Hematology Reports

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are not a single disease, but rather a heterogenous group of entities which are increasingly subclassified according to recurrent genetic abnormalities. Chromosomal translocations involving meningioma 1 (MN1) and ETS variant 6 (ETV6) genes are extremely rare, but recurrent in myeloid neoplasms. We describe the case of a patient with a myelodysplastic/myeloproliferative neoplasm with neutrophilia, who developed an extramedullary T-lymphoblastic crisis with the t(12;22)(p13;q12) translocation as the only cytogenetic abnormality. This case shares several clinical and molecular features with myeloid/lymphoid neoplasms with eosinophilia. The treatment of this patient was challenging, as the disease proved to be highly refractory to chemotherapy, with allogenic stem cell transplantation as the only curative option. This clinical presentation has not been reported in association with these genetic alterations and supports the concept of a hematopoietic neoplasm originating in an early uncommitted precursor cell. Additionally, it stresses the importance of molecular characterization in the classification and prognostic stratification of these entities. Full article

Introduction: Latent iron deficiency (LID), in which iron stores in the body are depleted without incidental anemia, poses a key diagnostic challenge. Reticulocyte hemoglobin content (Ret-Hb) is directly correlated with the functionally available iron for heme synthesis in erythroblasts. Consequently, Ret-Hb has been proposed as an efficient iron status marker. Aim: To assess the importance of Ret-Hb in detecting latent iron deficiency as well as its use in screening for iron deficiency anemia. Materials and Methods: A study involving 108 individuals was conducted at Najran University Hospital, 64 of whom had iron deficiency anemia (IDA) and 44 of whom had normal hemoglobin levels. All patients were subjected to complete blood count (CBC), reticulocyte percentage, Ret-Hb, serum iron, total iron binding capacity (TIBC), and serum ferritin measurements. Results: A significant decrease in Ret-Hb level was observed in IDA patients compared to non-anemic individuals, with a cut-off value of 21.2 pg (a value below which indicates IDA). Conclusion: The measurement of Ret-Hb, in addition to CBC parameters and indices, provides an accessible predictive marker for both iron deficiency (ID) and IDA. Lowering the Ret-Hb cut-off could better allow for its use as a screening parameter for IDA. Full article

Diffuse large B-cell lymphoma with spindle cell morphology is a rare variant. We present the case of a 74-year-old male who initially presented with a right supraclavicular (lymph) node enlargement. Histological analysis showed a proliferation of spindle-shaped cells with narrow cytoplasms. An immunohistochemical panel was used to exclude other tumors, such as melanoma, carcinoma, and sarcoma. The lymphoma was characterized by a cell-of-origin subtype of germinal center B-cell-like (GCB) based on Hans’ classifier (CD10-negative, BCL6-positive, and MUM1-negative); EBER negativity, and the absence of BCL2, BCL6, and MYC rearrangements. Mutational profiling using a custom panel of 168 genes associated with aggressive B-cell lymphomas confirmed mutations in ACTB, ARID1B, DUSP2, DTX1, HLA-B, PTEN, and TNFRSF14. Based on the LymphGen 1.0 classification tool, this case had an ST2 subtype prediction. The immune microenvironment was characterized by moderate infiltration of M2-like tumor-associated macrophages (TMAs) with positivity of CD163, CSF1R, CD85A (LILRB3), and PD-L1; moderate PD-1 positive T cells, and low FOXP3 regulatory T lymphocytes (Tregs). Immunohistochemical expression of PTX3 and TNFRSF14 was absent. Interestingly, the lymphoma cells were positive for HLA-DP-DR, IL-10, and RGS1, which are markers associated with poor prognosis in DLBCL. The patient was treated with R-CHOP therapy, and achieved a metabolically complete response. Full article

