Jelena Jelicic

Prognostic effect of comorbidity indices in elderly patients with multiple myeloma.

BACKGROUND Consideration of comorbidity, disability, and frailty represents a significant part of the treatment of elderly multiple myeloma (MM) patients. The aim of study was to analyze the effect of the Charlson Comorbidity Index (CCI) and scale of Instrumental Activities of Daily Living (IADL) on the course of disease. PATIENTS AND METHODS The study included 110 newly diagnosed MM patients older than 65 years of age. According to the CCI most patients had at least 1 comorbidity (CCI score of 1) and most of them (51 of 110 patients; 46.4%) had an age-adjusted CCI (aaCCI) score of 5 to 6. Most of our patients were capable of performing routine daily activities (IADL ≥ 6). Patients were treated with thalidomide- and bortezomib- based combinations, or with conventional chemotherapy. RESULTS International Staging System (ISS) score 3 correlated with high scores of CCI or aaCCI (R = 0.314, P < .003; R = .317, P < .002, respectively), and lower IADL (R = 0.259, P < .007). The probability of adverse events was 70% greater for CCI score ≥ 2 (odds ratio [OR], 1.72); 28% for aaCCI ≥ 5 (OR, 1.28) and 22% higher for IADL < 3 (OR, 2.25). The patients with a CCI score of 0 to 1 had significantly longer overall survival (OS; log rank, 6.538; P < .011). The patients with aaCCI ≥ 5 had significantly shorter OS (log rank, 4.209; P < .040), and the patients with IADL > 3 had significantly longer OS (log rank, 6.62; P < .001). In the proposed model, aaCCI ≥ 5 and IADL > 3 scores had a major effect on the OS (χ(2), 8.46; P = .037). CONCLUSION CCI, aaCCI, and IADL scale are clinical parameters of prognostic significance. A proposed model for a personalized treatment approach is based on variables such as scores for aaCCI ≥ 5 and IADL > 3.

Development and validation of multivariable predictive model for thromboembolic events in lymphoma patients.

Lymphoma patients are at increased risk of thromboembolic events but thromboprophylaxis in these patients is largely underused. We sought to develop and validate a simple model, based on individual clinical and laboratory patient characteristics that would designate lymphoma patients at risk for thromboembolic event. The study population included 1,820 lymphoma patients who were treated in the Lymphoma Departments at the Clinics of Hematology, Clinical Center of Serbia and Clinical Center Kragujevac. The model was developed using data from a derivation cohort (n = 1,236), and further assessed in the validation cohort (n = 584). Sixty‐five patients (5.3%) in the derivation cohort and 34 (5.8%) patients in the validation cohort developed thromboembolic events. The variables independently associated with risk for thromboembolism were: previous venous and/or arterial events, mediastinal involvement, BMI>30 kg/m2, reduced mobility, extranodal localization, development of neutropenia and hemoglobin level < 100g/L. Based on the risk model score, the population was divided into the following risk categories: low (score 0‐1), intermediate (score 2‐3), and high (score >3). For patients classified at risk (intermediate and high‐risk scores), the model produced negative predictive value of 98.5%, positive predictive value of 25.1%, sensitivity of 75.4%, and specificity of 87.5%. A high‐risk score had positive predictive value of 65.2%. The diagnostic performance measures retained similar values in the validation cohort. Developed prognostic Thrombosis Lymphoma – ThroLy score is more specific for lymphoma patients than any other available score targeting thrombosis in cancer patients. Am. J. Hematol. 91:1014–1019, 2016.

