Real-Life Multicenter Experience of Venetoclax in Combination with Hypomethylating Agents in Previously Untreated Adult Patients with Acute Myeloid Leukemia in Greece.

BACKGROUND: The landscape of first-line treatment for acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy has changed remarkably after venetoclax approval. Accumulating real-world data further apprises us with more knowledgeable use. To assess the efficacy and safety challenges in the real-life setting of the combination of hypomethylated agent (HMA) and venetoclax, we conducted a multi-center retrospective study. METHODS: Forty adult AML patients treated with the combination of HMA and venetoclax as a first-line treatment after full approval (2020) were included. To confirm VIALE-A results, this group was compared to a historical cohort of 17 chemotherapy-ineligible AML patients treated with HMA monotherapy before 2020. RESULTS: The combination of HMA-venetoclax achieved a composite complete response rate of 86.8% (p < 0.001), median overall survival, and event-free survival of 33.8 and 19.7 months, respectively, in a median follow-up of 17.8 months (pos < 0.001, HR = 0.276, CI: 0.132-0.575, pEFS = 0.004, HR = 0.367, CI: 0.174-0.773). High rates of neutropenia (90%) and consequent infection rates (57.5%) were noted. Only 55% of our patients received antifungal prophylaxis, as its use remains controversial, and invasive fungal infections were presented in 7.5%. CONCLUSIONS: Evidently, venetoclax-HMA yields high response rates and profound survival benefits in real life and has changed our approach to alternative chemotherapy options.

Primary Adrenal Lymphomas with Cushing's Syndrome: Two Cases with Evidence of Endogeneous Cortisol Production by the Neoplastic Lymphoid Cells.

Primary adrenal lymphoma (PAL) is a rare entity that presents as unilateral or bilateral rapidly growing adrenal masses, with signs and symptoms most commonly related to adrenal insufficiency due to the mass effect on the surrounding tissues. Although steroeidogenesis has not been previously described in PAL, we herein report two cases of PAL presenting as adrenal incidentalomas (AIs) that demonstrated autonomous cortisol production. A 52-year-old woman presented with lumbar pain; a computed tomography (CT) scan demonstrated a left AI measuring 8.5 × 15 × 10 cm. Similarly, an 80-year-old woman presented with lumbar pain, demonstrating in a CT scan a bilateral AI (right: 9 × 6.5 cm, left: 3.6 × 3.2 cm). Both cases underwent a full hormonal evaluation according to the algorithm for the investigation of AIs, demonstrating increased 24-h cortisol excretion, suppressed fasting adrenocorticotropic hormone (ACTH) levels, and non-suppressed serum cortisol levels in both the overnight and the low-dose dexamethasone suppression tests, indicating autonomous cortisol secretion and Cushing's syndrome. In a relatively short time, both patients developed night sweats, and their clinical picture deteriorated, while the CT scans showed increased dimensions of the masses with radiological characteristics compatible to lymphoma. Both patients underwent ultrasound-guided biopsies (FNBs), revealing infiltration of the left adrenal by diffuse large B-cell lymphoma in the first case, whereas bilateral adrenal infiltration from the same histological type was noted in the second case. Subsequently, they were treated with immunochemotherapy, but the second patient died from an infection shortly after the initiation of the treatment. To our knowledge, this is the first report of PAL presenting with Cushing's syndrome due to autonomous cortisol production, indicating that neoplastic lymphoid cells in PAL might acquire the potential for steroidogenesis; therefore, more cases of PAL should be analyzed so as to further elucidate the complex pathogenesis and the natural course of this entity.

Systemic Mastocytosis in a Patient with BCR-ABL1-Positive Chronic Myeloid Leukemia in the Remission Phase.

Systemic mastocytosis (SM) comprises a group of rare disorders resulting from tissue infiltration by pathological mast cells. In a percentage ranging from 5 to 40% in various patient series, SM appears to be associated with an accompanying hematologic neoplasm (SM-AHN). The coexistence of SM with chronic myelogenous leukemia (CML) is extremely rare with only 3 cases in the literature. The natural course of CML has changed dramatically over the past 2 decades with the use of tyrosine kinase inhibitors (TKIs). We report a case of diagnosing SM in a patient in complete molecular remission of CML after stopping TKI treatment.

