage I(E) disease is uncommon. In clinical practice, an abbreviated chemotherapy treatment regimen combined with radiotherapy (combined modality treatment [CMT]) is commonly used, although evidence from clinical trials is lacking. The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL. All newly diagnosed patients ≥18 years with stage I(E) anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma NOS (PTCL not otherise specified [NOS]) in 1989-2020 were identified in the Netherlands Cancer Registry. Patients were categorized according to treatment regimen, i.e., chemotherapy (CT), radiotherapy (RT), CMT, other therapy and no treatment. The primary endpoint was overall survival (OS). Patients with stage I(E) ALCL, AITL and PTCL NOS (n=576) were most commonly treated with CMT (28%) or CT (29%), 2% underwent SCT. RT only was given in 18%, and 8% received other therapy and 16% no treatment. Overall, the 5-year OS was 59%. According to subtype, 5-year OS was superior for ALCL as compared to PTCL NOS and AITL (68% vs. 55% and 52%, respectively; P=0.03). For patients treated with CMT, 5-year OS was significantly higher (72%) as compared to patients treated with either CT or RT alone (55% and 55%, respectively; P<0.01). In multivariable analysis, age per year increment (hazard ratio [HR] =1.06, 95% confidence interval [CI]: 1.05-1.07), male sex (HR=1.53, 95% CI: 1.23-1.90), and CT, or no treatment (HR=1.64, 95% CI: 1.21-2.21, and HR=1.55, 95% CI: 1.10-2.17, respectively) were associated with a higher risk of mortality. For stage I(E) ALCL, AITL and PTCL NOS, 5-year OS is 59%, comparing favorably to historical outcome in advanced-stage disease. Superior outcome estimates were observed in patients treated with CMT.

MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 – a Nordic Lymphoma Group study

Thu, 31 Aug 2023 00:00:00 +0000

The transcription factor MYC is a well-described oncogene with an important role in lymphomagenesis, but its significance for clinical outcome in mantle cell lymphoma (MCL) remains to be determined. We performed an investigation of the expression of MYC protein in a cohort of 251 MCL patients complemented by analyses of structural aberrations and mRNA, in a sub-cohort of patients. Fourteen percent (n=35) of patients showed high MYC protein expression with >20% positive cells (MYC^high), among whom only one translocation was identified, and 86% (n=216) of patients showed low MYC protein expression. Low copy number gains of MYC were detected in ten patients, but with no correlation to MYC protein levels. However, MYC mRNA levels correlated significantly to MYC protein levels with a R2 value of 0.76. Patients with a MYC^high tumor had both an independent inferior overall survival and an inferior progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.2-3.4 and HR=2.2, 95% CI: 1.04-4.6, respectively) when adjusted for additional high-risk features. Patients with MYChigh tumors also tended to have additional high-risk features and to be older at diagnosis. A subgroup of 13 patients had concomitant MYC^high expression and TP53/p53 alterations and a substantially increased risk of progression (HR=16.9, 95% CI: 7.4-38.3) and death (HR=7.8, 95% CI: 4.4-14.1) with an average overall survival of only 0.9 years. In summary, we found that at diagnosis a subset of MCL patients (14%) overexpressed MYC protein, and had a poor prognosis but that MYC rearrangements were rare. Tumors with concurrent MYC overexpression and TP53/p53 alterations pinpointed MCL patients with a dismal prognosis with a median overall survival of less than 3 years. We propose that MYC needs to be assessed beyond the current high-risk factors in MCL in order to identify cases in need of alternative treatment.

Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study

Thu, 31 Aug 2023 00:00:00 +0000

Therapies that demonstrate durable, long-term responses with manageable safety and tolerability are needed for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer, demonstrated single-agent antitumor activity in the pivotal phase II LOTIS-2 study in heavily pretreated patients with R/R DLBCL. Here we present updated efficacy and safety analyses from LOTIS-2, performed for all patients and in subsets of patients with a complete response (CR), including patients with CR who were event-free (no progressive disease or death) for ≥1 year and ≥2 years from cycle 1, day 1 of treatment. Lonca was administered every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles). As of the final data cutoff (September 15, 2022; median follow-up: 7.8 months [range, 0.3-42.6]), 70 of 145 (48.3%) patients achieved an overall response. Thirty-six (24.8%) patients achieved CR, of which 16 (44%) and 11 (31%) were event-free for ≥1 year and ≥2 years, respectively. In the all-treated population, the median overall survival was 9.5 months; the median progression-free survival was 4.9 months. Among patients with CR, median overall survival and progression-free survival were not reached, with 24-month overall and progression-free survival rates of 68.2% (95% CI: 50.0-81.0) and 72.5% (95% CI: 48.2-86.8), respectively. No new safety concerns were detected. With additional follow-up, Lonca continued to demonstrate durable, long-term responses with manageable safety and tolerability in patients with CR (clinicaltrials gov. Identifier: NCT03589469).

Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study

Thu, 28 Sep 2023 00:00:00 +0000

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (clinicaltrials.gov 02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus bendamustine and rituximab (BR) alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, N=6; phase II randomized cohort: Pola-BR, N=39; BR, N=41; phase Ib/II expansion cohort: Pola-BG, N=26). PET-CR rates were 66.7% (phase Ib safety run-in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.

Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma

Thu, 28 Sep 2023 00:00:00 +0000

Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and shortened the survival of MM tumor-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signaling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signaling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.

Single-cell analysis of the CD8⁺ T-cell compartment in multiple myeloma reveals disease specific changes are chiefly restricted to a CD69^- subset suggesting potent cytotoxic effectors exist within the tumor bed

Thu, 05 Oct 2023 00:00:00 +0000

Multiple myeloma (MM) is an incurable disease of the bone marrow (BM) characterized by the uncontrolled proliferation of neoplastic plasma cells. While CD8⁺ T cells have an established role in disease control, few studies have focused on these cells within the MM tumor microenvironment (TME). We analyzed CD8⁺ T cells in the BM and peripheral blood (PB) of untreated patients with MM and non-myeloma controls using flow cytometry, mass cytometry and single-cell RNA sequencing, using several novel bioinformatics workflows. Inter-tissue differences were most evident in the differential expression of Granzymes B and K, which were strongly associated with two distinct subsets of CD8⁺ T cells delineated by the expression of CD69, accounting for roughly 50% of BM-CD8⁺ T cells of all assessed cohorts. While few differences were observable between health and disease in the BM-restricted CD8CD69⁺ T-cell subset, the CD8⁺CD69^- T-cell subset in the BM of untreated MM patients demonstrated increased representation of highly differentiated effector cells and evident compositional parallels between the PB, absent in age-matched controls, where a marked reduction of effector cells was observed. We demonstrate the transcriptional signature of BM-CD8⁺ T cells from patients with MM more closely resembles TCR-activated CD8⁺ T cells from age-matched controls than their resting counterparts.

Targeting T_FH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study

Thu, 12 Oct 2023 00:00:00 +0000

The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (T_fh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting T_fh cells to desensitize DSA. The quantities of circulating Tfh (cT_fh) cell subsets in allograft candidates were abnormal, and these cells, including the cT_fh2 and cT_fhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cT_fh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cT_fh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of T_fh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.

Genome-wide assessment of genetic risk loci for childhood acute lymphoblastic leukemia in Japanese patients

Thu, 26 Oct 2023 00:00:00 +0000

BH3 profiling as pharmacodynamic biomarker for the activity of BH3 mimetics

Thu, 26 Oct 2023 00:00:00 +0000

Subcutaneous injection of IHP-102 prevents lung vaso-occlusion in sickle cell disease mice

Thu, 19 Oct 2023 00:00:00 +0000

Long-term outcome after autologous BCR::ABL1-negative peripheral blood stem cell transplantation in adults with Philadelphia-positive acute lymphoblastic leukemia: a comparative study

Thu, 30 Nov 2023 00:00:00 +0000

Glofitamab monotherapy induces high complete response rates and manageable safety in Chinese patients with heavily pretreated relapsed or refractory diffuse large B-cell lymphoma

Thu, 19 Oct 2023 00:00:00 +0000

Low-dose azacitidine, pioglitazone and all-trans retinoic acid is safe in patients aged ≥60 years with acute myeloid leukemia refractory to standard induction chemotherapy (AMLSG 26-16/AML-ViVA): results of the safety run-in phase

Thu, 26 Oct 2023 00:00:00 +0000

Comorbidity indices for prognostic evaluation in multiple myeloma: a comprehensive evaluation of the Revised Myeloma Comorbidity Index and other comorbidity indices with pro- and retrospective applications

Thu, 30 Nov 2023 00:00:00 +0000

Catheter-related thrombosis in stem cell recipients: comparison of different types of catheter

