Acute myeloid leukemia with rare recurring translocations-an overview of the entities included in the international consensus classification.

Two different systems exist for subclassification of acute myeloid leukemia (AML); the World Health Organization (WHO) Classification and the International Consensus Classification (ICC) of myeloid malignancies. The two systems differ in their classification of AML defined by recurrent chromosomal abnormalities. One difference is that the ICC classification defines an AML subset that includes 12 different genetic abnormalities that occur in less than 4% of AML patients. These subtypes exhibit distinct clinical traits and are associated with treatment outcomes, but detailed description of these entities is not easily available and is not described in detail even in the ICC. We searched in the PubMed database to identify scientific publications describing AML patients with the recurrent chromosomal abnormalities/translocations included in this ICC defined patient subset. This patient subset includes AML with t(1;3)(p36.3;q21.3), t(3;5)(q25.3;q35.1), t(8;16)(p11.2;p13.3), t(1;22)(p13.3;q13.1), t(5;11)(q35.2;p15.4), t(11;12)(p15.4;p13.3) (involving NUP98), translocation involving NUP98 and other partner, t(7;12)(q36.3;p13.2), t(10;11)(p12.3;q14.2), t(16;21)(p11.2;q22.2), inv(16)(p13.3q24.3) and t(16;21)(q24.3;q22.1). In this updated review we describe the available information with regard to frequency, biological functions of the involved genes and the fusion proteins, morphology/immunophenotype, required diagnostic procedures, clinical characteristics (including age distribution) and prognostic impact for each of these 12 genetic abnormalities.

Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation.

Hyperammonemia is a rare and often fatal complication following the conditioning therapy in autologous and allogeneic stem cell transplant recipients. It is characterized by anorexia, vomiting, lethargy and coma without any other apparent cause. The diagnosis is often delayed because symptoms can be subtle and ammonia is usually not included among the routine analyzes. Previous reports have not identified the molecular mechanisms behind hyperammonemia in stem cell transplant recipients. Urea cycle disorders (UCDs) are inborn errors of metabolism leading to hyperammonemia that usually presents in early childhood, whereas first presentation in adults is less common. Here we describe an adult woman with hyperammonemia following autologous stem cell transplantation for multiple myeloma. No apparent cause of hyperammonemia was identified, including portosystemic shunting, liver dysfunction or recent hyperammonemia-inducing chemotherapy. Hyperammonemia, normal blood glucose as well as anion gap and a previous history of two male newborns that died early after birth, prompted biochemical and genetic investigations for a UCD. A heterozygous variant in the X-linked gene encoding ornithine transcarbamylase (OTC) was identified and was regarded as a cause of UCD. The patient improved after treatment with nitrogen scavengers and high caloric intake according to a UCD protocol. This case report suggests that UCD should be considered as a possible cause of hyperammonemia following stem cell transplantation.

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity.

Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients.

Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up.

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with a substantial burden on patient's quality of life. CARDINAL was a 2-part, open-label, single-arm, multicenter phase 3 study evaluating the C1s inhibitor, sutimlimab, for treatment of CAD. Part A consisted of the pivotal study phase, with the part B extension phase assessing long-term safety and durability of response including patient-reported outcomes, which is the focus of this report. Altogether, 22 patients continued from part A to part B, majority female (68.2%) with a median age of 71.5 years (range, 55-85). Throughout treatment, score improvement on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale exceeded a predefined, group-level clinically important change of ≥5 points vs baseline, with a mean (standard error [SE]) change of 11.7 (3.7) points at week 135. The 12-Item Short Form Health Survey physical and mental component scores remained above baseline, with week 123 mean change (SE) exceeding clinically important changes of 3.9 for physical and 2.8 for mental component scores at 4.7 (2.8) and 3.8 (5.7) points, respectively. EuroQol Visual Analogue Scale, scoring patients' self-rated health, also remained above baseline with a change of 17.1 (5.6) points at week 135. Patient Global Impression of (fatigue) Severity improved vs baseline, corroborating FACIT-Fatigue scores. Patient Global Impression of Change indicated a reduction in perceived disease burden. Data from CARDINAL part B support sustained alleviation of CAD disease burden after long-term treatment with sutimlimab over 2 years, returning toward baseline upon treatment cessation. This trial was registered at www.clinicaltrials.gov as #NCT03347396.

