Microbial metabolomics in acute myeloid leukemia: From pathogenesis to treatment.

Acute myeloid leukemia (AML), the most common leukemia in adults, is a biologically heterogeneous disease arising from clonally proliferating hematopoietic stem cells. Increased appreciation of novel genetic methods has improved the understanding of AML biology. Recently, the emerging field of metabolomics has indicated qualitative and quantitative alterations in metabolic profiles in AML pathogenesis, progression and treatment. Multiple metabolic and molecular pathways regulate human metabolism and host-microbiome interactions may significantly affect this biochemical machinery. Microbiota have been found to play a significant role in hematopoietic function, metabolism and immunity, contributing to AML occurrence. A large number of studies have highlighted the importance of the composition and diversity of the gut microbiota (GM) in response to treatment and prognosis in AML. Moreover, strong evidence emphasizes the detrimental link between dysbiosis and infectious complications, a leading cause of morbidity and mortality for patients with AML. Several microbiota-related mechanisms have been linked to particular changes in host physiology so far, and microbial-derived metabolites belong to one of the most important. Circulating in the body, they modulate human conditions both locally and systemically. The extensive and diverse repertoire of bacterial metabolic functions plays a critical role in numerous processes, including leukemogenesis. Integrative analysis of microbiome and metabolome data is a promising avenue for better understanding the complex relationship between the microbiota, biochemical alterations and AML pathogenesis to effectively prevent, treat and mitigate its outcomes. This review concentrates on the pathologic roles and therapeutic implications of microbe-derived metabolites in AML settings.

Recent advances in acute gastrointestinal graft versus host disease (aGvHD): aspects of steroid-resistant disease.

Acute Graft versus Host Disease (aGvHD) is a common immunological complication occurring in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Moreover, aGvHD is associated with a higher risk of infections and metabolic complications, affecting non-relapse mortality. Progress in transplantation has changed the prophylactic and therapeutic strategies of aGvHD and improved patient outcomes. The standard first-line therapy remains steroids, with a response rate of about 50%. The Janus Kinase 2 (JAK2) inhibitor, ruxolitinib, is an effective second-line therapy. The management of patients who developed a disease that is refractory to steroids and ruxolitinib, especially in the severe gastrointestinal forms of aGvHD, is not validated and remains an unmet medical need. In the article, we present the current clinical practice, as well as the latest advances targeting pathophysiological pathways of GvHD and gut microbiota, which may be a potential future of aGvHD therapy.

Adenovirus infections after allogeneic hematopoietic cell transplantation in children and adults: a study from the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation.

The objective of the study was the analysis of clinical types, outcomes, and risk factors associated with the outcome of adenovirus (ADV) infection, in children and adults after allo-HCT. A total number of 2529 patients (43.9% children; 56.1% adults) transplanted between 2000 and 2022 reported to the EBMT database with diagnosis of ADV infection were analyzed. ADV infection manifested mainly as viremia (62.6%) or gastrointestinal infection (17.9%). The risk of 1-year mortality was higher in adults (p = 0.0001), and in patients with ADV infection developing before day +100 (p < 0.0001). The 100-day overall survival after diagnosis of ADV infections was 79.2% in children and 71.9% in adults (p < 0.0001). Factors contributing to increased risk of death by day +100 in multivariate analysis, in children: CMV seropositivity of donor and/or recipient (p = 0.02), and Lansky/Karnofsky score <90 (p < 0.0001), while in adults: type of ADV infection (viremia or pneumonia vs gastrointestinal infection) (p = 0.0004), second or higher HCT (p = 0.0003), and shorter time from allo-HCT to ADV infection (p = 0.003). In conclusion, we have shown that in patients infected with ADV, short-term survival is better in children than adults. Factors directly related to ADV infection (time, clinical type) contribute to mortality in adults, while pre-transplant factors (CMV serostatus, Lansky/Karnofsky score) contribute to mortality in children.

T-cell exhaustion in multiple myeloma.

