Impact of CALR and JAK2V617F Mutations on Clinical Course and Disease Outcomes in Essential Thrombocythemia: A Multicenter Retrospective Study in Turkish Patients.

Objective: In this study, we investigated the effects of calreticulin (CALR) and JAK2V617F mutational status on clinical course and disease outcomes in Turkish patients with essential thrombocythemia (ET). Materials and Methods: Seventeen centers from Türkiye participated in the study and CALR- and JAK2V617F-mutated ET patients were evaluated retrospectively. Results: A total of 302 patients were included, of whom 203 (67.2%) and 99 (32.8%) were JAK2V617F- and CALR-positive, respectively. CALR-mutated patients were significantly younger (51 years vs. 57.5 years, p=0.03), with higher median platelet counts (987x109/L vs. 709x109/L, p<0.001) and lower median hemoglobin levels (13.1 g/dL vs. 14.1 g/dL, p<0.001) compared to JAK2V617F-mutated patients. Thromboembolic events (TEEs) occurred in 54 patients (17.9%), 77.8% of which were arterial. Compared to CALR mutation, JAK2V617F was associated with a higher risk of thrombosis (8.1% vs. 22.7%, p=0.002). Rates of transformation to myelofibrosis (MF) and leukemia were 4% and 0.7%, respectively, and these rates were comparable between JAK2V617F- and CALR-mutated cases. The estimated overall survival (OS) and MF-free survival of the entire cohort were 265.1 months and 235.7 months, respectively. OS and MF-free survival durations were similar between JAK2V617F- and CALR-mutated patients. Thrombosis-free survival (TFS) was superior in CALR-mutated patients compared to JAK2V617F-positive patients (5-year TFS: 90% vs. 71%, respectively; p=0.001). Age at diagnosis was an independent factor affecting the incidence of TEEs. Conclusion: In our ET cohort, CALR mutations resulted in higher platelet counts and lower hemoglobin levels than JAK2V617F and were associated with younger age at diagnosis. JAK2V617F was strongly associated with thrombosis and worse TFS. Hydroxyurea was the most preferred cytoreductive agent for patients with high thrombosis risk.

Immune Thrombotic Thrombocytopenic Purpura in Elderly Patients: The Roles of PLASMIC and French Scores

Objective: In recent years, new developments have been incorporated into daily practice in the management of immune thrombotic thrombocytopenic purpura (iTTP). In particular, clinical scoring systems could help clinicians with clinical decision-making and early recognition. However, older patients frequently present with more organ involvement and in unusual ways. The ways in which age could affect these clinical prediction scoring systems remain unclear. We evaluated the use of PLASMIC and French scores in patients over 60 years of age. Materials and Methods: We performed a retrospective cross-sectional analysis of patients over 60 years of age with a presumptive diagnosis of iTTP between 2014 and 2022 at 10 centers. We calculated PLASMIC and French scores and compared our data with a single-center analysis of younger patients presenting with thrombotic microangiopathy. Results: Our study included 30 patients over 60 years of age and a control group of 28 patients younger than 60 years. The diagnostic sensitivity and specificity of a French score of ≥1 were lower in older patients compared to the control group (78.9% vs. 100% and 18.2% vs. 57.1%, respectively). The diagnostic sensitivity and specificity of a PLASMIC score of ≥5 were 100% vs. 95% and 27.3% vs. 100% for the study group and control group, respectively. Our study showed a higher mortality rate in older patients compared to the control group (30% vs. 7.1%, p=0.043). Conclusion: For a limited number of patients (n=6), our results showed that rituximab can reduce mortality. Given that the reliability of clinical prediction scores for iTTP in older patients may be lower, more caution must be undertaken in interpreting their results.

Novel Janus-kinase (JAK) Inhibitors in Myelofibrosis.