Robust spike-specific CD4+ and CD8+ T cell responses in SARS-CoV-2 vaccinated hematopoietic cell transplantation recipients: a prospective, cohort study.

Poor overall survival of hematopoietic stem cell transplantation (HSCT) recipients who developed COVID-19 underlies the importance of SARS-CoV-2 vaccination. Previous studies of vaccine efficacy have reported weak humoral responses but conflicting results on T cell immunity. Here, we have examined the relationship between humoral and T cell response in 48 HSCT recipients who received two doses of Moderna's mRNA-1273 or Pfizer/BioNTech's BNT162b2 vaccines. Nearly all HSCT patients had robust T cell immunity regardless of protective humoral responses, with 18/48 (37%, IQR 8.679-5601 BAU/mL) displaying protective IgG anti-receptor binding domain (RBD) levels (>2000 BAU/mL). Flow cytometry analysis of activation induced markers (AIMs) revealed that 90% and 74% of HSCT patients showed reactivity towards immunodominant spike peptides in CD8+ and CD4+ T cells, respectively. The response rate increased to 90% for CD4+ T cells as well when we challenged the cells with a complete set of overlapping peptides spanning the entire spike protein. T cell response was detectable as early as 3 months after transplant, but only CD4+ T cell reactivity correlated with IgG anti-RBD level and time after transplantation. Boosting increased seroconversion rate, while only one patient developed COVID-19 requiring hospitalization. Our data suggest that HSCT recipients with poor serological responses were protected from severe COVID-19 by vaccine-induced T cell responses.

Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare, autoimmune, classical complement pathway (CP)-mediated hemolytic anemia. Sutimlimab selectively inhibits C1s of the C1 complex, preventing CP activation while leaving the alternative and lectin pathways intact. In Part A (26 weeks) of the open-label, single-arm, Phase 3 CARDINAL study in patients with CAD and a recent history of transfusion, sutimlimab demonstrated rapid effects on hemolysis and anemia. Results of the CARDINAL study Part B (2-year extension) study, described herein, demonstrated that sutimlimab sustains improvements in hemolysis, anemia, and quality of life over a median of 144 weeks of treatment. Mean last-available on-treatment values in Part B were improved from baseline for hemoglobin (12.2 g/dL on-treatment versus 8.6 g/dL at baseline), bilirubin (16.5 µmol/L on-treatment versus 52.1 µmol/L at baseline), and FACIT-Fatigue scores (40.5 on-treatment versus 32.4 at baseline). In the 9-week follow-up period after sutimlimab cessation, CP inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Overall, sutimlimab was generally well tolerated in Part B. All 22 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (54.5%) patients experienced ≥1 serious TEAE, including seven (31.8%) with ≥1 serious infection. Three patients discontinued due to a TEAE. No patients developed systemic lupus erythematosus or meningococcal infections. After cessation of sutimlimab, most patients reported adverse events consistent with recurrence of CAD. In conclusion, the CARDINAL 2-year results provide evidence of sustained sutimlimab effects for CAD management, but that disease activity reoccurs after treatment cessation. NCT03347396. Registered November 20, 2017.

[Chronic graft-versus-host disease]. / Kronisk transplantat-mot-vert-sykdom.

Chronic graft-versus-host disease is a late complication of allogeneic stem cell transplantation and leads to chronic inflammation and fibrosis in various organs due to dysregulation of donor immune cells. The disease can occur in all organs, but is most frequently seen in the skin, eyes, oral cavity, gastrointestinal tract, genitalia, lungs, muscles, fascia and joints. Chronic graft-versus-host disease is associated with considerable morbidity and mortality, and treatment requires close collaboration between different parts of the specialist health services. This article provides a clinical review of chronic graft-versus-host disease based on a non-systematic literature search and the authors' own clinical experience.