Although daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, and dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, have been approved for the treatment of renal anemia in Japan, their efficacy and safety for patients aged 80 years or older with low-risk myelodysplastic syndrome (MDS)-related anemia have not been demonstrated. Our case series comprised two men and one woman aged >80 years with low-risk MDS-related anemia and diabetic mellitus (DM)-related chronic kidney disease who were dependent on red blood cell transfusions and in whom erythropoiesis-stimulating agents had been insufficient. All three patients received daprodustat and additional dapagliflozin achieved red blood cell transfusion independence and were followed up for >6 months. Daily oral daprodustat was well tolerated. There were no fatalities or progression to acute myeloid leukemia during the >6-month follow-up after daprodustat initiation. On the basis of these outcomes, we consider 24 mg of daprodustat combined with 10 mg of dapagliflozin daily an effective form of treatment for low-risk MDS-related anemia. Further studies are required to clarify the synergistic effects of daprodustat and dapagliflozin, which correct chronic kidney disease-related anemia by promoting endogenous erythropoietin production and normalizing iron metabolism to manage low-risk MDS in the long term. Full article

Myeloproliferative neoplasms (MPN) such as essential thrombocythemia (ET) and polycythemia vera (PV) are rare during pregnancy. However, they are harmful because they are associated with an increased risk of thromboembolic, hemorrhagic, or microcirculatory disturbances or placental dysfunction leading to fetal growth restriction or loss. Low-dose aspirin and low-molecular-weight heparin (LMWH) are recommended to reduce pregnancy complications, and interferon (IFN) is the only treatment option for cytoreductive therapy based on the likelihood of live birth in pregnant women with MPN. Since ropeginterferon alfa-2b is the only available IFN in South Korea, we present a case report of ropeginterferon alfa-2b use during pregnancy in an MPN patient. A 40-year-old woman who had been diagnosed with low-risk PV in 2017 and had been maintained on phlebotomy, hydroxyurea (HU), and anagrelide (ANA) for 4 years was confirmed as 5 weeks pregnant on 9 December 2021. After stopping treatment with HU and ANA, the patient showed a rapid increase in platelet count (1113 × 10⁹/L to 2074 × 10⁹/L, normal range, 150–450 × 10⁹/L) and white blood cell count (21.93 × 10⁹/L to 35.55 × 10⁹/L, normal range, 4.0–10.0 × 10⁹/L). Considering the high risk of complications, aggressive cytoreductive treatment was required, for which we chose ropeginterferon alfa-2b, as it is the only available IFN agent in South Korea. The patient underwent 8 cycles of ropeginterferon alfa-2b over 6 months during pregnancy and delivered without any neonatal or maternal complications. This case report highlights the importance of considering treatment options for MPN patients who are pregnant or planning a pregnancy, as well as the need for further investigation into the safety and efficacy of ropeginterferon alfa-2b in this population. Full article

Non-Hodgkin’s lymphoma presenting as a primary cardiac lymphoma (PCL) is extremely unusual. Having a predilection for the right side of the heart and accounting for 1% of all cardiac tumours, the difficulty in diagnosing the lesion, owing to the location and vague presenting symptoms and signs, often leads to delayed diagnosis and poor prognosis. In our case report, a middle-aged male was diagnosed with PCL presenting as pyrexia of unknown origin with the help of F18-fluorodeoxyglucose positron emission tomography (18 FDG-PET). PET-CT is an invaluable tool in patients with pyrexia of unknown origin (PUO), especially caused by neoplasms as it helps in localizing the target lesion, aiding in selecting the appropriate intervention for rapid tissue diagnosis. This case serves to sensitize the physicians of PCL presenting with PUO and mimicking a relatively common cardiac tumour such as atrial myxoma. Full article