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

The possible benefit from total tumour resection in primary diffuse large B-cell lymphoma of central nervous system – a one-decade single-centre experience

Background and methods. The aim of the study was to evaluate retrospectively clinical course of 27 patients with primary central nervous system lymphoma (PCNSL) diagnosed and treated by different surgical approaches. Initial therapy-diagnostic approach included surgery with total tumour reduction (TTR) performed in 12 patients (44.4%), while partial reduction and biopsy were performed in 8 (29.7%) and 7 (25.9%) patients, respectively. All patients were treated with chemotherapy based on high-dose methotrexate (HD-MTX) with/without whole-brain radiotherapy (WBRT). Results. The median overall survival (OS) and event-free survival were 37 and 31 months, respectively, with overall response rate of 74%. The patients who underwent an open surgery with TTR had significantly longer OS (median not reached), comparing with partial tumour reduction or biopsy only (Log-Rank χ2 6.08, p = 0.014) when median OS was 23 months. In patients with performance status according to Eastern Cooperative Oncology Group (ECOG PS) ≥ 3, OS was 23 months, contrary to ECOG PS 1–2 when median was not reached. The International Extranodal Lymphoma Study Group score (low, intermediate and high) also influenced OS between three risk groups (Log-Rank χ2 12.5, p = 0.002). Conclusion. The treatment of PCNSL still remains doubtful, however possible benefit from the TTR followed with HD-MTX with/without WBRT should be reconsidered.

The Revised International Staging System Compared to the Classical International Staging System Better Discriminates Risk Groups among Transplant-Ineligible Multiple Myeloma Patients

Background: The Revised International Staging System (R-ISS) has recently been introduced as a comprehensive prognostic score for multiple myeloma (MM). Validation of the R-ISS in patients treated outside of clinical trials is the focus of current investigations. The aim of this study was to test the prognostic role of the R-ISS in MM patients ineligible for autologous stem cell transplantation. Patients and Methods: A total of 102 newly diagnosed MM patients were analyzed. All patients were initially treated with thalidomide-based combinations. Results: An overall response rate was achieved in 77.4% patients. Both the International Staging System (ISS) and the R-ISS influenced the event-free survival and the overall survival (OS). However, the ISS was unable to discriminate patients in stages ISS1 and ISS2 regarding OS. On the contrary, the R-ISS clearly differentiated risk categories regarding OS and provided an improved discriminative power of 6.3% compared to the ISS. Furthermore, among the parameters that were significant in univariate analysis (presence of renal impairment, anemia, platelet count < 130 × 109/l, and R-ISS), the multivariate model pointed to the R-ISS (p = 0.001) as the most important parameter influencing OS. Conclusion: The R-ISS represents a useful tool for risk stratification of transplant-ineligible MM patients and should be considered as a prognostic index in daily clinical practice.

Single-center experience in the treatment of primary testicular lymphoma.

Background: Primary testicular lymphoma (PTL) is a rare and highly aggressive extranodal non-Hodgkins lymphoma. Patients and Methods: We evaluated the clinical and histopathological features and outcomes of 10 PTL patients treated in the period of 2003-2013 with multimodal therapy (rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), intrathecal prophylaxis, irradiation of the contralateral testis) following orchiectomy. Results: Complete remission was achieved in 8 patients after first-line therapy while 2 patients had disease progression. The median follow-up duration was 30 months (range 6-110 months). Relapse occurred in 3 patients. 1 patient relapsed in the contralateral testis, while the other 2 patients relapsed to the skin and the central nervous system (CNS), respectively. The time to relapse was 2, 8, and 9 months. Patients with disease progression and relapse received ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) as salvage treatment, except for 1 patient who was treated with palliative radiotherapy. After second-line therapy, only 1 patient had a short partial remission of 2 months. The median overall survival was 48 months, and the mean progression-free survival was 36 months (the median was not reached). Conclusions: We evaluated 10 patients with PTL treated with rituximab plus CHOP, prophylactic intrathecal chemotherapy, and prophylactic irradiation of the contralateral testis, resulting in good outcome and low incidence of relapse in the contralateral testis; however, the benefit of intrathecal chemotherapy is not yet confirmed.