Kinetics of Nucleocapsid, Spike and Neutralizing Antibodies, and Viral Load in Patients with Severe COVID-19 Treated with Convalescent Plasma.

COVID-19 is an ongoing pandemic with high morbidity and mortality. Despite meticulous research, only dexamethasone has shown consistent mortality reduction. Convalescent plasma (CP) infusion might also develop into a safe and effective treatment modality on the basis of recent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor-binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody (pseudotype NAb) titers were determined at the same time points. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and Nab, reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled by a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early in infection shows the presence of high levels of binding and neutralizing antibodies and potent clearance of the virus.

Predicting outcome in higher-risk myelodysplastic syndrome patients treated with azacitidine.

5-Azacitidine (5-AZA) is widely used for the treatment of higher-risk myelodysplastic syndromes. However, response and survival rates vary considerably, while indicated treatment duration remains undefined. For these reasons, factors determining response and survival are of major importance. Clinical, morphological, flow cytometry, cytogenetic and molecular factors are discussed in this review. Biomarkers predictive of response and prognosis, as well as their link to the mode of action of 5-AZA are also addressed, shifting the focus from clinical practice to investigational research. Their use could further improve prognostic classification of 5-AZA treated higher-risk myelodysplastic syndromes in the near future.

Lay abstract Myelodysplastic syndrome is a disorder in which patients have dysfunctional blood cells. The only chance of curing patients with high-risk myelodysplastic syndrome (HR-MDS) is allogeneic stem cell transplantation. However, most HR-MDS patients are not young or fit enough to receive such a toxic treatment. For these patients, hypomethylating drugs such as 5-azacitidine (5-AZA) and decitabine are preferable treatments. These drugs work by reducing the number of molecules known as methyl groups that are attached to DNA, which can lead to cell death. About half of patients respond to it, and those who do respond, survive longer than those who do not. In addition, 5-AZA delays disease progression from HR-MDS to acute myeloid leukemia, a type of blood cancer, and may help patients who do not improve to live longer. However, 5-AZA has side effects that can be hard to bear, such as an increased need for red blood cells and/or platelet transfusions. For this reason, it would be good to predict the clinical and biological factors associated with either response or final outcome following treatment. In this manuscript, we attempt to summarize current knowledge on this topic.

Prognostic molecular biomarkers in diffuse large B-cell lymphoma in the rituximab era and their therapeutic implications.

Diffuse large B-cell lymphoma (DLBCL) represents a group of tumors characterized by substantial heterogeneity in terms of their pathological and biological features, a causal factor of their varied clinical outcome. This variation has persisted despite the implementation of rituximab in treatment regimens over the last 20 years. In this context, prognostic biomarkers are of great importance in order to identify high-risk patients that might benefit from treatment intensification or the introduction of novel therapeutic agents. Herein, we review current knowledge on specific immunohistochemical or genetic biomarkers that might be useful in clinical practice. Gene-expression profiling is a tool of special consideration in this effort, as it has enriched our understanding of DLBCL biology and has allowed for the classification of DLBCL by cell-of-origin as well as by more elaborate molecular signatures based on distinct gene-expression profiles. These subgroups might outperform individual biomarkers in terms of prognostication; however, their use in clinical practice is still limited. Moreover, the underappreciated role of the tumor microenvironment in DLBCL prognosis is discussed in terms of prognostic gene-expression signatures, as well as in terms of individual biomarkers of prognostic significance. Finally, the efficacy of novel therapeutic agents for the treatment of DLBCL patients are discussed and an evidence-based therapeutic approach by specific genetic subgroup is suggested.

Solitary extramedullary plasmacytoma of the nasopharynx: The role of flow cytometry.