INTRODUCTION: Chimeric Antigen Receptor (CAR) T-cells and Bispecific Antibodies (BsAb) are the leading platforms for redirecting the immune system against cells expressing the specific antigen, revolutionizing the treatment of hematological malignancies, including multiple myeloma (MM). In MM, drug-resistant relapses are the main therapy-limiting factor and the leading cause of why the disease is still considered incurable. T-cell-engaging therapies hold promise in improving the treatment of MM. However, the effectiveness of these treatments may be hindered by T-cell fitness. T-cell exhaustion is a condition of a gradual decline in effector function, reduced cytokine secretion, and increased expression of inhibitory receptors due to chronic antigen stimulation. AREAS COVERED: This review examines findings about T-cell exhaustion in MM in the context of T-cell redirecting BsAbs and CAR-T treatment. EXPERT OPINION: The fitness of T-cells has become an important factor in the development of T-cell redirecting therapies. The way T-cell exhaustion relates to these therapies could affect the further development of CAR and BsAbs technologies, as well as the strategies used for clinical use. Therefore, this review aims to explore the current understanding of T-cell exhaustion in MM and its relationship to these therapies.

Optimizing Outcomes in Mismatched Unrelated Donor Allogeneic Transplantation: Post-Transplant Cyclophosphamide's Dual Impact on Graft versus Host Disease Incidence and Overall Survival: Retrospective Analysis on Behalf of Polish Adult Leukemia Group.

Allogeneic hematopoietic cell transplantation (allo-HSCT) stands as an effective treatment method for various hematologic malignancies. However, graft-versus-host disease (GvHD), an intricate immunological phenomenon where donor immune cells target recipient tissues, remains a significant challenge, particularly in mismatched unrelated donors (MMUD). Post-transplant cyclophosphamide (PTCy) has emerged as a promising immunosuppressive strategy, revolutionizing haploidentical transplantation and demonstrating promise in MMUD settings. Background/Objectives: This study aimed to evaluate the impact of PTCy on MMUD allo-HSCT outcomes, specifically its effects on GvHD incidence and overall survival, compared to anthitymocyte globulin (ATG). Methods: One hundred seventy-four patients were classified into three groups based on the type of transplantation: PTCy-haplo (114/174; 65.5%), PTCy-MMUD (23/174; 13.2%), and ATG-MMUD (37/174; 21.2%). Results: Our findings showed that PTCy-MMUD significantly reduced acute GvHD occurrence compared to PTCy-haplo and ATG-MMUD approaches (p = 0.006). The delayed onset of acute GvHD in the PTCy-MMUD group suggests a more controlled immune reconstitution, contributing to the lower incidence. Importantly, PTCy-MMUD exhibited enhanced five-year overall survival rates, aligning with the notion that reduced GvHD correlates with improved patient outcomes (p = 0.032). Conclusions: We believe that this study contributes valuable insights into PTCy-MMUD's management, underscoring its potential to significantly reduce GvHD incidence and enhance survival outcomes. Although further investigations and clinical trials are warranted, this research underscores the promising role of PTCy-based GvHD prophylaxis in improving MMUD allo-HCT success.

Mass spectrometry-based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma.

ABSTRACT: Mass spectrometry (MS) can detect multiple myeloma-derived monoclonal proteins in the peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during posttransplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of posttransplant maintenance with either carfilzomib, lenalidomide, and dexamethasone, or with lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in the PB in the posttransplant setting, despite unavailability of pretreatment calibration samples. There was high agreement between MRD by MS in the PB and paired bone marrow (BM) MRD results at the 10-5 threshold, assessed by either next-generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which, in landmark analysis, reached statistical significance after 18 cycles after transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared with MRD negativity by only 1 modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, posttransplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.

Comparing the Outcomes of Matched and Mismatched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation with Different Anti-Thymocyte Globulin Formulations: A Retrospective, Double-Centre Experience on Behalf of the Polish Adult Leukemia Group.

Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies have performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations-specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients who had undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to the ATG-G group (7.5% vs. 38.3%, p = 0.001). The negative impact of ATG-G on cGvHD was confirmed by multivariate analysis (HR 8.12, 95% CI 2.06-32.0, p = 0.003). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p < 0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p = 0.008) and a higher median CMV copy number (1000 vs. 0, p = 0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p = 0.005). By multivariate analysis, only aGvHD had an influence on CMV reactivations (HR 0.18, 95% CI 0.04-0.75, p = 0.019). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year relapse-free survival (RFS) while comparing ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544, respectively).