Allogeneic stem cell transplantation in adults 2015-21. / Allogen stamcelletransplantasjon hos voksne 2015­21.

BACKGROUND: Allogeneic stem cell transplantation is the only curative treatment for several malignant and non-malignant haematological diseases, and is associated with a risk of serious complications. In recent years, several changes have been introduced with the aim of reducing treatment-related complications. This retrospective study reviews quality indicators for patients who underwent transplantation in the period 2015-21. MATERIAL AND METHOD: The study included 589 adult patients who were treated with allogeneic stem cell transplantation for the first time at Oslo University Hospital in the period May 2015 to May 2021. Three two-year periods are compared using descriptive methods. RESULTS: In the period 2015-2021, the number of first-time transplant patients per year increased from 85 to 113. One-year survival increased from 68 % in the first two-year period to 74 % in the second period and 82 % in the last period. Both acute and chronic GVHD were reduced, and one-year GVHD-free and relapse-free survival increased from 42 % to 60 % during the study period. INTERPRETATION: Since 2015, the number of transplants has increased, while survival has improved and the risk of complications is lower.

Early response evaluation by single cell signaling profiling in acute myeloid leukemia.

Aberrant pro-survival signaling is a hallmark of cancer cells, but the response to chemotherapy is poorly understood. In this study, we investigate the initial signaling response to standard induction chemotherapy in a cohort of 32 acute myeloid leukemia (AML) patients, using 36-dimensional mass cytometry. Through supervised and unsupervised machine learning approaches, we find that reduction of extracellular-signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in the myeloid cell compartment 24 h post-chemotherapy is a significant predictor of patient 5-year overall survival in this cohort. Validation by RNA sequencing shows induction of MAPK target gene expression in patients with high phospho-ERK1/2 24 h post-chemotherapy, while proteomics confirm an increase of the p38 prime target MAPK activated protein kinase 2 (MAPKAPK2). In this study, we demonstrate that mass cytometry can be a valuable tool for early response evaluation in AML and elucidate the potential of functional signaling analyses in precision oncology diagnostics.

Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study.

Cold agglutinin disease (CAD) is a rare chronic autoimmune haemolytic anaemia, driven mainly by classical complement pathway activation, leading to profound fatigue and poor quality of life. In the Phase 3 CADENZA trial, sutimlimab-a C1s complement inhibitor-rapidly halted haemolysis, increased haemoglobin levels and improved fatigue versus placebo in patients with CAD without a recent history of transfusion. Patient-reported outcomes (PROs) included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change (PGIC) and Patient Global Impression of (fatigue) Severity (PGIS). Sutimlimab resulted in significant rapid and meaningful improvements versus placebo in PROs. From Week 1, the FACIT-Fatigue mean score increased >5 points above baseline (considered a clinically important change [CIC]). Least-squares (LS) mean change in FACIT-Fatigue score from baseline to treatment assessment timepoint was 10.8 vs. 1.9 points (sutimlimab vs. placebo; p < 0.001). Improvements in physical (PCS) and mental (MCS) component scores of the SF-12 were also considered CICs (LS mean changes from baseline to Week 26: PCS 5.54 vs. 1.57 [p = 0.064]; MCS 5.65 vs. -0.48 [p = 0.065]). These findings demonstrate that in addition to improving haematologic parameters, sutimlimab treatment demonstrates significant patient-reported benefits. Study registered at www.clinicaltrials.gov: NCT03347422.

Sutimlimab improves quality of life in patients with cold agglutinin disease: results of patient-reported outcomes from the CARDINAL study.

