Single agent vemurafenib or rituximab-vemurafenib combination for the treatment of relapsed/refractory hairy cell leukemia, a multicenter experience.

BACKGROUND: Hairy cell leukemia (HCL) is a rare mature B-cell malignancy that is primarily treated with purine analogues. However, relapse remains a significant challenge, prompting the search for alternative therapies. The BRAF V600E mutation prevalent in HCL patients provides a target for treatment with vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study included nine patients with relapsed/refractory (R/R) HCL from six different centers. Patient data included demographics, prior treatments, clinical outcomes, and adverse events. RESULTS: Patients received different treatment regimens between centers, including vemurafenib alone or in combination with rituximab. Despite the differences in protocols, all patients achieved at least a partial response, with seven patients achieving a complete response. Adverse events were generally mild with manageable side effects. The absence of myelotoxic effects and manageable side effects make BRAF inhibitors attractive, especially for patients ineligible for purine analogues or those with severe neutropenia. CONCLUSION: Single agent vemurafenib or in combination with rituximab appears to be a promising therapeutic option for R/R HCL. Further research is needed to establish standardized treatment protocols and to investigate long-term outcomes.

Management of Adult Primary Immune Thrombocytopenia: Delphi-Based Consensus Recommendations.

Introduction: Primary immune thrombocytopenia (pITP) is an acquired autoimmune disorder related with increased destruction or/and impaired production of platelets. Diagnosis and management of ITP is challenging and require expertise and interpretation of international consensus reports and guidelines with national variations of availability. We aimed to assess the agreement of hematologists in Türkiye on certain aspects of both first line and second line management of patients with pITP. Methods: As a modified Delphi method, Turkish National ITP Working Group (14 steering committee members) founded under Turkish Society of Hematology (TSH) developed a 21-item questionnaire consisting of statements regarding diagnosis-first line and second line treatments of pITP and 107 adult Hematologists working either in university or state hospitals voted for their agreement or disagreement of the statements for two consequential rounds. Results: Participants have reached consensus on the use of corticosteroids as first line treatment and with limited duration. Methylprednisolone was the choice of corticosteroids rather than dexamethasone. Use of intravenous immunoglobulin was not preferred in patients without bleeding. It was also agreed that thrombopoietin receptor antagonists (TPO-RA) or rituximab should be recommended as second-line treatment, and that splenectomy could be considered 12-24 months after diagnosis in chronic pITP patients. Conclusion: The optimization of the dose and duration of cortTPO-RAs in addition to corticosteroids is necessary to improve the management of patients with pITP.

Effect of Tyrosine Kinase Inhibitor Therapy on Estimated Glomerular Filtration Rate in Patients with Chronic Myeloid Leukemia.

INTRODUCTION: The advent of tyrosine kinase inhibitors (TKIs) was revolutionary in the management of chronic myeloid leukemia (CML). Although TKIs were generally considered to be safe, they can be associated with renal injury. We evaluated the effect of TKIs on renal functions in a cohort of patients with long-term follow-up. MATERIAL AND METHODS: We retrospectively examined patients with chronic phase CML treated with TKIs. We analyzed the estimated glomerular filtration rate (eGFR) of patients from the initiation of TKI to the last follow-up. eGFR values of CML patients were compared to those of patients with stage 1 or 2 chronic kidney disease (CKD). RESULTS: A total of 195 patients with CML and 138 patients with CKD were examined. eGFR decline was 1.556 ml/min/1.73m2/year for patients with CML (P = .221). Patients receiving second-generation TKIs (2GTKI) were estimated to have 0.583 ml/min/1.73m2 higher eGFR value than that of the imatinib group, but it was not significant (P = .871). eGFR of patients who had used bosutinib had a downward trend. Duration of TKI therapy, age, and hypertension were found to be significant factors in eGFR decline for CML patients. Lower baseline GFR was associated with an increased risk of CKD development. CONCLUSION: Imatinib could result in a decline in eGFR which was clinically similar to early-stage CKD patients. We did not observe significant kidney function deterioration in patients receiving 2GTKIs including dasatinib and nilotinib. We recommend close renal function monitoring in patients receiving imatinib, especially for elderly patients with lower baseline eGFR and hypertension.

Factors affecting medical students' satisfaction with online learning: a regression analysis of a survey.