Extramedullary plasmacytoma (EMP) represents a distinct yet rare entity among the plasma cell neoplasms. Given its rarity, no therapeutic consensus has been met. We report the case of a 57-year-old man with a one-year history of nasal congestion and occasional dyspnoea. Imaging showed a hypermetabolic mass in the right nasopharynx extending backward towards the adjacent oropharynx, infiltrating the epiglottis. As incisional biopsy showed histologic and immunophenotypic features consistent with plasma cell neoplasm, whereas the possibility of a marginal zone lymphoma with plasmacytic differentiation was included in the differential diagnosis. A final diagnosis of EMP was reached by using flow cytometry (FC) of a cell suspension from the neoplastic tissue. The patient received local radiotherapy (RT) which resulted to complete remission. In conclusion, flow cytometry might serve as an auxiliary method in cases where immunohistochemistry cannot differentiate between a plasma cell dyscrasia and a B-non-Hodgkin lymphoma. In cases of an established diagnosis of solitary nasopharyngeal EMP RT represents an excellent treatment modality offering prolonged disease-free survival.

A Phase II Study on the Use of Convalescent Plasma for the Treatment of Severe COVID-19- A Propensity Score-Matched Control Analysis.

COVID-19 is a global pandemic associated with increased morbidity and mortality. Convalescent plasma (CP) infusion is a strategy of potential therapeutic benefit. We conducted a multicenter phase II study to evaluate the efficacy and safety of CP in patients with COVID-19, grade 4 or higher. To evaluate the efficacy of CP, a matched propensity score analysis was used comparing the intervention (n = 59) to a control group (n = 59). Sixty patients received CP within a median time of 7 days from symptom onset. During a median follow-up of 28.5 days, 56/60 patients fully recovered and 1 patient remained in the ICU. The death rate in the CP group was 3.4% vs. 13.6% in the control group. By multivariate analysis, CP recipients demonstrated a significantly reduced risk of death [HR: 0.04 (95% CI: 0.004-0.36), p: 0.005], significantly better overall survival by Kaplan-Meir analysis (p < 0.001), and increased probability of extubation [OR: 30.3 (95% CI: 2.64-348.9), p: 0.006]. Higher levels of antibodies in the CP were independently associated with significantly reduced risk of death. CP infusion was safe with only one grade 3 adverse event (AE), which easily resolved. CP used early may be a safe and effective treatment for patients with severe COVID-19 (trial number NCT04408209).

Discontinuation of the renin-angiotensin system inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes.

Renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) has been related to anemia in various situations. We aimed to investigate whether discontinuation of RAS inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes (LR-MDSs). Seventy-four patients with LR-MDS were divided into three groups matched for gender and age. Group A consisted of 20 hypertensive patients who discontinued RAS inhibitors and received alternative medications. Group B consisted of 26 patients who continued to receive ACEi/ARB and Group C included 28 patients (50% hypertensive) never exposed to ACEi/ARB. Half of the patients in each group were under treatment with recombinant human erythropoietin (rHuEPO). Data were collected at baseline and after 3, 6 and 12 months. Group A showed a significant increase in hemoglobin from 10.4 ± 1g/dL at baseline to 12.6 ± 1.2 g/dL after 12 months (p = 0.035) and in hematocrit (31.4 ± 3% versus 37.9 ± 4%, p = 0.002). Incident anemia decreased from 100% at baseline to 60% at 12 months (p = 0.043) despite a concomitant dose reduction in rHuEPO by 18% (p = 0.035). No changes in hemoglobin and hematocrit were observed in both Group B and Group C. In the subset of patients not treated with rHuEPO, improvement of erythropoiesis was found only in Group A, as measured by changes in hemoglobin (11.5 ± 1 g/dL versus 12.4 ± 1.3 g/dL, p = 0.041) and hematocrit (34.5 ± 3% versus 37.1 ± 4%, p = 0.038) after 12 months. In contrast, Group B and Group C decreased hemoglobin and hematocrit after 12 months (p < 0.05). In conclusion, discontinuation of ACEi/ARB in LR-MDS patients is followed by a significant recovery of erythropoiesis after 12 months.