Venous thromboembolic events in lymphoma patients: Actual relationships between epidemiology, mechanisms, clinical profile and treatment

Venous thromboembolic events (VTE) are an underestimated health problem in patients with lymphoma. Many factors contribute to the pathogenesis of thromboembolism and the interplay between various mechanisms that provoke VTE is still poorly understood. The identification of parameters that are associated with an increased risk of VTE in lymphoma patients led to the creation of several risk-assessment models. The models that evaluate potential VTE risk in lymphoma patients in particular are quite limited, and have to be validated in larger study populations. Furthermore, the VTE prophylaxis in lymphoma patients is largely underused, despite the incidence of VTE. The lack of adequate guidelines for the prophylaxis and treatment of VTE in lymphoma patients, together with a cautious approach due to an increased risk of bleeding, demands great efforts to ensure the implementation of current knowledge in order to reduce the incidence and complications of VTE in lymphoma patients.

CHRONIC LYMPHOCYTIC LEUKEMIA INVOLVEMENT OF CENTRAL NERVOUS SYSTEM: A SINGLE CENTRE EXPERIENCE

using p < 0.05 determined statistical significance. Results: Compared to pre‐treatment baseline samples, both Ibrutinib and Venetoclax treatment resulted in a significant increase in the frequency and absolute number of both MDSC (HLADRCD11bCD33) and normal monocytes (HLADRCD11bCD33+) to the same level (Ibrutinib) or in excess (Venetoclax) to those seen in healthy controls (Fig. 1). The frequency of mDC (HLADRCD11c) was significantly increased following Ibrutinib (but not Venetoclax) treatment. Following both Ibrutinib and Venetoclax treatment, a significant increase in the frequency of NK cells (CD3CD56) was seen, although only Venetoclax treatment resulted in a normalisation of NK cells comparable to healthy controls. Both Ibrutinib and Venetoclax treatment resulted in a significant increase in the frequency of γδ T cells. Conclusion: BTK and Bcl‐2 inhibitors have different effects on innate immune subsets. Whist the immunological profile of patients improves with both, immunological recovery is greatest in those treated with Venetoclax. This provides an opportunity for the potential introduction of immunotherapies following small molecule therapy to promote anti‐ CLL immunity and improve durability of responses.

COMPARATIVE ANALYSIS OF PREDICTIVE MODELS FOR THROMBOEMBOLIC EVENTS IN LYMPHOMA PATIENTS

ing the side effect profile. Methods: Data from 2012 to 2016 were collected retrospectively from pharmacy records for all lymphoma patients treated with thalidomide. The majority of these patients were multiply relapsed. Patients were all started on 50 mg daily, with dose escalation to 200 mg daily as tolerated, in addition to pulsed dexamethasone. Results: 27 patients were treated: ‐ 11 DLBCL (2 transformed low‐ grade) ‐ 3 Follicular lymphoma‐ 2 B‐NHL unspecified‐ 3 Hodgkins disease‐ 2 Waldenströms macroglobulinaemia‐ 1 mantle cell‐ 5 angioimmunoblastic T cell‐ Age range of patients 52–58 (median age 75)‐ Line of treatment was 1–5 (median 2)‐ 17/27 patients were treated for >4 weeks (others stopped due to SEs or early relapse/ death)‐ 7 of those 17 achieved disease control for >6 months. Conclusion: The patients examined in this study were all multiply relapsed and/or too frail for conventional chemotherapy. Prognosis in such a cohort is very poor and, unsurprisingly, many of the cases we looked at died shortly after starting treatment. However, a subset of these patients achieved long disease control—one patient is still alive 5 years after starting thalidomide. Thalidomide has a variety of mechanisms including immunomodulatory and anti‐angiogenic properties so it is a logical choice of treatment in chemotherapy‐resistant cases. Given the generally well‐tolerated side effect profile and low cost of thalidomide not to mention the ease of administration, a trial of thalidomide is worth considering when no other options remain, where it may buy precious months, or even years, of life.