Concurrent Cobalamin C and Plasminogen Deficiencies in a Patient with Chronic Thrombotic Microangiopathy.

BACKGROUND: Although most patients with atypical hemolytic uremic syndrome (aHUS) have variants in genes participating in alternative complement pathways, rare variants in non-complement pathway-related genes, including DGKE, INF2, MMACHC, PLG, and THBD, have also been described. CASE PRESENTATION: We report an 18-year-old male patient with renal biopsy-proven chronic thrombotic microangiopathy that raised suspicion of aHUS. Whole-exome sequencing revealed a novel pathogenic homozygous MMACHC c.484G>T (p.Gly162Trp) variant. Subsequently, clinical and laboratory findings confirmed cobalamin C (Cbl C) deficiency. Also, homozygous missense c.1112C>T PLG (p.Thr371Ile) variant was detected (it had been reported as a variant of unknown significance). However, the low serum plasminogen (PLG) activity proved the pathogenicity of c.1112C>T. Hence, the patient was diagnosed with concurrent Cbl C and PLG deficiencies. Segregation analysis revealed that the mother and father had the same heterozygous PLG and MMACHC variants. PLG variants have generally been described in aHUS patients concomitant with complement gene variants in the literature; therefore, the association between aHUS and PLG variants is controversial. The possible contribution of PLG deficiency to thrombotic microangiopathy was also discussed in this case. CONCLUSION: Non-complement-mediated aHUS is an exceptional disorder. A limited number of genes are involved in this entity. To our knowledge, this is the first aHUS patient diagnosed with both Cbl C and PLG deficiencies in the literature.

Baseline inflammation indexes and neutrophil-to-LDH ratio for prediction of the first mobilization failure without plerixafor-based regimens in multiple myeloma and lymphoma patients: A single-center retrospective study.

BACKGROUND: Many factors were identified for mobilization failure (MF) in autologous hematopoietic stem-cell transplantation. To our knowledge, this is the first study to investigate the efficacy of baseline inflammation indexes and neutrophil-to-lactate dehydrogenase (LDH) ratio to predict MF in multiple myeloma (MM) and lymphoma. METHODS: A total of 240 patients with lymphoma or MM hospitalized between January 2014 and June 2022 for the first stem cell mobilization were included in this retrospective single-center study. We evaluated the impact of baseline demographic, clinical, and laboratory data (before granulocyte colony-stimulating factor and chemotherapy implementation), including neutrophil, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), neutrophil-to-C-reactive protein, and neutrophil-to-LDH ratios on MF. RESULTS: A total of 240 patients were divided into successful (214 patients, 89.16%) and poor mobilizers (26 patients, 10.84%). Poor mobilizers had lower neutrophil, NLR, SII, and neutrophil-to-LDH ratios (P values were .001, .022, .001, and .001, respectively). Among these markers, only the neutrophil-to-LDH ratio was statistically low in both poor mobilizer MM and lymphoma patients. Receiving operator characteristic curve analysis was performed to evaluate neutrophil, SII, and neutrophil-to-LDH ratios for MF. Neutrophil-to-LDH ratio had the highest specificity (93.93%, for ≤9.904 cut-off) compared to the other two variables. Multivariate logistic regression analysis showed that neutrophil-to-LDH ratio ≤ 9.904 (cut-off) (odds ratio: 7.116, P = .001), neutrophil counts ≤3300/mm3 (cut-off) (odds ratio: 3.248, P = .021), and lymphoma diagnosis (odds ratio: 2.674, P = .039) were independent risks for MF. CONCLUSION: The neutrophil-to-LDH ratio could be a novel marker in lymphoma and MM patients to predict the first MF. New studies should be conducted for the optimization of this index.

Comprehensive mastocytosis data analysis from a single center.

Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma or localized mast cell (MC) tumors. The wide range of complaints may cause patients to consult various clinics, with resulting mis- or underdiagnosis. Therefore, cooperation between different subspecialties is of paramount importance. In this article, we have compiled 104 adult mastocytosis cases diagnosed and followed in our Hematology and other clinics. 86 (82.7%) of 104 patients had systemic mastocytosis. Osteoporosis, disease-related complications, and secondary malignancies are important topics in this group. We know that indolent form has great survival. But smoldering or aggressive mastocytosis has a poor prognosis. CM and indolent SM have a significantly better prognosis compared to aggressive SM (p < 0.001). We found that the presence of more than 25% of mast cells in the bone marrow, the presence of concomitant marrow dysplasia, and the presence of disease-related complications affect survival (p < 0.001). In addition to the WHO classification, the IPSM scoring system is indicative of the prognosis in this rare disease.