Upregulated hypoxia inducible factor 1α signaling pathway in high risk myelodysplastic syndrome and acute myeloid leukemia patients is associated with better response to 5-azacytidine-data from the Hellenic myelodysplastic syndrome study group.

5-azacytidine (5-AZA) is considered the standard of care for patients with high-risk myelodysplastic syndromes (MDS) and patients with acute myeloid leukemia (AML) not candidate for intensive chemotherapy. However, even after an initial favorable response, almost all patients relapse, with the exact mechanisms underlying primary or secondary 5-AZA resistance remaining largely unknown. Several reports have previously demonstrated the significance of hypoxia in the regulation of both physiological and malignant hematopoiesis. In MDS, high hypoxia inducible factor 1α (Hif-1α) expression has been correlated with poor overall survival and disease progression, while its involvement in the disease's pathogenesis was recently reported. We herein investigated the possible association of the Hif-1α signaling pathway with response to 5-AZA therapy in MDS/AML patients. Our data demonstrated that 5-AZA-responders present with higher Hif-1α mRNA and protein expression compared to 5-AZA-non-responders/stable disease patients, before the initiation of therapy, while, interestingly, no significant differences in Hif-1α mRNA expression at the 6-month follow-up were observed. Moreover, we found that 5-AZA-responders exhibited elevated mRNA levels of the Hif-1α downstream targets lactate dehydrogenase a (LDHa) and BCL2 interacting protein 3 like (BNIP3L), a further indication of an overactivated Hif-1a signaling pathway in these patients. Kaplan-Meier survival analysis revealed a significant correlation between high Hif-1α mRNA expression and better survival rates, while logistic regression analysis showed that Hif-1α mRNA expression is an independent predictor of response to 5-AZA therapy. From the clinical point of view, apart from proposing Hif-1α mRNA expression as a significant predictive factor for response to 5-AZA, our data offer new perspectives on MDS combinational therapies, suggesting a potential synergistic activity of 5-AZA and Hif-1α inducers, such as propyl hydroxylases inhibitors (PHDi).

Red Blood Cell Abnormalities as the Mirror of SARS-CoV-2 Disease Severity: A Pilot Study.

PURPOSE: Unraveling the pathophysiology of COVID-19 disease is of crucial importance for designing treatment. The purpose of this study is to investigate the effects of the disease on erythrocytes (RBCs) and to correlate the findings with disease severity. MATERIALS AND METHODS: Hospitalized patients (n = 36) with COVID-19 and control group of healthy volunteers (n = 18) were included in the study. Demographic data, clinical, laboratory and chest Computed Tomography (CT) findings at time of admission were recorded. Laboratory measurements included: Hemoglobin (H b), indirect billirubin, LDH, D-Dimers, and plasma free hemoglobin (plasma free-Hb). On RBCs were performed: osmotic fragility (MCF), Free-Hb after mechanical stress (Free-Hb-MECH), intracellular RBC concentration of calcium ions (iCa2+), intracellular ROS (iROS), G6PD, intracellular active caspase-3 (RBC-caspase-3), IgG immunoglobulins (RBC-IgGs), which are bound on RBCs' senescent neo-antigen proteins and RBC surface phosphatidylserine (RBC-PS). RESULTS: The percentage of males was 50 and 66% and the mean age was 65.16 ± 14.24 and 66.33 ± 13.48 years among patients and controls respectively (mean ± SD, p = 0.78). Upon admission patients' PO2/FiO2 ratio was 305.92 ± 76.75 and distribution of infiltration extend on chest CT was: 0-25% (N = 19), 25-50%: (N = 7), and 50-75% (N = 9). Elevated hemolysis markers (LDH and plasma free-Hb) were observed in patients compared to the control group. Patients' RBCs were more sensitive to mechanical stress, and exhibited significantly elevated apoptotic markers (iCa2+, RBC-PS). Plasma free Hb levels correlated with the extend of pulmonary infiltrates on chest CT in COVID-19 patients. Surprisingly, patients' RBC-iROS were decreased, a finding possibly related with the increased G6PDH levels in this group, suggesting a possible compensatory mechanism against the virus. This compensatory mechanism seemed to be attenuated as pulmonary infiltrates on chest CT deteriorated. Furthermore, RBC-IgGs correlated with the severity of pulmonary CT imaging features as well as the abnormality of lung function, which are both associated with increased disease severity. Lastly, patients' D-Dimers correlated with RBC surface phosphatidylserine, implying a possible contribution of the red blood cells in the thrombotic diathesis associated with the SARS-CoV-2 disease. CONCLUSION: This pilot study suggests that SARS-CoV-2 infection has an effect on red blood cells and there seems to be an association between RBC markers and disease severity in these patients.