Patients with cold agglutinin disease (CAD) experience fatigue and poor quality of life. However, previous CAD-related studies have not explored patient-reported outcomes such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Sutimlimab, a C1s complement inhibitor, has been shown to halt haemolysis in CAD. Here, we present 26-weeks' patient-reported data from CARDINAL Part A (ClinicalTrials.gov, NCT03347396), which assessed efficacy and safety of sutimlimab in patients with CAD and recent history of transfusion. Aside from measuring changes in haemolytic markers, FACIT-Fatigue was measured at the treatment assessment timepoint (TAT; average of weeks 23, 25, and 26). Exploratory endpoints included the change in EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) and the 12-Item Short Form Health Survey (SF-12) at TAT, and Patient Global Impression of Change (PGIC), and Patient Global Impression of (fatigue) Severity (PGIS) at week 26. Mean (range) FACIT-Fatigue scores increased from 32.5 (14.0-47.0) at baseline (a score indicative of severe fatigue) to 44.3 (28.0-51.0) at TAT. Considerable improvements were reported for EQ-5D-5L at TAT, SF-12 scores at TAT, and PGIC and PGIS scores at week 26. Sutimlimab treatment resulted in sustained improvements in symptoms of fatigue and overall quality of life in patients with CAD. NCT03347396. Registered 20 November, 2017.

IL-6 Responsiveness of CD4+ and CD8+ T Cells after Allogeneic Stem Cell Transplantation Differs between Patients and Is Associated with Previous Acute Graft versus Host Disease and Pretransplant Antithymocyte Globulin Therapy.

Graft-versus-host disease (GVHD), one of the most common and serious complications after allogeneic stem cell transplantation, is mediated by allocative T cells. IL-6 mediates both pro- and anti-inflammatory effects and modulates T cell response through classical signaling and trans-signaling. We investigated the effects on the mTOR and JAK/STAT pathways after various types of IL-6 signaling for circulating T cells were derived from 31 allotransplant recipients 90 days post-transplant. Cells were stimulated with IL-6 alone, hyper-IL-6 (trans-signaling), IL-6+IL-6 receptor (IL-6R; classical + trans-signaling) and IL-6+IL-6R+soluble gp130-Fc (classical signaling), and flow cytometry was used to investigate the effects on phosphorylation of AKT (Thr308), mTOR (Ser2442), STAT3 (Ser727) and STAT3 (Tyr705). CD3+CD4+ and CD3+C8+ T cells responded to classical and trans IL-6 stimulation with increased STAT3 (Tyr705) phosphorylation; these responses were generally stronger for CD3+CD4+ cells. STAT3 (Tyr705) responses were stronger for patients with previous acute GVHD; CD3+CD4+ cells from GVHD patients showed an additional STAT3 (Ser727) response, whereas patients without acute GVHD showed additional mTOR (Ser2448) responses. Furthermore, treatment with antithymocyte globulin as a part of GVHD prophylaxis was associated with generally weaker STAT3 (Tyr705) responses and altered STAT3 (Ser727) responsiveness of CD3+CD4+ cells together with increased mTOR (Ser2448) responses for the CD3+CD8+ cells. Thus, early post-transplant CD3+CD4+ and CD3+ CD8+ T cell subsets differ in their IL-6 responsiveness; this responsiveness is modulated by antithymocyte globulin and differs between patients with and without previous acute GVHD. These observations suggest that allotransplant recipients will be heterogeneous with regard to the effects of post-transplant IL-6 targeting.

MicroRNA serum profiles and chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is the most common long-term complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). During the last decade, the interest of micro RNAs (miRNAs) in the pathophysiological process of cGVHD has increased. The objectives of this study were to investigate a wide range of serum miRNAs in allografted patients and identify associations between miRNAs and cGVHD. The study included 79 allotransplanted adults, where serum samples were obtained 1 year after the allo-HSCT, and miRNA profiling analysis in serum was performed. Fifty of the 79 patients (63%) had signs of cGVHD at the 1-year post-allo-HSCT control. miRNA sequencing analysis revealed 1380 different miRNAs detected for at least 1 patient, whereas 233 miRNAs (17%) were detected in >70 patients. We identified 10 miRNAs that differed significantly between patients with and without cGVHD (P < .005; false discovery rate <0.1), and all of these miRNAs were detected for >75 of the patients. Furthermore, 5 distinct miRNAs, miR-365-3p, miR-148-3p, miR-122-5p, miR-378-3p, and miR-192-5p, were found to be particularly associated with cGVHD in our analysis and were validated by receiver operating characteristics analysis. Based on only 3 miRNAs, miR-365-3p, miR-148-3p, and miR-378-3p, we developed a miRNA signature that, by bioinformatic approaches and linear regression model, utterly improved our potential diagnostic biomarker model for cGVHD. We conclude that miRNAs are differently expressed among patients with and without cGVHD, although further and larger studies are needed to validate our present findings.