BACKGROUND: Medical education requires the implementation of different teaching methods and strategies for future doctors to achieve broad learning objectives. This wide range of methods and strategies includes the use of Information Technologies. For a long time, there was a call for a change in medical education for blending new teaching approaches to lessen medical students' class time. The COVID-19 pandemic then sped up the transition to the new way of medical education and classroom lectures were quickly moved to a virtual environment. We expect that these changes will continue, and online learning will be one of the main teaching strategies in medical education. Therefore, educational experiences during the COVID-19 pandemic will improve our understanding of online learning and will help to develop blended medical school curricula in the future. For this reason, we aimed to determine students' overall satisfaction with their online learning experience and to define the main factors affecting students' satisfaction with their online learning program at Cerrahpasa Medical Faculty. METHODS: A cross-sectional survey study was conducted to determine medical students' overall satisfaction with online learning methods and to identify factors associated with positive and negative satisfaction levels. A questionnaire, consisting of 24 questions to collect demographic characteristics, factors associated with online education experience and overall satisfaction levels was developed and distributed to 1600 medical students. Multivariable linear regression analysis was used to determine the factors associated with positive and negative satisfaction levels. RESULTS: Regression analysis showed that being familiar with online teaching techniques (ß = 0.19, 95% CI [0.07, 0.30], faculty members' higher online teaching skill levels (ß = 0.42, 95% CI [0.32, 0.51], interactive online teaching approaches (ß = 0.54, 95% CI [0.41, 0.67], having a personal workspace (ß = 0.43, 95% CI [0.19, 0.67], and a self-reported longer attention span (ß = 0.75, 95% CI [0.57, 0.92] were associated with higher overall satisfaction with online learning. The occurrence of technical problems (ß = -0.19, 95% CI [-0.26, -0.12] was associated with lower overall satisfaction. CONCLUSIONS: Higher online teaching skills of faculty members, use of interactive approaches, students' familiarity with online teaching techniques, provision of a personal workspace, and self-reported longer attention spans positively contributed to higher levels of student satisfaction with online learning. Considering the increasing significance of online educational methods, our study identified key components that affect students' level of satisfaction. This information might contribute to the development of online educational programs in the future.

Acute Thrombocytopenia Complicating the Initial Administration of Obinutuzumab: Is It More Frequent Than We Think?

Thrombocytopenia has been reported more frequently with obinutuzumab in clinical trials where it was directly compared with rituximab. However, more significant than the frequency, a unique form of severe thrombocytopenia manifesting very early after the first obinutuzumab infusion has been published in case reports. To further explore this subject, we went through the records of our clinic to identify similar cases of obinutuzumab-induced acute thrombocytopenia (OIAT). Among 24 patients who received obinutuzumab outside of clinical trials, we recovered three cases with OIAT. This paper describes these three cases in detail, placing emphasis on the timing, severity, and the clinical course. Notably, all three patients developed severe OIAT within 5 days of their first obinutuzumab exposure, responded well to transfusion, and recovered within a few days without severe bleeding. None of the patients experienced a similar event in the second course of the obinutuzumab-based therapy. Our observations suggest that OIAT may be a frequent, possibly non-relapsing, and unique event that deserves more attention than it currently receives.

Does discontinuing bleomycin due to toxicity increase the risk of lymphoma progression? Real-life data from a homogeneous population of advanced stage Hodgkin lymphoma.

Hodgkin Lymphoma (HL) is often curable with ABVD therapy and improving outcomes is a main goal of ongoing research. Bleomycin-associated pneumonitis (BAPT) is a potentially life-threatening complication that necessitates bleomycin discontinuation. We conducted this study on a homogenous cohort of advanced stage HL treated only with ABVD for frontline therapy to assess if bleomycin discontinuation increases the risk of lymphoma progression. After the exclusion of patients who received radiotherapy or other drugs, 106 and 28 patients in the six-cycle ABVD and BAPT groups respectively had similar survival curves for progression and death with a 49-month median follow-up. PFS rates were also very similar at two and four years from diagnosis with 2-year PFS rates of 83.9% and 82.1% (RR = 1.1 95%CI = 0.45-2.2). Outcome comparisons were also similar between the two groups when stratified according to early response assessment with PET/CT. Patients who discontinued bleomycin due to toxicity did not experience an increased risk of progression compared to patients who completed six ABVD cycles.

Pulmonary Hypertension Due to High-Output Heart Failure: Hereditary Hemorrhagic Telangiectasia.