Risk factors for Nocardia infection among allogeneic hematopoietic cell transplant recipients: A case-control study of the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation.

OBJECTIVES: Nocardiosis is a rare but life-threatening infection after hematopoietic cell transplantation (HCT). We aimed at identifying risk factors for nocardiosis after allogeneic HCT and clarifying the effect of trimethoprim-sulfamethoxazole prophylaxis on its occurrence. METHODS: We performed a retrospective multicenter case-control study of patients diagnosed with nocardiosis after allogeneic HCT between January 2000 and December 2018. For each case, two controls were matched by center, transplant date, and age group. Multivariable analysis was conducted using conditional logistic regression to identify potential risk factors for nocardiosis. Kaplan-Meier survival curves of cases and controls were compared using log-rank tests. RESULTS: Sixty-four cases and 128 controls were included. Nocardiosis occurred at a median of 9 months after allogeneic HCT (interquartile range: 5-18). After adjustment for potential confounders in a multivariable model, Nocardia infection was associated with tacrolimus use (adjusted odds ratio [aOR] 9.9, 95 % confidence interval [95 % CI]: 1.6-62.7), lymphocyte count < 500/µL (aOR 8.9, 95 % CI: 2.3-34.7), male sex (aOR 8.1, 95 % CI: 2.1-31.5), recent use of systemic corticosteroids (aOR 7.9, 95 % CI: 2.2-28.2), and recent CMV infection (aOR 4.3, 95 % CI: 1.2-15.9). Conversely, use of trimethoprim-sulfamethoxazole prophylaxis was associated with a significantly decreased risk of nocardiosis (aOR 0.2, 95 % CI: 0.1-0.8). HCT recipients who developed nocardiosis had a significantly decreased survival, as compared with controls (12-month survival: 58 % and 90 %, respectively; p < 0.0001). CONCLUSIONS: We identified six factors independently associated with the occurrence of nocardiosis among allogeneic HCT recipients. In particular, trimethoprim-sulfamethoxazole prophylaxis was found to protect against nocardiosis.

Effective treatment of Clostridioides difficile infection improves survival and affects graft-versus-host disease: a multicenter study by the Polish Adult Leukemia Group.

Clostridioides difficile infection (CDI) is the most common cause of infectious diarrhea after allogeneic hematopoietic cell transplantation (allo-HCT). The impact of CDI and its treatment on allo-HCT outcomes and graft-versus-host disease (GVHD), including gastrointestinal GVHD (GI-GVHD) is not well established. This multicenter study assessed real-life data on the first-line treatment of CDI and its impact on allo-HCT outcomes. Retrospective and prospective data of patients with CDI after allo-HCT were assessed. We noted statistically significant increase in the incidence of acute GVHD and acute GI-GVHD after CDI (P = 0.005 and P = 0.016, respectively). The first-line treatment for CDI included metronidazole in 34 patients, vancomycin in 64, and combination therapy in 10. Treatment failure was more common with metronidazole than vancomycin (38.2% vs. 6.2%; P < 0.001). The need to administer second-line treatment was associated with the occurrence or exacerbation of GVHD (P < 0.05) and GI-GVHD (P < 0.001) and reduced overall survival (P < 0.05). In the multivariate analysis, the risk of death was associated with acute GVHD presence before CDI (hazard ratio [HR], 3.19; P = 0.009) and the need to switch to second-line treatment (HR, 4.83; P < 0.001). The efficacy of the initial CDI treatment affects survival and occurrence of immune-mediated GI-GVHD after allo-HCT. Therefore, agents with higher efficacy than metronidazole (vancomycin or fidaxomicin) should be administered as the first-line treatment.

Acute Myeloid Leukemia Post Cytotoxic Therapy in Breast Cancer Survivors-Over 23 Years of Single Center Analysis.