Biosimilar Rituximab (Redditux) Added to CHOP Chemotherapy for De Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single-Center Experience

Objective: Redditux® (RED), as a biosimilar rituximab, was approved in Turkey for all indications of the original Mabthera® (MAB) in March 2018. The aim of our study was to evaluate the efficacy and safety of RED in de novo diffuse large B-cell lymphoma. Materials and Methods: Fifty-one patients received RED combined with the CHOP regimen. The median follow-up was 31 months. The historical control group included 219 patients treated with the MAB-CHOP regimen and the median follow-up time was 38 months. We compared the response rates and survival outcomes of these RED-CHOP and MAB-CHOP cohorts. Results: In the RED cohort, the overall response rate (ORR) at the end of the treatment protocol was 86%, with 37 (72.5%) cases of complete response (CR) and 7 (13.5%) cases of partial response (PR). In the historical MAB cohort, the ORR was 84%, with CR and PR rates of 82% and 2%, respectively. The 24-month progression-free survival (PFS) rates were 73.76% (95% confidence interval [CI]: 0.59-0.84) and 85.2% (95% CI: 0.79-0.90) for the RED and MAB cohorts, respectively (p=0.0106). The 24-month overall survival rates were 78.4% (95% CI: 0.64-0.87) and 81.4% (95% CI: 0.75-0.86) for the RED and MAB cohorts, respectively (p=0.7461). For patients with high revised International Prognostic Index scores, 24-month PFS was 45.5% (95% CI: 0.17-0.71) and 63% (95% CI: 0.37-0.80) for the RED and MAB cohorts, respectively (p=0.0711). In the RED cohort, central nervous system (CNS) relapse was significantly increased compared to the MAB cohort (10% vs. 1.83%, p=0.004). Among the RED cohort, bone involvement at the time of diagnosis was a risk factor for CNS relapse (p=0.028). Thirteen patients died in follow-up. There were no serious adverse events causing the cessation of the drugs. Conclusion: RED has an ORR similar to that of MAB. However, PFS rates were worse in the RED cohort. Additionally, CNS relapse ratio was a major concern for our RED cohort. Large prospective controlled studies and real-life data with longer follow-up are needed to document the non-inferiority of RED compared to MAB.

Malnutrition treatment and follow-up in clinical nutrition outpatient clinics associated with increased muscle mass.

OBJECTIVE: Clinical nutrition outpatient clinics (CNOCs) are the mainstay of the nutrition bundle in hospitals. They are important for the diagnosis, treatment, and follow-up of outpatients with malnutrition (MN) and sarcopenia. The aim of this study was to evaluate changes in muscle mass during the treatment of MN in patients admitted to CNOCs. METHODS: A total number of 1118 patients were included in this retrospective cohort descriptive study. Data including medical history, weight loss, anthropometric measurements, MN diagnosis (according to ESPEN definition), nutrition treatment, bioelectrical impedance analysis and laboratory examinations were noted for the first admission and the follow-up. RESULTS: This retrospective, cohort descriptive study included 1118 patients. The mean age of the participants was 54 ± 22 y (18-101 y) and half of the patients were men. Of the 1118 patients, 37,7% were ≥65 y of age. Cancer (32.2%) was the most frequent diagnosis followed by diabetes (16.7%) and dementia (11.3%). MN prevalence was 51.6%. Protein- and energy-enriched diet, oral enteral nutrition supplementation, tube enteral feeding, and parenteral nutrition were used in 42.7%, 69.6%, 11%, and 2.7% of the patients with MN, respectively. Skeletal muscle mass was significantly increased in MN, cancer, neuromuscular diseases (NMD) and patients ≥65 y of age in the first 6 mo, and could be maintained during the next 6 mo of follow-up. Patients with cancer, chronic kidney disease, and NMD and those ≥65 y of age were able to increase their body mass index. CONCLUSIONS: MN treatment and follow-up can restore muscle mass especially in patients ≥65 y of age and in those with chronic diseases. CNOCs are beneficial in the treatment and follow-up of MN.