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes.

BACKGROUND: 5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic syndromes (MDSs) and oligoblastic acute myeloid leukemia (AML); however, predictive factors for response and outcome have not been consistently studied. METHODS: This study of the Hellenic MDS Study Group included 687 consecutive patients with higher-risk MDS and oligoblastic AML treated with 5-AZA. RESULTS: The International Prognostic Scoring System (IPSS) revised version (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 or 1 versus ⩾2) and baseline serum ferritin (SF) levels > 520 ng/ml were shown to independently predict response to 5-AZA. In the survival analysis, the IPSS and IPSS-R risk classification systems along with the ECOG PS and SF levels > 520 ng/ml proved to be independent prognosticators for overall survival (OS), as well as for leukemia-free survival (LFS). Next, we built new multivariate models for OS and LFS, incorporating only ECOG PS and SF levels besides IPSS or IPSS-R risk classification systems. Thereby, the new modified IPSS and IPSS-R risk classification systems (H-PSS, H-PSS-R) could each discriminate a low, an intermediate and a high-risk patient group regarding OS and LFS. The H-PSS and H-PSS-R proved to be better predictors of OS than their previous counterparts as well as the French prognostic score, while the most powerful OS predictor was the new, H-PSS-R system. CONCLUSIONS: ECOG PS and SF levels > 520 ng/ml independently predict response to 5-AZA, OS and LFS. Their incorporation in the IPSS and IPSS-R scores enhances these scores' predictive power in 5-AZA-treated higher-risk MDS and oligoblastic AML patients.

Multiple osteolytic lesions due to Double-Expressor Primary non-Hodgkin Lymphoma of the Bone.

Primary non-Hodgkin lymphoma of the bone (PLB) is a rare type of non-Hodgkin's lymphoma (NHL) that affects the skeletal system with or without regional lymph node involvement. We present the case of a 74-year-old female patient with pain due to multifocal osteolytic lesions. The diagnosis of diffuse large B-cells (non-GCB) phenotype was made by clinical, laboratory, histopathological examination accompanied by an extensive immunohistochemical profile of one of the skeletal lesions.

Erdheim-Chester Disease and Acute Myeloid Leukemia with Mutated NPM1 in a Patient with Clonal Hematopoiesis: A Case Report.

BACKGROUND: Erdheim-Chester Disease (ECD) is a clonal non-Langerhans histiocytosis, classified as a macrophage-dendritic cell neoplasm in the 2016 WHO classification. The exact cell of origin of ECD is unknown, although some limited evidence suggests that it arises from myeloid progenitors. CASE PRESENTATION: A 43-year-old patient, diagnosed with BRAF V600E mutated ECD, developed NPM1+/FLT3+ acute myeloid leukemia (AML) with wild-type BRAF, 15 months after the initial ECD diagnosis. The patient received intensive chemotherapy plus midostaurin, followed by midostaurin maintenance. Six months into maintenance, the patient remains in complete remission with low-level measurable residual disease, whereas ECD shows a sustained partial metabolic response. Molecular karyotype at several distinct timepoints, namely ECD diagnosis, AML diagnosis, and following treatment of AML, highlighted a molecular signature, indicative of a persistent, underlying clonal hematopoiesis. CONCLUSION: This case report suggests that ECD and AML might represent an expansion of two distinct clones in a background of clonal hematopoiesis, indicating their shared origin. Moreover, molecular karyotype might serve as a strong, inexpensive tool for revealing clonal hematopoiesis in cases of negative targeted next-generation sequencing. Finally, the moderate response of ECD to midostaurin suggests that kinase inhibition might have a potential role in ECD treatment.