Background: Acute myeloid leukemia post cytotoxic therapy (AML-pCT) among breast cancer (BC) survivors represents a life-threatening complication. This study aims to assess the clinical outcomes of AML-pCT post BC. Methods: An analysis of all AML patients treated at a single hematology center (2000-2023) was performed to select patients with AML-pCT post BC. We applied the 2022 ELN criteria to define the genetic risk. Results: Among 847 AML patients, 28 were diagnosed with AML-pCT following BC. Complex karyotype (CK) occurred in 23.8% of patients. The median overall survival (OS) was 40 months. The survival outcomes were better after allogenic hematopoietic stem cell transplantation (alloHCT) treatment compared to chemotherapy alone (median OS: 47 versus 7 months, p = 0.008). Patients demonstrating CK showed lower survival compared to those without CK (2-year OS: 25.0% versus 66.2%, p = 0.0048). The multivariable Cox proportional hazards regression model indicated that treatment with alloHCT emerged as a significant factor associated with improved OS. The treatment was associated with superior OS (HR = 0.07, 95% CI = 0.01-0.86, p = 0.04). Conclusions: Patients with AML-pCT following BC were characterized with the highest frequency of adverse genetic risk profiles and demonstrated worse survival rates. AlloHCT should be performed as early as possible in such patients. The growing need for studies on inherited cancer susceptibility underscores the importance of close AML-pCT development monitoring in BC survivors.

Prevalence, management, and new treatment modalities of EBV-DNA-emia and EBV-PTLD after allo-HCT: survey of Infectious Diseases Working Party EBMT.

The aim of this study was to determine the current approach of EBV-driven post-transplant complications in context of monitoring, diagnosis, prevalence and treatment in EBMT transplant centers. Routine serology testing in patient and donor before HCT is performed in 95.5% centers. Pretransplant EBV-DNA is routinely tested in all patients in 32.7% centers. Monitoring for EBV infection is feasible in 98.2% centers: including 66.7% centers using standardized PCR. Post-HCT regular monitoring is performed in all patients in 80.5% centers. Anti-EBV prophylaxis with rituximab is used in 12.4% centers. Frequency of csEBV-DNA-emia was 7.4% (adults: 6.2%, children: 12.6%). The PCR threshold used to start preemptive treatment was differentiated among centers. Frequency of EBV-PTLD was 1.6% (adults: 1.3%; children: 3.5%). First-line therapy of EBV-driven complications was rituximab and reduction of immunosuppressive therapy. The rate of failure of first-line preemptive treatment was 12.0%. EBV-specific viral-specific T-lymphocytes were available in 46.0% centers. A number of new experimental therapies were given in 28 patients with resistant/refractory PTLD. In conclusion, the prevalence of EBV-DNA-emia and EBV-PTLD over the period 2020-2021 decreased in comparison to historical data. New trends (routine pretransplant screening for EBV-DNA, wider access to VST, new experimental therapies) are being observed in management of EBV infection after allo-HCT.

FRONTIER1: a partially randomized phase 2 study assessing the safety, pharmacokinetics, and pharmacodynamics of Mim8, a factor VIIIa mimetic.

BACKGROUND: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality. OBJECTIVES: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors. METHODS: The MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab. RESULTS: Mim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5). CONCLUSION: These data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase.

A Panoramic X-ray as a Supportive Diagnostic Tool for the Screening of Osteoporosis in Patients with Hemophilia A and B.

BACKGROUND: Hemophilia is associated with an increased risk of developing osteoporosis and osteopenia. The aim of the study was to interpret the usefulness of fractal analysis of the trabecular bone of the mandible (FD) and selected radiomorphic indices (the antegonial index (AI) and Klemetti index (KI)) to assess the risk of reduced bone mineral density (BMD) in patients with hemophilia A/B. METHODS: The study group consisted of 50 patients with type A/B hemophilia. The control group consisted of 25 males without congenital bleeding disorders. The patients had a panoramic radiograph taken with the same X-ray machine (Vistapano S, Durr Dental, Bietigheim-Bissingen, Germany). The AudaXCeph software (Audax d.o.o., Ljubljana, Slovenia) was used to evaluate the AI index, and the ImageJ, software with a specially prepared script, was used to evaluate the FD. The mandibular cortex was assessed distal to the mental foramen using the Klemetti index. RESULTS: There were no statistically significant differences between the AI, KI and FD values between the study group and the control group. CONCLUSIONS: This study indicated the lack of usefulness of AI, KI and fractal analysis in identifying patients with hemophilia at risk of reduced bone mass.