Thu, 02 Nov 2023 00:00:00 +0000

Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes

Thu, 19 Oct 2023 00:00:00 +0000

Factor VIII genotype and the risk of developing highresponding or low-responding inhibitors in severe hemophilia A: data from the PedNet Hemophilia Cohort of 1,202 children

Thu, 26 Oct 2023 00:00:00 +0000

CD38 expression by plasma cells in extramedullary multiple myeloma

Thu, 09 Nov 2023 00:00:00 +0000

A patient with minimal myeloma treatment who survived for 20 years

Thu, 05 Oct 2023 00:00:00 +0000

Emergence of TP53 mutation during lenalidomide therapy of myelodysplastic syndrome with del(5q) and its subsequent disappearance following salvage therapy with decitabine

Naseema Gangat, Naresh Bellam, Kaaren Reichard, Ayalew Tefferi — Thu, 30 Nov 2023 00:00:00 +0000

Erratum to: Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia

Mon, 01 Apr 2024 00:00:00 +0000

Erratum to: Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes

Mon, 01 Apr 2024 00:00:00 +0000

Haematologica

Anti-CD19 chimeric antigen receptor T-cell therapy for B-cell acute lymphoid leukemia

Eligibility criteria: too big, too small or just right?

More than a lonca-shot: beating the odds in relapsed/ refractory diffuse large B-cell lymphoma

Using machine learning to unravel the intricacy of acute myeloid leukemia

MYC overexpression: adding another piece to the puzzle of high-risk mantle cell lymphoma

First-line MAPK inhibition in pediatric histiocytosis: are we ready?

A key to engineering natural killer cells to attack acute myeloid leukemia

How we manage a high D-dimer

Use, variability, and justification of eligibility criteria for phase II and III clinical trials in acute leukemia

Association of NUDT15 gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase

Prognostic value of European LeukemiaNet 2022 criteria and genomic clusters using machine learning in older adults with acute myeloid leukemia

Immune checkpoint molecule DNAM-1/CD112 axis is a novel target for natural killer-cell therapy in acute myeloid leukemia

HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation

Tissue factor pathway inhibitor is associated with risk of venous thromboembolism and all-cause mortality in patients with cancer

Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders

Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation

Outcome of combined modality treatment in first-line for stage I(E) peripheral T-cell lymphoma; a nationwide population-based cohort study from the Netherlands

MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 – a Nordic Lymphoma Group study

Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study

Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study

Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma

Single-cell analysis of the CD8+ T-cell compartment in multiple myeloma reveals disease specific changes are chiefly restricted to a CD69- subset suggesting potent cytotoxic effectors exist within the tumor bed

Targeting TFH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study

Genome-wide assessment of genetic risk loci for childhood acute lymphoblastic leukemia in Japanese patients

BH3 profiling as pharmacodynamic biomarker for the activity of BH3 mimetics

Subcutaneous injection of IHP-102 prevents lung vaso-occlusion in sickle cell disease mice

Long-term outcome after autologous BCR::ABL1-negative peripheral blood stem cell transplantation in adults with Philadelphia-positive acute lymphoblastic leukemia: a comparative study

Glofitamab monotherapy induces high complete response rates and manageable safety in Chinese patients with heavily pretreated relapsed or refractory diffuse large B-cell lymphoma

Low-dose azacitidine, pioglitazone and all-trans retinoic acid is safe in patients aged ≥60 years with acute myeloid leukemia refractory to standard induction chemotherapy (AMLSG 26-16/AML-ViVA): results of the safety run-in phase

Comorbidity indices for prognostic evaluation in multiple myeloma: a comprehensive evaluation of the Revised Myeloma Comorbidity Index and other comorbidity indices with pro- and retrospective applications

Catheter-related thrombosis in stem cell recipients: comparison of different types of catheter

Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes

Factor VIII genotype and the risk of developing highresponding or low-responding inhibitors in severe hemophilia A: data from the PedNet Hemophilia Cohort of 1,202 children

CD38 expression by plasma cells in extramedullary multiple myeloma

A patient with minimal myeloma treatment who survived for 20 years

Emergence of TP53 mutation during lenalidomide therapy of myelodysplastic syndrome with del(5q) and its subsequent disappearance following salvage therapy with decitabine

Erratum to: Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia

Erratum to: Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes

Single-cell analysis of the CD8⁺ T-cell compartment in multiple myeloma reveals disease specific changes are chiefly restricted to a CD69^- subset suggesting potent cytotoxic effectors exist within the tumor bed

Targeting T_FH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study