The Real-World Experience With Single Agent Ibrutinib in Relapsed/Refractory CLL.

INTRODUCTION/BACKGROUND: The emergence of novel agents targeting the B-cell receptor pathway and BCL-2 has significantly changed the therapeutic landscape of CLL. We evaluated the safety and efficacy of single-agent ibrutinib in relapsed/refractory CLL in real-world settings. PATIENTS/METHODS: A total of 200 relapsed/refractory CLL patients with a median age of 68 were included in this retrospective, multicenter, non-interventional study. Data of the study were captured from the patient charts of the participating centers. RESULTS: The median for lines of previous chemotherapy was 2 (1-6); 62 (31.8%) patients had del17p and/or p53 mutations (del17p+/p53mut). Of the study group, 146 (75%) patients achieved at least PR, while 16 (8.7%) patients discontinued ibrutinib due to TEA. The most common drug-related adverse events were neutropenia (n: 31; 17.4%) and thrombocytopenia (n: 40; 22.3%), which were ≥ grade 3 in 9 (5%) and 5 (3.9%) patients, respectively. Pneumonia (n: 42; 23.7%) was the most common nonhematologic TEA. Atrial fibrillation (n: 5; 2.8%) and bleeding (n: 11; 6.3%) were relatively rare during the study period. Within a median follow-up period of 17 (1-74) months, 42 (21%) patients died. The estimated median OS of the study cohort was 52 months. Only the response to ibrutinib (CR/PR vs. SD/PD) was significantly associated with OS. CONCLUSION: Our results indicate good safety and efficacy for single-agent ibrutinib in R/R CLL in daily practice.

Prognostic significance of 68Ga-Pentixafor PET/CT in multiple myeloma recurrence: a comparison to 18F-FDG PET/CT and laboratory results.

PURPOSE: This study investigates the prognostic value of 68Ga-Pentixafor PET/CT using PET-derived quantitative in multiple myeloma (MM) patients with suspected recurrence in comparison to 18F-FDG PET/CT and clinical data. METHODS: Twenty-four MM patients with suspicion for relapse who underwent 68Ga-Pentixafor and 18F-FDG PET/CT were retrospectively evaluated. Total bone marrow glycolysis for 18F-FDG (TBMFDG) and total bone marrow uptake for 68Ga-Pentixafor PET/CT (TBMCXCR4) were calculated using whole-body metabolic tumor burden obtained by dedicated software (MIM 7.0.6). The patients were followed for 19-24 months, and the association of PET-derived quantitative data with overall survival (OS) was analyzed. RESULTS: 68Ga-Pentixafor PET/CT was positive in 17 patients, of which 13 were also positive on 18F-FDG PET/CT, whereas 7 patients were negative on both scans. The positive rate of 68Ga-Pentixafor and 18F-FDG PET/CT on a patient-based approach was 70.8% and 54.1%, respectively. 68Ga-Pentixafor positivity was significantly associated with OS (p = 0.009), and 18F-FDG positivity was at the margin of statistical significance (p = 0.056). TBMCXCR4 and TBMFDG were negatively correlated with OS (r = -0.457, p = 0.025 and r = -0.617, p = 0.001, respectively). The OS was negatively correlated with beta-2-microglobulin levels (r = -0.511, p = 0.01) and CRAB score (r = -0.592, p = 0.002) as an indicator of the end-organ disease, which confirmed these results. Serum beta-2-microglobulin levels and CRAB score were also correlated with TBMCXCR4 (r = 0.442, p = 0.039 and r = 0.573, p = 0.003, respectively) and TBMFDG (r = 0.543, p = 0.009 and r = -0.424, p = 0.003, respectively). CONCLUSION: 68Ga-Pentixafor PET/CT positivity is a negative prognostic factor in the survival outcome of MM patients. Complementary 68Ga-Pentixafor PET/CT has the potential to overcome 18F-FDG PET/CT limitations and helps a more precise risk stratification.

Case Report: Severe COVID-19 Pneumonia in a Patient With Relapsed/Refractory Hodgkin's Lymphoma.