Prognostic Impact of Copy Number Alterations' Profile and AID/RAG Signatures in Acute Lymphoblastic Leukemia (ALL) with BCR::ABL and without Recurrent Genetic Aberrations (NEG ALL) Treated with Intensive Chemotherapy.

Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients included BCR::ABL1pos subgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNAhigh/IKZF1pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNAneg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNAneg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNApos increased the odds for CNAhigh/IKZF1pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1pos and NEG patients.

Four-tract probabilistic tractography technique for target selection in essential tremor treatment with magnetic resonance-guided focused ultrasound.

OBJECTIVES: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a novel, minimally invasive ablative treatment for essential tremor (ET). The use of a four-tract probabilistic tractography technique, targeting the intersection between the dentato-rubro-thalamic tracts (both decussating and non-decussating), while evaluating the corticospinal tract and the medial lemniscus, may obtain immediate clinical results with reduced adverse events. Our aim is to present our experience with the four-tract technique for patients undergoing ET treatment with MRgFUS. METHODS: Retrospective analysis of a prospective database of consecutive patients undergoing ET treatment in a single center from February 2022 to February 2023. Procedural parameters were collected, and tremor improvement was assessed with the Clinical Rating Scale for Tremor (CRST) at baseline and at 3 and 6 months. Adverse events were also reported. RESULTS: Forty-three patients (median age, 72 years [interquartile range, 66-76]; 22 females) were evaluated. Tremor improved significatively in all CRST subsections at 3 months, including the CRST part A + B treated hand tremor (22 [19-27] vs 4 [2-7], p < 0.001) and CRST part C (16 [13-19] vs 3 [1-4], p < 0.001). Differences persisted significant at 6 months. Adverse events were few (4.1% of paresthesias and 12.5% of objective gait disturbance at follow-up) and recorded as mild. The median number of sonications was 7 [6-8] and mean operative time 68.7 ± 24.2 min. CONCLUSION: Our data show support for the feasibility and benefits of systematic targeting approach with four-tract probabilistic tractography for treating ET using MRgFUS. CLINICAL RELEVANCE STATEMENT: An approach with four-tract probabilistic tractography for treating essential tremor (ET) patients with magnetic resonance-guided focused ultrasound decreases interindividual variability with good clinical outcomes, low number of sonications, few adverse effects, and short procedure times. KEY POINTS: • The optimal target for the treatment of essential tremor with MR-guided focused ultrasound remains unknown. • Four-tract probabilistic tractography is a feasible technique that reduces interindividual variability, with good clinical results, few side effects, and short operative time. • The four-tract tractography approach can be performed using different MRI scanners and post-processing software in comparison with the initial description of the technique.

Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial.

Previous studies suggest that postautologous stem cell transplant (ASCT) recovery of polyclonal immunoglobulin from immunoparesis in patients with multiple myeloma is a positive prognostic marker. We performed a longitudinal analysis of polyclonal immunoglobulin concentrations and unique B-cell sequences in patients enrolled in the phase 3 ATLAS trial that randomized 180 subjects to either carfilzomib, lenalidomide, dexamethasone (KRd) or lenalidomide (R) maintenance. In the KRd arm, standard-risk patients with minimal residual disease negativity after six cycles de-escalated to R alone after cycle 8. One year from the initiation of maintenance at least partial recovery of polyclonal immunoglobulin was observed in more patients on the R arm (58/66, p < 0.001) and in those who de-escalated from KRd to R (27/38, p < 0.001) compared to the KRd arm (9/36). In patients who switched from KRd to R, the concentrations of uninvolved immunoglobulin and the number of B-cell unique sequences increased over time, approaching values observed in the R arm. There were no differences in progression-free survival between the patients with at least partial immunoglobulin recovery and the remaining population. Our analysis indicates that patients receiving continuous therapy after ASCT experience prolonged immunoparesis, limiting prognostic significance of polyclonal immunoglobulin recovery in this setting.