INTRODUCTION: JAK inhibitors (JAKis), used in the treatment of myelofibrosis, have entered standard treatment, providing significant improvements in spleen size and symptom burden. Although splenomegaly provides a reduction and some improvement in cytopenia, there is still a way to go. Novel JAKis are being investigated to overcome barriers to treatment access, such as therapeutic challenges, intolerance, and unresponsiveness. AREAS COVERED: This review includes the current status of JAKi treatment for myelofibrosis, mainly focusing on investigational JAKis; jaktinib, lestaurtinib, itacitinib, gandotinib, BMS-911543, ilginatinib, TQ05105, and flonoltinib maleate. MEDLINE and clinicaltrials.gov were screened to identify all completed or active studies on this topic. The outcomes of the preclinical studies and clinical trials are presented and discussed for each drug. EXPERT OPINION: In patients with myelofibrosis, momelotinib was effective in treating anemia, whereas jaktinib was effective in both anemia and Total Symptom Score (TSS). More phase 3 studies are needed to provide more precise evidence. The increasing variety of JAKis will allow for more personalized treatment options for myelofibrosis in the future. The potential impact on disease progression, molecular responses, and the duration of this response will become important parameters for future evaluations of these drugs.

The Effects of Second Primary Malignancies and Frailty on Overall Survival and Mortality in Geriatric Turkish Patients with Multiple Myeloma.

The study aims to investigate second primary malignancy (SPM) development and frailty in Turkish geriatric patients with multiple myeloma (MM) and to assess the relationship between overall survival (OS) and various characteristics including SPM and frailty. Seventy-two patients diagnosed with and treated for MM were enrolled in the study. Frailty was determined by the IMWG Frailty Score. Fifty-three participants (73.6%) were found to have clinically-relevant frailty. Seven patients (9.7%) had SPM. Median follow-up was 36.5 (22-48.5) months, and 17 patients died during the follow-up period. Overall (OS) was 49.40 (45.01-53.80) months. Shorter OS was found in patients with SPM (35.29 (19.66-50.91) months) compared to those without (51.05 (46.7-55.4) months) (Kaplan-Meier; p = 0.018). The multivariate cox proportional hazards model revealed that patients with SPM had 4.420-fold higher risk of death than those without (HR: 4.420, 95% CI: 1.371-14.246, p = 0.013). Higher ALT levels were also independently associated with mortality (p = 0.038). The prevalence of SPM and frailty was high in elderly patients with MM in our study. The development of SPM independently reduces survival in MM; however, frailty was not found to be independently associated with survival. Our results suggest the importance of individualized approaches in the management of patients with MM, particularly with regard to SPM development.

Investigation of the frequency of bortezomib neuropathy in patients with multiple myeloma diagnosis with normal and abnormal genetic characteristics.

INTRODUCTION: Bortezomib-induced peripheral neuropathy in patients with multiple myeloma is an undesirable and sometimes severe side effect. Our study aimed to examine whether there was a difference in bortezomib-induced peripheral neuropathy between multiple myeloma patients with normal and abnormal genetic characteristics. METHODS: This retrospective analysis is based on the assessment of bortezomib-induced peripheral neuropathy frequency in newly-diagnosed multiple myeloma patients with normal (n = 68) and abnormal (n = 45) genetic profiles. A total of 113 patients diagnosed with multiple myeloma according to the International Myeloma Working Group criteria, between 2016 and 2021, were included in this study. RESULTS: Neuropathy was detected in 42 (37.1%) patients. The most common genetic anomalies were 13q del (in 28.9%), t(4.14) (in 22.2%), and trisomy 7 (in 20.0%). When patients with and without bortezomib-induced peripheral neuropathy were compared, the only significant differences were observed for age (p = 0.032) and genetic grouping (p = 0.001); whereas other characteristics that could be associated with bortezomib-induced peripheral neuropathy were similarly distributed in both groups. Bortezomib-induced peripheral neuropathy was significantly more frequent in multiple myeloma patients with normal genetic characteristics (p = 0.001). CONCLUSION: As a result of our study, it was observed that the frequency of bortezomib neuropathy was significantly higher in patients with normal genetic features compared to those with abnormal genetic features. This result suggested that factors other than genetic factors should be investigated to clarify the etiology of bortezomib-associated neuropathy in patients with multiple myeloma.