Pulmonary hypertension (PH) is a complex disorder that should be managed with a multidisciplinary approach. Although most of the underlying causes of left heart disease can be easily diagnosed with cardiac imaging, some pathologies might necessitate careful investigation to go beyond the obvious. High-output heart failure (HF) due to arteriovenous malformation (AVMs) is an unnoticeable cause for HF and PH. Patients with hepatic AVMs should always be carefully evaluated with regard to hereditary hemorrhagic telangiectasia (HHT) since they can have multiple signs related to the other systems without any symptoms. In this case report, we discussed a patient who was initially diagnosed as PH associated with HF with preserved ejection fraction but eventually was found to have PH associated with high-output HF due to hereditary hemorrhagic telangiectasia (HHT, or Osler Weber Rendu syndrome) after detailed evaluation.

A cross-sectional study on restless legs syndrome (RLS) in polycythemia vera (PV): is iron deficiency the only culprit?

INTRODUCTION: In polycythemia vera (PV) patients undergoing phlebotomy, iron deficiency (ID) may develop. ID has been linked to restless legs syndrome (RLS), and in one study, 29.6% of PV patients had RLS. We aimed to evaluate the frequency of RLS in PV and to evaluate factors that might play a role in RLS development among PV and essential thrombocythemia (ET) patients. METHODS: We consecutively included PV cases as the patient group, and ET and ID patients and healthy subjects (HSs) were included as controls. Those with conditions that could lead to RLS were excluded. All subjects were questioned according to the diagnostic criteria of the International Restless Legs Syndrome Study Group. RESULTS: Twenty-seven PV, 23 ET, and 22 ID patients and 23 HSs were included. RLS was detected in 25.9%, 34.8%, and 45.5% of PV, ET, and ID patients, respectively. None of the HSs had RLS. In univariate analysis, interferon-α and anagrelide use, magnesium levels, and the Leeds assessment of neuropathic symptoms and signs (LANSS) scores had a significant impact on RLS in PV and ET patients (p = 0.014, p = 0.032, p = 0.036, and p = 0.003, respectively). CONCLUSION: RLS was more common among PV and ET patients than HSs, which was irrespective to the iron status. RLS was more frequent in ET patients than that observed in PV cases, indicating that ID may not be the only causative factor for RLS development in PV. Further prospective studies are needed to determine the prevalence and risk factors of RLS developing in PV and ET.

Management of humoral secondary immunodeficiency in hematological malignancies and following hematopoietic stem cell transplantation: Regional perspectives.

Secondary immunodeficiency (SID) can occur as a result of multiple factors, including hematological malignancies, hematopoietic stem cell transplantation (HSCT), immunosuppressive treatment, biologics, and anti-inflammatory drugs. SID includes disorders resulting from impairment of both cellular and humoral immunity. This review focuses on the current risk factors, implications, and challenges in managing SID patients with impaired humoral immunity, which includes quantitative (hypogammaglobulinemia) and/or functional antibody and B-cell deficiencies specifically related to hematological malignancies and post-HSCT. Increased physician awareness is needed surrounding the disease presentation and early risk factors, as SID may be caused by several etiologies. Careful clinical assessment is then required to optimize management, which encompasses close monitoring of clinical parameters, vaccination, antibiotic prophylaxis, and immunoglobulin replacement therapy (IGRT). Novel methods of IGRT administration are associated with enhanced pharmacokinetics, IgG trough level stability, no need for venous access, as well as fewer systemic adverse events and better administration flexibility compared with traditional methods. Published international guidelines supported by observations from clinical data are broadly followed; however, best practices within each country have nuances that underline the need to tailor treatment plans to the individual patient.

Level of Awareness of Acquired Hemophilia A Among Physicians in Türkiye: A Survey Study

This survey study aimed to evaluate the level of awareness and knowledge of acquired hemophilia A (AHA) among physicians from various specialties. Data were collected by administering a questionnaire containing questions about two patient profiles to evaluate the approaches of physicians from different specialties. The study included a total of 945 physicians. The most common suspected diagnosis for the clinical patient profile was immune thrombocytopenia, followed by hemophilia. For the laboratory patient profile, the most common suspected diagnosis was hemophilia. While only 9.4% of the physicians stated that they had good knowledge of this disease, only 21.6% wanted to learn more about AHA. Most of the participating physicians do not rank AHA first in the differential diagnosis of a patient with clinical and laboratory findings of AHA. Appropriate educational activities to raise awareness of AHA will help reduce disease-related morbidity and mortality.

Epidemiology, treatment patterns, and disease burden of cytomegalovirus in hematopoietic cell transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America. METHODS: The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011-17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden. RESULTS: Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%-61.2% (23 studies) and 2.9%-15.7% (10 studies), respectively. Recurrence occurred in 19.8%-37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%-10% of recipients (five studies). Patient-reported outcomes and economic data were scarce. CONCLUSION: The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.