Necrotizing Bacterial Myositis as the Initial Presentation of Severe Aplastic Anaemia.

INTRODUCTION: Necrotizing soft tissue infections are rapidly progressing infections associated with severe inflammation and cytokine release. Early recognition and surgical intervention are key factors to secure survival. The current case presents a patient with multifocal necrotizing soft tissue infection as the initial presentation of severe aplastic anaemia. Case Presentation. A man in his fifties was admitted with septic shock with multiorgan failure and severe pancytopenia, after two days of malaise with high fever and right flank pain. The diagnosis streptococcal necrotizing myositis was significantly delayed due to atypical clinical findings. After initial surgical exploration, the decision was made to defer from surgical debridement due to extensive involvement of several muscle groups, grave pancytopenia, and suspected dismal prognosis. Surprisingly, the patient stabilized after antibiotics and intensive care treatment. Based on severe pancytopenia and hypocellular bone marrow, with no evidence of other bone marrow disorders, the patient was diagnosed with aplastic anaemia. Treatment for aplastic anaemia with antithymocyte globulin, cyclosporine, and eltrombopaq was started, and 2 months later, a partial haematological recovery was observed. The patient could be discharged from hospital without antibiotic treatment. CONCLUSIONS: This case illustrates the crucial role of a multidisciplinary approach on admission and further during the clinical course. Clinical improvement despite severe neutropenia and stabilization during immunosuppressive therapy suggest that immunological factors modulate clinical course in necrotizing soft tissue infections.

Cytokine Release Syndrome in the Immunotherapy of Hematological Malignancies: The Biology behind and Possible Clinical Consequences.

Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction associated with (i) chimeric antigen receptor (CAR)-T cell therapy, (ii) therapeutic antibodies, and (iii) haploidentical allogeneic stem cell transplantation (haplo-allo-HSCT). Severe CRS can be life-threatening in some cases and requires prompt management of those toxicities and is still a great challenge for physicians. The pathophysiology of CRS is still not fully understood, which also applies to the identifications of predictive biomarkers that can forecast these features in advance. However, a broad range of cytokines are involved in the dynamics of CRS. Treatment approaches include both broad spectrum of immunosuppressant, such as corticosteroids, as well as more specific inhibition of cytokine release. In the present manuscript we will try to review an update regarding pathophysiology, etiology, diagnostics, and therapeutic options for this serious complication.

A young woman with dyspnoea and proteinuria. / En ung kvinne med pustevansker og proteinuri.

BACKGROUND: Systemic lupus erythematosus and anti-phospholipid syndrome may cause severe haematological complications despite few other symptoms of disease. CASE PRESENTATION: A previously healthy woman in her late twenties was admitted to hospital with chest pain and dyspnoea. CT of the thorax revealed bilateral pulmonary embolism and urine sampling showed haematuria and proteinuria. A few days after hospital admission, she developed transfusion-requiring anaemia. The investigation revealed a positive direct antiglobulin test, presence of anti-nuclear antibodies, lupus anticoagulant, anti-cardiolipin and anti-glycoprotein antibodies. INTERPRETATION: Pulmonary embolism in a young, previously healthy woman may be caused by different predisposing conditions. Systemic lupus erythematosus with accompanying anti-phospholipid syndrome was the diagnosis in this case. Severe autoimmune haemolytic disease may occur as a secondary phenomenon to systemic lupus erythematosus, and the condition must not be overlooked.