First identified in China in December 2019, coronavirus disease 2019 (COVID-19) has rapidly evolved into a global pandemic. The presence of haematological malignancies are expected to increase the risk of adverse outcomes from this viral infection due to the immunosuppression brought about by the underlying cancer and the effects of therapy. We present a 55-year-old woman diagnosed with relapsed/refractory Hodgkin's lymphoma (HL) who had been heavily pretreated with multiagent chemotherapy, autologous hematopoietic stem cell transplantation (autoHCT), allogeneic hematopoietic stem cell transplantation (alloHCT) and was complicated with EBV associated posttransplant lymphoproliferative disease (PTLD) and chronic graft-versus-host-disease (GVHD). The patient was recently treated with brentuximab and donor lymphocyte infusion (DLI) for relapse after alloHCT. She suffered from severe COVID-19 pneumonia and eventually succumbed to acute respiratory distress syndrome (ARDS) and multiorgan failure. Of note, this is the first reported case of COVID-19 in a HL patient who was being treated with brentuximab for relapse after alloHCT.

Impaired endothelial function irrespective of systemic inflammation or atherosclerosis in mastocytosis.

BACKGROUND: Knowledge on endothelial dysfunction and its relation to atherosclerosis in mastocytosis is limited. OBJECTIVE: To investigate the endothelial function in mastocytosis by flow-mediated dilatation (FMD) and biomarkers related to vascular endothelia and to evaluate its relationship with the presence of subclinical atherosclerosis by carotid intima media thickness (CIMT). METHODS: A total of 49 patients with mastocytosis and 25 healthy controls (HCs) were included. The FMD and CIMT during transthoracic echocardiography biomarkers including endocan, endothelin-1, and vascular endothelial growth factor (VEGF) were measured in the sera of participants. Tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein were determined as inflammatory biomarkers. RESULTS: The mean FMD % was lower in the patients than HCs (11.26% ± 5.85% vs 17.84% ± 5.27% P < .001) and was the lowest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group among the patients (P = .03). The median value of VEGF was considerably higher in patients than HCs (73.30 pg/mL; minimum-maximum 32.46-295.29 pg/mL vs 46.64 pg/mL; minimum-maximum, 11.09-99.86 pg/mL; P = .001) and it was the highest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group (P = .01). The FMD was inversely correlated with endocan (r = -0.390; P = .006), endothelin-1 (r = -0.363; P = .01) and VEGF (r = -0.402; P = .004) but there were no correlations between FMD and tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein. No differences in CIMT values between patients and HCs and no correlation between CIMT and the biomarkers were observed. CONCLUSION: Endothelial dysfunction in mastocytosis becomes evident with decreased FMD and elevated serum VEGF in the absence of atherosclerosis or systemic inflammation and is related to disease severity.

A comprehensive update of ICET-A Network on COVID-19 in thalassemias: what we know and where we stand.

A review of the literature on COVID-19 pandemic in patients with thalassemias is presented. Globally, the prevalence of COVID-19 among  ß-thalassemia patients seems to be lower than in general population; associated co-morbidities aggravated the severity of  COVID- 19, leading to a poorer prognosis, irrespective of age. A multicenter registry will enhance the understanding of COVID-19 in these patients and will lead to more evidence-based management recommendations.

A Case with Hepatic Involvement Mimicking Metastatic Disease in Multiple Myeloma.

Multiple myeloma is a type of plasma cell disorder and can be seen in different forms. According to current knowledge, it is not a curable disease. Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma. We present a 53-year-old female patient who started with SMM which turned into multiple myeloma after four years. Despite 26 cycles of lenalidomide treatment, we performed the second autologous stem transplantation. After 12 years from the diagnosis of the disease, it was transformed into plasma cell leukemia and widespread nodular lesions were seen in the liver. Different presentations could be seen due to malignant plasma cell infiltrations or primary amyloidosis. Liver involvement is one of them and is less common than other organ involvement. We report a case of myeloma presenting with extensive nodular involvement in the liver and misdiagnosed as metastatic disease. It is important because of its rarity and change of the treatment approach.

Preliminary Data on COVID-19 in Patients with Hemoglobinopathies: A Multicentre ICET-A Study.