Primary cutaneous B-cell lymphomas (PCBCLs) constitute a rare subset of non-Hodgkin lymphoma (NHL), with distinctive clinical and biological characteristics. The risk of autoimmune or neoplastic comorbidities in subjects with NHL has been extensively reported in the literature, but the data available are not directly applicable to PCBCLs. The aim of our study was to determine the frequency of relevant medical conditions, with a primary focus on autoimmune and neoplastic disorders, in subjects with PCBCL. We performed a retrospective observational study involving 56 patients diagnosed histologically with PCBCL and 54 sex- and age-matched controls. Our results show a statistically significant association for neoplastic comorbidities in general (41.1% vs. 22.2%, p = 0.034) and hematological malignancies specifically (19.6% vs. 1.9%, p = 0.0041) with PCBCL compared to controls. We did not highlight a statistically significant difference in the frequency of autoimmune comorbidities (21.4% vs. 9.3%, p = 0.1128) and of chronic viral hepatitis (7.1% vs. 0, p = 0.1184). Finally, type 2 diabetes (19.6% vs. 1.9%, p = 0.0041) was significantly associated with PCBCL. Our preliminary data supporting the association between PCBCLs and neoplastic disorders suggest that altered immune surveillance may be a common predisposing mechanism. Full article

Frailty is a hot topic in the field of multiple myeloma (MM). Clinicians have realised that frail myeloma patients can struggle with treatment, resulting in dose reductions and treatment discontinuation, which risk shorter progression-free and overall survival. Efforts have focused on the validity of existing frailty scores and on the development of new indices to identify frail patients more accurately. This review article explores the challenges of the existing frailty scores, including the International Myeloma Working Group (IMWG) frailty score, the revised Myeloma Co-morbidity Index (R-MCI), and the Myeloma Risk Profile (MRP). We conclude that the missing link is for frailty scoring to translate into a tool useful in real-world clinical practice. The future of frailty scores lies in their ability to be woven into clinical trials, to create a robust clinical evidence base for treatment selection and dose modification, and also to identify a cohort of patients who merit additional support from the wider MM multidisciplinary team. Full article

The purpose of this narrative review was to provide an overview that allows readers to improve their understanding of hemophilia A, which is considered a genetic disease with a high impact on the quality of life of people who suffer from it is considered one of the diseases with the highest cost for health systems (In Colombia it is part of the five diseases with the greatest economic impact). After this exhaustive review, we can see that the treatment of hemophilia is on the way to precision medicine, which involves genetic variables specific to each race and ethnicity, pharmacokinetics (PK), as well as environmental factors and lifestyle. Knowing the impact of each of these variables and their relationship with the efficacy of treatment (prophylaxis: regular infusion of the missing clotting factor VIII in order to prevent spontaneous bleeding) will allow for individualizing the medical behavior in a cost-effective way. For this is required to build more strong scientific evidence with statistical power that allows us to infer. Full article

Sickle cell disease (SCD) is characterized by the presence of the variant S hemoglobin (HbS). The homozygous genotype (HbSS) is sickle cell anemia (SCA), while the double heterozygous of HbS and HbC (HbSC) is defined as SC hemoglobinopathy. The pathophysiology is based on chronic hemolysis, inflammation, endothelial dysfunction, and vaso-occlusion, which results in vasculopathy and serious clinical manifestations. Sickle leg ulcers (SLUs) are cutaneous lesions around the malleoli frequent in 20% of Brazilian patients with SCD. SLUs present a variable clinical and laboratory pattern modulated by several characteristics that are not fully understood. Hence, this study aimed to investigate laboratory biomarkers and genetic and clinical parameters associated with the development of SLUs. This descriptive cross-sectional study included 69 SCD patients, 52 without SLU (SLU−) and 17 with active or previous SLU history (SLU+). The results showed a higher incidence of SLU in SCA patients and there was no observed association of α-3.7 Kb thalassemia in SLU occurrence. Alterations in NO metabolism and hemolysis were associated with clinical evolution and severity of SLU, in addition to hemolysis modulating the etiology and recurrence of SLU. Our multifactorial analyses demonstrate and extend the role of hemolysis driving the pathophysiological mechanism of SLU. Full article