Impact of COVID-19 on Outcomes of Patients with Hematologic Malignancies: A Multicenter, Retrospective Study.

Objectives: Patients with hematological malignancies have a high risk of mortality from coronavirus disease 2019 (COVID-19). This study aimed to investigate the impact of COVID-19 on mortality rates in patients with various hematological malignancies and to determine risk factors associated with all-cause mortality. Methods: A multicenter, observational retrospective analysis of patients with hematological malignancies infected with COVID-19 between July 2020 and December 2021 was performed. Demographic data, clinical characteristics, and laboratory parameters were recorded. Patients were grouped as non-survivors and survivors. All-cause mortality was the primary outcome of the study. Results: There were 569 patients with a median age of 59 years. Non-Hodgkin lymphoma (22.0%) and multiple myelomas (18.1%) were the two most frequent hematological malignancies. The all-cause mortality rate was 29.3%. The highest mortality rates were seen in patients with acute myeloid leukemia (44.3%), acute lymphoid leukemia (40.5%), and non-Hodgkin lymphoma (36.8%). The non-survivors were significantly older (p<0.001) and had more comorbidities (p<0.05). In addition, there were significantly more patients with low lymphocyte percentage (p<0.001), thrombocytopenia (p<0.001), and high CRP (p<0.001) in the non-survived patients. Age ≥ 65years (p=0.017), cardiac comorbidities (p=0.041), and continuation of ongoing active therapy for hematological cancer (p<0.001) were the independent risk factors for the prediction of mortality. Conclusions: In patients with hematological malignancies, coexistent COVID-19 leads to a higher mortality rate in elderly patients with more comorbidities. Acute myeloid and lymphoid leukemia and non-Hodgkin lymphoma have the highest mortality rates. Older age, cardiac diseases, and continuation of ongoing active therapy for hematological cancer are the independent risk factors for mortality in hematological malignancy patients with COVID-19.

Preoperative prediction of retroperitoneal lymph node involvement in clinical stage IB and IIA cervical cancer.

Objective: Lymph node metastasis (LNM) is the most important factor affecting survival in early-stage cervical cancer (CC). International Federation of Gynecology and Obstetrics revised the staging of CC in 2018 and reported LNM as a staging criterion. We investigated the preoperatively assessable risk factors associated with LNM in surgically treated stage IB1-IIA2 CC patients. Materials and Methods: This was a retrospective cohort study of women who underwent radical hysterectomy and pelvic lymphadenectomy with or without para-aortic lymphadenectomy for CC stage IB1-IIA2 from 2004 to 2019. All patients included in this study were examined with speculum inspection, parametrial assessment by rectovaginal palpation under general anesthesia, transvaginal ultrasonography, magnetic resonance imaging (MRI), and chest radiography. Clinical staging was done according to the preoperative findings. MRI was used to measure tumor and lymph node dimensions. Results: Out of the 149 women included in the study, 29 (19.4%) had LNM. Univariate analysis revealed that larger tumor size (≥30 mm), lymphovascular space invasion (LVSI) detected with diagnostic biopsy, parametrial involvement, and deep stromal invasion status were significantly different between the group with LNM and the group without LNM. In multivariate analysis, specific preoperative risk factors such as MRI based tumor diameter ≥30 mm and LVSI (+) on the diagnostic biopsy were found to be independent risk factors for LNM in the multivariate analysis. Conclusion: The rate of LNM is high in patients with CC with a tumor size ≥30 mm and preoperative biopsy LVSI status even if they are clinically in early stages. Surgeons can take this into account while deciding between primary surgery and chemoradiotherapy in the treatment of CC.