Upregulation of SPINK2 in acute myeloid leukemia.

Objectives: Acute myeloid leukemia (AML) is a highly heterogeneous disease. Although patients can be classified into risk groups based on their genetic changes, the prognosis of disease within these categories varies widely. This situation raises the need to search for new molecular markers related to AML. Serine peptidase inhibitor Kazal type 2 (SPINK2) has recently been reported to be upregulated in AML and associated with poor outcomes by meta-analysis and in a limited number of AML patients. Methods: We analyzed SPINK2 mRNA expression in 62 patients (45 adult and 17 pediatric) with AML and 11 cell lines using quantitative Real-Time PCR (qRT-PCR). SPINK2 protein level was determined using ELISA in cell lines. Results: We found that the expression of SPINK2 mRNA and protein levels in AML cell lines (HL60 and NB4) have increased compared to other cell lines (K562, Jurkat and NALM6, MCF7, HeLa, HUVEC, hFOB, 293T, U87). SPINK2 mRNA expression was upregulated in patients with AML compared to controls (p=0.004) and significantly lower in t(8;21)-positive patients compared to negative patients (p=0.0006). Conclusions: Our results suggest that SPINK2 serves an important role in AML development. Further studies are needed to evaluate SPINK2 expression in AML patients with t(8.21) and investigate to clarify its prognostic value in various subgroups of AML.

Acquired Hemophilia A In Adults: A Multicenter Study from Turkey.

Acquired hemophilia A (AHA) is a rare disease caused by autoantibodies inhibiting factor VIII (FVIII) activity. Although the conditionis usually idiopathic, there may be other underlying diseases. Treatment consists of two steps: treatment of acute bleeding and immunosuppression. In this multicenter study, we aimed to demonstrate the clinical characteristics, management details, and survival of AHA patients in Turkey. Data was collected from eleven centers in Turkey. aPTT, FVIII, FVIII inhibitor, and hemoglobin (HB) levels, mixing test results, and demographics at diagnosis, treatment information, adverse events, bleeding episodes during follow-up, relapses, and outcome were analyzed. Twenty-nine patients were analyzed (58.6% female). No underlying disorder could be detected in 14 patients. The most prevalent etiologies were pregnancy, malignancy and infections. The median FVIII activity and FVIII inhibitor titer at diagnosis were 0.7% (0.0-29.4%) and 32.6 BU (0.6-135.6 BU) respectively. Bleeding was severe in 44.8% of patients. The HB value was significantly lower in patients with severe bleeding. Most of the patients (n = 25, 86.2%) had only one bleeding episode without relapse, three patients (10.3%) had two bleeding episodes, and one patient had more than three bleedings. 21 (75%) patients received hemostatic therapy. The use of recombinant FVIIa was slightly higher than activated prothrombin complex concentrate (15 versus 10 patients). Immunosuppressive treatment was initiated in 26 (93%) patients. Regimens containing steroid, cyclophosphamide, and rituximab in different combinations were the most preferred. The median follow-up period was 13 months (2-156 months). Median overall survival was 154.97 months. Four and six-year survival were 90.9 ± 0.8% and 77.9 ± 14.1% respectively. This is a unique study that investigated the demographic characteristics, treatment approaches, and patient survival of AHA in Turkey.

Short-Term Clinical Outcomes of Packed Red Blood Cell Transfusions with Isolated Enzyme-Phase Crossmatch Incompatibility: A Single-Center Cross-Sectional Study

Acute hemolytic transfusion reactions (AHTRs) are feared complications of packed red blood cell (PRBC) transfusions. This study aimed to investigate the clinical consequences of isolated enzyme-phase crossmatch-incompatible PRBC transfusions by clinically observing all events during the study period at a single institution with the primary goal of detecting AHTRs. Ninety-four transfusions of interest were administered during the study period. Laboratory investigations were adequate in 73 episodes, where no AHTR developed and a mean hemoglobin concentration rise of 1.1 g/dL was documented. Three transfusions were terminated prematurely; however, further investigations ruled out AHTR. The remaining 21 transfusions were also completed uneventfully without noteworthy clinical deterioration. This study's results provide clinical validation to omit pretransfusion screening with enzyme-phase crossmatch and document the safety and short-term efficacy of isolated enzyme-phase incompatible transfusions. The findings may encourage future clinical research to better understand the long-term efficacy of such transfusions, which may be valuable for transfusion-dependent patients.