Estimated glomerular filtration rate independently predicts outcome of azacitidine therapy in higher-risk Myelodysplastic syndromes. Results from 536 patients of the Hellenic National Registry of Myelodysplastic and Hypoplastic syndromes.

Higher-risk Myelodysplastic syndromes (MDS) patients undergoing treatment with 5-azacytidine (AZA) are typically elderly with several comorbidities. However, the effect of comorbidities on the effectiveness and safety of AZA in real-world settings remains unclear. We analyzed data from 536 AZA-treated patients with higher-risk MDS, Myelodysplastic/Myeloproliferative neoplasms and low blast count Acute Myeloid Leukemia enrolled to the Hellenic National Registry of Myelodysplastic and Hypoplastic Syndromes. Multivariate analysis adjusted also for the International Prognostic Scoring System (IPSS), its revised version (IPSS-R) and the French Prognostic Scoring System (FPSS), demonstrated independent associations of overall and leukemia-free survival with estimated glomerular filtration rate (eGFR) <45 mL min-1 /1.73 m2 (P = .039, P = .023, respectively), ECOG performance status <2 (P = .015, P = .006), and presence of peripheral blood blasts (P = .008, P = .034), while secondary MDS also correlated with significantly shorter leukemia-free survival (P = .039). Addition of eGFR <45 mL min-1 /1.73 m2 , in IPSS-R and FPSS increased the predictive power of both models. Only FPSS ≤2 and eGFR <45 mL min-1 /1.73 m2 predicted worse response to AZA in multivariate analysis, whereas eGFR <45 mL min-1 /1.73 m2 correlated significantly with death from hemorrhage (P = .003) and cardiovascular complications (P = .006). In conclusion, in the second largest real-world series of AZA-treated MDS patients, we show that an eGFR <45 mL min-1 /1.73 m2 is an independent predictor of worse response and survival. This higher cut-off, instead of the commonly used serum creatinine >2 mg/dL, can be utilized as a more precise indicator of renal comorbidity during AZA therapy. Incorporation of eGFR in the prognostic assessment of AZA-treated MDS patients may prove useful not only in routine practice, but also for the appropriate patient stratification in clinical trials with AZA combinations.

Multiple osteolytic lesions due to Double-Expressor Primary non-Hodgkin Lymphoma of the Bone

Primary non-Hodgkin lymphoma of the bone (PLB) is a rare type of non-Hodgkin's lymphoma (NHL) that affects the skeletal system with or without regional lymph node involvement. We present the case of a 74-year-old female patient with pain due to multifocal osteolytic lesions. The diagnosis of diffuse large B-cells (non-GCB) phenotype was made by clinical, laboratory, histopathological examination accompanied by an extensive immunohistochemical profile of one of the skeletal lesions.

Coexistence of Myeloid and Lymphoid Neoplasms: A Single-Center Experience.

The coexistence of a myeloid and a lymphoid neoplasm in the same patient is a rare finding. We retrospectively searched the records of the Hematology Division of the Second Department of Internal Medicine and Research Institute at Attikon University General Hospital of Athens from 2003 to 2018. Nine cases have been identified in a total of 244 BCR-/ABL1- negative MPN and 25 MDS/MPN patients and 1062 LPD patients referred to our institution between 2003 and 2018. Each case is distinct in the diversity of myeloid and lymphoid entities, the chronological occurrence of the two neoplasms, and the patient clinical course. All of them exhibit myeloproliferative (6 JAK2 V617F-positive cases) and lymphoproliferative features, with 1 monoclonal B-cell lymphocytosis (MBL), 3 B-chronic lymphocytic leukemias (B-CLL), 3 B-non-Hodgkin lymphomas (B-NHL), 1 multiple myeloma (MM), and 1 light and heavy deposition disease (LHCDD), while in three cases myelodysplasia is also present. The challenges in identifying and dealing with these rare situations in everyday clinical practice are depicted in this article.