Castleman Disease: A Multicenter Case Series from Turkey

Objective: Castleman disease (CD) is a rare disease also known as angiofollicular lymph node hyperplasia. The two main histological subtypes are the hyaline vascular and plasma cell variants. It is further classified as unicentric CD (UCD) or multicentric CD (MCD) according to the anatomical distribution of the disease and the number of lymph nodes involved. The aim of this multicenter study was to evaluate all cases of CD identified to date in Turkey to set up a national registry to improve the early recognition, treatment, and follow-up of CD. Materials and Methods: Both adult (n=130) and pediatric (n=10) patients with lymph node or involved field biopsy results reported as CD were included in the study. Patients' demographic information, clinical and laboratory characteristics, imaging study results, treatment strategies, and clinical outcomes were evaluated retrospectively. Results: A total of 140 patients (69 male and 71 female) with a diagnosis of UCD (n=73) or MCD (n=67) were included. The mean age was 39 years in the UCD group and 47 years in the MCD group. Female patients were more common in the UCD group. The most common histological subtype was hyaline vascular for both UCD and MCD patients. Asymptomatic patients were more common in the UCD group. Anemia, elevations of acute phase reactants, and hypoalbuminemia were more common in the MCD group. The most commonly used treatment strategies for UCD were surgical excision, rituximab, and radiotherapy, respectively. All UCD patients were alive at a median of 19.5 months of follow-up. The most commonly used treatment strategies for MCD were methyl prednisolone, R-CHOP, R-CVP, and rituximab. Thirteen MCD patients had died at a median of 34 months of follow-up. Conclusion: This study is important in presenting the patient characteristics and treatment strategies for CD from Turkey, with the potential of increasing awareness about CD. Treatment data may help in making decisions, particularly in countries that do not have access to siltuximab. However, larger prospective studies are needed to make definitive conclusions.

Diffuse Large B-Cell Lymphoma Involvement in Two Different Localizations: A Case Report.

The genital system and skin involvement of diffuse B-cell lymphomas are quite rare. The appearance of these rare types in the same patient and the same period makes the treatment of the disease difficult. But both types respond well to anthracyclines and immunotherapies. A 74-year-old woman was treated with R-CHOP (Rituximab, cyclophosphamide, doxorubicine, vincristine, prednisolone) without surgery and/or radiotherapy, and no recurrence at 2 years follow-up. Despite the poor prognosis of these types of lymphomas, treatment responses are quite good as they are in other subtypes.

Predicting malignant potential of gastrointestinal stromal tumors: Role of p16 and E2F1 expression.

Altered expression of cell cycle regulatory proteins in GISTs (gastrointestinal stromal tumors) may be the mechanism for their diversity in clinical behavior. The use of these tumorigenetic and cell proliferative proteins may provide an alternative route for follow-up and treatment. The aim of this study was to determine the prognostic relevance of the E2F1 and p16 expression in GISTs. Tissues from 21 cases with GIST were collected retrospectively. Tumor grade was designated according to the consensus system. Immunohistochemistry was done with antibodies against Ki-67, p16, E2F1. For statistical analysis, Ki-67 proliferation index was evaluated in 2 categories: < or =10% and >10%, whereas p16 expression was scored as negative or positive. E2F1 expression cutoff values were tested for risk group variables as >5% and >10%. Correlation between the presence of necrosis, Ki-67 proliferation index, p16, E2F1 expression and the risk grade was determined by Spearman correlation test. Sensitivity and specificity were determined by Fisher exact test with P < or =0.05 considered as significant. High E2F1 expression (over 10%) and high Ki-67 proliferation index (over 10%) correlated significantly with increasing risk grade. There was also a significant correlation between the presence of necrosis and high-risk grade. No correlation was found between the risk grade and p16 expression. Our results suggest that in addition to high Ki-67 proliferation index, high E2F1 expression may also be a useful predictive marker for malignant potential of GISTs.