Hodgkin’s lymphoma carries an excellent prognosis with modern chemotherapy, but a significant proportion of patients remain refractory to or relapse after first-line treatment. Immunological changes post-treatment, such as chemotherapy-induced neutropenia (CIN) or lymphopenia, have shown prognostic significance in multiple tumor types. Our study aims to investigate the prognostic value of immunologic changes in Hodgkin’s lymphoma by examining the post-treatment lymphocyte count (pALC), neutrophil count (pANC) and the neutrophil-lymphocyte ratio (pNLR). Patients treated for classical Hodgkin’s lymphoma at the National Cancer Centre Singapore using ABVD-based regimens were retrospectively analyzed. An optimal cut-off value for high pANC, low pALC and high pNLR in predicting progression-free survival was determined by receiver operating curve analysis. Survival analysis was performed using the Kaplan–Meier method and multivariable Cox proportional models. Overall OS and PFS were excellent, with a 5-year OS of 99.2% and a 5-year PFS of 88.2%. Poorer PFS was associated with high pANC (HR 2.99, p = 0.0392), low pALC (HR 3.95, p = 0.0038) and high pNLR (p = 0.0078). In conclusion, high pANC, low pALC and high pNLR confer a poorer prognosis for Hodgkin’s lymphoma. Future studies should evaluate the potential of improving treatment outcomes by the adjustment of chemotherapy dose intensity based on post-treatment blood counts. Full article

Purpose: To describe a patient with sickle cell disease, a prothrombotic disorder, who underwent successful embryo cryopreservation for the purposes of fertility preservation prior to hematopoietic stem cell transplant. Methods: To report a successful case of gonadotropin stimulation and embryo cryopreservation using the aromatase inhibitor letrozole to maintain low serum estradiol to minimize thrombotic risk in a patient with sickle cell disease (SCD) and history of retinal artery thrombosis planning hematopoietic stem cell transplant (HSCT). The patient was given letrozole (5 mg daily) as well as prophylactic enoxaparin while undergoing gonadotropin stimulation with an antagonist protocol to preserve fertility prior to HSCT. After the oocyte retrieval, letrozole was continued for one additional week. Results: The patient’s peak serum estradiol concentration was 172 pg/mL during gonadotropin stimulation. Ten mature oocytes were retrieved and a total of 10 blastocysts were cryopreserved. The patient required pain medication and intravenous fluids after oocyte retrieval due to pain but had significant improvement at the scheduled post-operative day one follow-up. No embolic events occurred during stimulation or 6 months thereafter. Conclusion: The utilization of definitive treatment for SCD with stem cell transplant is increasing. We successfully used letrozole to maintain low serum estradiol during gonadotropin stimulation along with prophylactic enoxaparin in a patient with SCD to minimize her risk of thrombosis. This approach will allow patients planning definitive treatment with stem cell transplant the opportunity to preserve their fertility safely. Full article

Interactions between the novel hypomethylating agent (HMA) thio-deoxycytidine (T-dCyd) and the BCL-2 antagonist ABT-199 (venetoclax) have been examined in human myelodysplastic syndrome (MDS) cells. The cells were exposed to agents alone or in combination, after which apoptosis was assessed, and a Western blot analysis was performed. Co-administration of T-dCyd and ABT-199 was associated with the down-regulation of DNA methyltransferase 1 (DNMT1) and synergistic interactions documented by a Median Dose Effect analysis in multiple MDS-derived lines (e.g., MOLM-13, SKM-1, and F-36P). Inducible BCL-2 knock-down significantly increased T-dCyd’s lethality in MOLM-13 cells. Similar interactions were observed in the primary MDS cells, but not in the normal cord blood CD34⁺ cells. Enhanced killing by the T-dCyd/ABT-199 regimen was associated with increased reactive oxygen species (ROS) generation and the down-regulation of the anti-oxidant proteins Nrf2 and HO-1, as well as BCL-2. Moreover, ROS scavengers (e.g., NAC) reduced lethality. Collectively, these data suggest that combining T-dCyd with ABT-199 kills MDS cells through an ROS-dependent mechanism, and we argue that this strategy warrants consideration in MDS therapy. Full article