OBJECTIVES: This study aims to investigate, retrospectively, the epidemiological and clinical characteristics, laboratory results, radiologic findings, and outcomes of COVID-19 in patients with transfusion-dependent ß thalassemia major (TM), ß-thalassemia intermedia (TI) and sickle cell disease (SCD). DESIGN: A total of 17 Centers, from 10 countries, following 9,499 patients with hemoglobinopathies, participated in the survey. MAIN OUTCOME DATA: Clinical, laboratory, and radiologic findings and outcomes of patients with COVID-19 were collected from medical records and summarized. RESULTS: A total of 13 patients, 7 with TM, 3 with TI, and 3 with SCD, with confirmed COVID-19, were identified in 6 Centers from different countries. The overall mean age of patients was 33.7±12.3 years (range:13-66); 9/13 (69.2%) patients were females. Six patients had pneumonia, and 4 needed oxygen therapy. Increased C-reactive protein (6/10), high serum lactate dehydrogenase (LDH; 6/10), and erythrocyte sedimentation rate (ESR; 6/10) were the most common laboratory findings. 6/10 patients had an exacerbation of anemia (2 with SCD). In the majority of patients, the course of COVID-19 was moderate (6/10) and severe in 3/10 patients. A 30-year-old female with TM, developed a critical SARS-CoV-2 infection, followed by death in an Intensive Care Unit. In one Center (Oman), the majority of suspected cases were observed in patients with SCD between the age of 21 and 40 years. A rapid clinical improvement of tachypnea/dyspnea and oxygen saturation was observed, after red blood cell exchange transfusion, in a young girl with SCD and worsening of anemia (Hb level from 9.2 g/dl to 6.1g/dl). CONCLUSIONS: The data presented in this survey permit an early assessment of the clinical characteristics of COVID 19 in different countries. 70% of symptomatic patients with COVID- 19 required hospitalization. The presence of associated co-morbidities can aggravate the severity of COVID- 19, leading to a poorer prognosis irrespective of age.

Myelomatous Pleural Effusion: A Rare Involvement in Myeloma.

Extramedullary disease (EMD) incidence is between 7% and 18% in multiple myeloma. Overall survival of patients who develop EMD is significantly shorter than that of patients without EMD. Malignant myelomatous pleural effusions (MPEs) are rarely observed, occurring in less than 1% of cases. The diagnosis of MPE was confirmed by the detection of myeloma cells in the pleural fluid using flow cytometric analyses. We present a case of a 67-year-old male patient with IgG-kappa myelom. After a few line treatment regimens, he was admitted to hospital with back pain and blurred consciousness, and pleural effusion was detected. Pleural fluid analysis showed malignant plasma cells. It is a rare presentation of multiple myeloma, but important in diagnosis.

Immunosuppressive Treatment in C3 Glomerulopathy: Is it Really Effective?

BACKGROUND: C3 glomerulopathy (C3GP) is a recently identified and described disease that has a high risk of progressing into end-stage renal disease. We aimed to evaluate the effects of various immunosuppressive regimens on C3GP progression because there are conflicting data on the treatment modalities. METHODS: In this retrospective study of 66 patients with C3GP, 27 patients received mycophenolate mofetil (MMF)-based treatment, 23 received non-MMF-based treatment (prednisolone or cyclophosphamide), and 16 received conservative care. The study groups were compared with each other with specific focus on primary outcomes defined as (1) kidney failure and (2) estimated glomerular filtration rate (eGFR) decline ≥50% from the baseline value. RESULTS: Overall, 17 (25.8%) patients reached the primary outcome after a median period of 28 months. The number of patients who reached the primary outcome were similar among the study groups (MMF-based: 8/27 [29.6%], non-MMF-based: 4/23 [17.4%], and conservative care: 5/16 [31.3%], p = 0.520). In the Cox regression analysis, age (HR 0.912, p = 0.006), eGFR (HR 0.945, p = 0.001), and proteinuria levels (HR 1.418, p = 0.015) at the time of biopsy, percentage of crescentic (HR 1.035, p = 0.001) and sclerotic glomeruli (HR 1.041, p = 0.006), severity of interstitial fibrosis (HR 1.981, p = 0.048), as well as no remission of proteinuria (HR 2.418, p = 0.002) predicted the primary outcome. CONCLUSION: Although patients receiving immunosuppressive treatments had higher proteinuria and lower serum albumin at baseline, there were no differences between these patients and those receiving conservative care alone in proteinuria remission or in the decline of renal function. Younger age, higher proteinuria, lower eGFR, and the presence of crescentic and sclerotic glomeruli, severity of interstitial fibrosis, and no remission of proteinuria predicted the progression of kidney disease.