The presence of additional cytogenetic aberrations in chronic myeloid leukemia cells at the time of diagnosis or their appearance on tyrosine kinase inhibitor therapy predicts the imatinib treatment failure.

Currently used treatment of CML dramatically improved the prognosis of disease. However, additional chromosome aberrations (ACA/Ph+) are still one of the adverse prognostic factors. OBJECTIVES: evaluation of the impact of ACA/Ph+ appearance during disease outcome on the response to treatment. THE STUDY GROUP: consisted of 203 patients. The median time of follow-up was 72 months. ACA/Ph+ was found in 53 patients. RESULTS: patients were divided into four groups: standard risk, intermediate, high and very high risk. When ACA/Ph+ presence was documented at diagnosis time the optimal response was observed in 41.2%, 25%, and 0% of pts with intermediate, high and very high risk, respectively. If ACA/Ph+ were detected during imatinib treatment the optimal response was in 4.8% of patients. The risk of blastic transformation for patients with standard risk, intermediate, high and very high risk was 2.7%, 18.4%, 20% and 50%, respectively. CONCLUSIONS: the presence of ACA/Ph+ at diagnosis time or their appearance on therapy seems to be clinically relevant not only in terms of the risk of blastic transformation but also in terms of the treatment failure. Gathering patients with various karyotypes and their responses to treatment would allow to set better guidelines and predictions.

BCR::ABL1-like acute lymphoblastic leukaemia: a single institution experience on identification of potentially therapeutic targetable cases.

BACKGROUND: BCR::ABL1-like acute lymphoblastic leukaemia (BCR::ABL1-like ALL) is characterized by inferior outcomes. Current efforts concentrate on the identification of molecular targets to improve the therapy results. The accessibility to next generation sequencing, a recommended diagnostic method, is limited. We present our experience in the BCR::ABL1-like ALL diagnostics, using a simplified algorithm. RESULTS: Out of 102 B-ALL adult patients admitted to our Department in the years 2008-2022, 71 patients with available genetic material were included. The diagnostic algorithm comprised flow cytometry, fluorescent in-situ hybridization, karyotype analysis and molecular testing with high resolution melt analysis and Sanger Sequencing. We recognized recurring cytogenetic abnormalities in 32 patients. The remaining 39 patients were screened for BCR::ABL1-like features. Among them, we identified 6 patients with BCR::ABL1-like features (15.4%). Notably, we documented CRLF2-rearranged (CRLF2-r) BCR::ABL1-like ALL occurrence in a patient with long-term remission of previously CRLF2-r negative ALL. CONCLUSIONS: An algorithm implementing widely available techniques enables the identification of BCR::ABL1-like ALL cases in settings with limited resources.

Decrease of lethal infectious complications in the context of causes of death (COD) after hematopoietic cell transplantation: COD-2 and COD-1 study of the Infectious Diseases Working Party EBMT.

We previously analyzed trends in incidence and factors associated with lethal complications in ALL/AML/CML patients (causes of deaths; COD-1 study). The objective of this study was the analysis of incidence and specific causes of death after HCT, with focus on infectious deaths in two time periods, 1980-2001 (cohort-1) and 2002-2015 (cohort-2). All patients with HCT for lymphoma, plasma cell disorders, chronic leukemia (except CML), myelodysplastic/myeloproliferative disorders, registered in the EBMT-ProMISe-database were included (n = 232,618) (COD-2 study). Results were compared to those in the ALL/AML/CML COD-1 study. Mortality from bacterial, viral, fungal, and parasitic infections decreased in very early, early and intermediate phases. In the late phase, mortality from bacterial infections increased, while mortality from fungal, viral, or unknown infectious etiology did not change. This pattern was similar for allo- and auto-HCT in COD-1 and COD-2 studies, with a distinct and constant lower incidence of all types of infections at all phases, after auto-HCT. In conclusion, infections were the main cause of death before day +100, followed by relapse. Mortality from infectious deaths significantly decreased, except late phase. Post-transplant mortality has significantly decreased in all phases, from all causes after auto-HCT; it has decreased in all phases after allo-HCT except late phase.