Renal recovery after acute kidney injury requiring urgent hemodialysis is not associated with improved survival of the patients with multiple myeloma.

BACKGROUND: Severe acute kidney injury (AKI) requiring urgent hemodialysis (uHD) is associated with considerable morbidity and mortality in patients with multiple myeloma (MM). PURPOSE: To evaluate the renal function, outcome, and survival status of patients with MM who received uHD and to compare their overall survival with MM patients who did not receive uHD. MATERIALS AND METHODS: A total of 70 eligible MM patients who received uHD were included together with 70 control patients with MM. RESULTS: In the study group, 11 patients (15.7%) were known to have pre-existing chronic kidney disease. Thirty-four percent of the study group had AKI requiring uHD at MM diagnosis. Seventy-eight percent of the study group had severe AKI due to myeloma kidney. Renal function recovered in 36 patients (51.4%). Patients with MM who became hemodialysis dependent had significantly higher serum creatinine (sCr) levels at the time of AKI compared to patients with renal recovery (p < 0.05). Logistic regression analysis showed that high sCr on admission was significantly associated with hemodialysis dependence (odds ratio 0.78; 95% CI: 0.63-0.96; p = 0.018). The median overall survival was 30 months [IQR: 26] in the study group and 84 months [IQR: 96.25] in the control group (p < 0.05). Cox regression analysis showed that the need for uHD at initial MM diagnosis was associated with reduced survival (hazard ratio (HR) 1.9; 95% CI: 1.1-3.2; p = 0.017). Renal recovery did not provide a survival benefit. CONCLUSION: The need for uHD was associated with poor survival. Recovery of renal function was not associated with improved survival.

Diagnosis and Management of Classical Hodgkin Lymphoma During the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has brought life to a standstill globally. Intermittent quarantines were applied to control the pandemic and reduce contamination. During the pandemic, patients with hematological malignancies were among the most vulnerable population. Our aim was to compare in terms of demographic data, disease-related factors, symptom-to-diagnosis interval, diagnosis-to-treatment interval , and interim and end-of-treatment response in classical Hodgkin lymphoma patients diagnosed during the pandemic and in the pre-pandemic periods. A total of 90 patients were included, of which 65 and 25 were diagnosed in the 2 years before the pandemic and the 12-month period during the pandemic, respectively. Demographic features were comparable in both groups. Although the percentage of patients with advanced-stage disease was higher during the pandemic (64% vs 53.8%), this difference did not reach statistical significance (P = 0.384). The median symptom-to-diagnosis interval was significantly longer during the pandemic than was observed within the pre-pandemic era (16 weeks vs 8 weeks, P = 0.042). The median diagnosis-to-treatment intervals was similar in both groups (13 days vs 15 days, P = 0.253). In the pre-pandemic and pandemic periods, 85.2% and 72.7% of the patients had complete response at end-of-treatment evaluation, respectively (P = 0.208). We found that symptom-to-diagnosis interval was significantly prolonged during the pandemic. Higher percentage of patients with advanced-stage disease during the pandemic might also be due to this delay, nevertheless, this difference did not reach to a significant difference regarding treatment response in both groups.

Somatic hypermutation defects in two adult hyper immunoglobulin M patients.

Hyper immunoglobulin M (HIGM) syndrome is a rare disorder of the immune system with impaired antibody functions. The clinical picture of the patients varies according to the underlying genetic variation. In this study, we identified two novel variants in AID and UNG genes, which are associated with autosomal recessive type HIGM, by targeted next-generation sequencing (NGS) panel. A biallelic 11 base pair deletion (c.278_288delATGTGGCCGAC) in the coding sequence of activation-induced cytidine deaminase (AID) gene was identified in a 36-year-old patient. Biallelic two base pair insertion in exon 7 of uracil nucleoside glycosylase (UNG) gene (c.924_925insGG) was identified in a 40-year-old patient. Both variants were confirmed by Sanger sequencing. HIGM, like many of the other primary immunodeficiencies, is a rare and difficult-to-diagnose entity with heterogeneous clinical phenotypes. It should be suspected in patients with a history of early-onset recurrent respiratory infections, enlarged lymph nodes, and autoimmune disorders. There might be a delay in diagnosis until adulthood especially in subtle cases or if HIGM is not included in the differential diagnosis due lacking of awareness. In this regard, genetic testing with NGS-based diagnostic panels provide a rapid and reasonable tool for the molecular diagnosis of patients with immunodeficiencies and hence, decrease the time to diagnose and prevent infection-related complications associated with increased morbidity and mortality.