Objectives: To investigate and characterize JAK2 mutations in myelodysplastic syndrome (MDS), we present three cases with diverse JAK2 mutations and review the literature. Methods: The institutional SoftPath software was used to find MDS cases between January 2020 and April 2022. The cases with a diagnosis of a myelodysplastic/myeloproliferative overlap syndrome including MDS/MPN with ring sideroblasts and thrombocytosis were excluded. The cases with molecular data by next generation sequencing looking for gene aberrations commonly seen in myeloid neoplasms were reviewed for the detection of JAK2 mutations including variants. A literature review on the identification, characterization, and significance of JAK2 mutations in MDS was performed. Results: Among 107 cases of the MDS reviewed, a JAK2 mutation was present in three cases, representing 2.8% of the overall cases. A JAK2 V617F mutation was found in one case representing slightly less than 1% of all the MDS cases. In addition, we found JAK2 R564L and JAK2 I670V point mutation variants to be associated with a myelodysplastic phenotype. Conclusions: JAK2 mutations in MDS are rare and represent less than 3% of cases. It appears that JAK2 variant mutations in MDS are diverse and further studies are needed to understand their role in the phenotype and prognosis of the disease. Full article

Anaplastic myeloma (AM) is an extremely rare and aggressive histological variant of myeloma. It is characterized by extramedullary presentation in the young and has a poor prognosis. It can be a diagnostic challenge when myeloma is not suspected and even more when the immunophenotype is unexpected. We present a rare presentation of anaplastic myeloma with cardiovascular involvement. Though the patient did not have the typical clinical features of myeloma, except lytic lesion in the femur, the cardiac biopsy showed sheets of anaplastic cells, and some with multinucleation. There were also some areas with a more plasmacytoid appearance. The initial immunohistochemical panel was negative for CD3, CD20, CD138, AE1/3, and kappa. It was positive for lambda. This led to an extended panel which showed positivity for CD79a and MUM1 and negative for LMP-1, HHV-8, CD43, CD117, CD56, and CD30. Even the flow cytometry on the bone marrow showed a small population of atypical cells positive for CD38 and negative for CD138 with lambda restriction. This is an unusual case of anaplastic myeloma with cardiovascular involvement and CD138 negativity. This case highlights the need to add a panel of plasma cell markers when myeloma is suspected, and it is pertinent to read flow cytometry with caution to avoid missing atypical plasma cells which maybe CD38+/CD138−. Full article

In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non-CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (e.g., according to the Shiny method) has been the subject of numerous reports that have fully validated their performance. In the present systematic review, we evaluated six treatments proposed for RRMM, including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The endpoint was overall survival (OS). Our results showed statistically significant differences in OS across these treatments. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non-CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to interpret the results of OS published in these studies. Full article

Myelodysplastic syndrome (MDS) immunity plays an important role in the proliferation and apoptosis of aberrant cells. Immune dysregulation has been studied in various prognostic subgroups. This study analyzed 60 patients with MDS via multidimensional flow cytometry to evaluate the expression of aberrant markers, such as CD7 and cytoplasmic CD3 on lymphocytes. The Revised International Prognostic Scoring System (IPSS-R) scores were used to classify the patients into risk groups. The results showed a significant downregulation of CyCD3− T cells in low–intermediate versus high-risk patients (p = 0.013). This study is the first to show that a significant decrease in cyCD3− T cells in patients with a lower IPSS-R score may indicate microenvironmental changes conducive to transformation in MDS. Full article

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called “smoldering” MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients’ survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities. Full article