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B Introduction: b Diffuse Large B- cell Lymphoma (DLBCL) is characterized by genetic and clinical heterogeneity. In univariate analysis only advanced stage, high LDH and low versus high R-IPI had statistically significant impact on OS ( I p i values 0.007, 0.003 and 0.002 respectively) and PFS ( I p i -values 0.001, 0.002 and <0.001 respectively). Regarding PFS the LDH- DQB1*03 model displayed also statistical significancy ( I p i = 0.001) in a similar way with DQB1*03 increasing the risk of death while keeping LDH within normal ranges. [Extracted from the article]

Background: Despite treatment improvements a considerable proportion of newly diagnosed multiple myeloma (MM) patients experience early progressive disease (EPD) defined as progression or relapse in < 18 months following initial response to first line treatment., Methods: We evaluated 1436 newly diagnosed MM patients out of whom 23.3% had EPD., Results: Patients with EPD had higher median age, β2-microglobulin, LDH and lower hemoglobin and eGFR, compared to others (P < .05); EPD population presented more commonly with advanced stage (ISS3, RISS3, and R2-ISS stage III/IV). Ultra-high-risk MM (UHR-MM) i.e., detection of ≥ 2 high-risk molecular abnormalities was more frequent in EPD population (P < .001). The percentage of patients treated with lenalidomide-based regimens was not significantly different. Daratumumab-based therapies (DBT) were administered less frequently in patients with EPD (2% vs. 10%; P < .001); 11% of patients with EPD versus 33% underwent ASCT (P < .001); Complete response to induction therapy was significantly lower in EPD patients (12% vs. 27%; P < .001). Binary logistic regression analysis demonstrated that ISS, RISS, R2-ISS, UHR-MM, ASCT and DBT were significant predictors for EPD (P < .05). In multivariate analysis R2-ISS, ASCT, and DBT were independent prognosticators for EPD (P < .001). Median PFS and OS were 10 versus 40 months and 29 versus 76 months in patients with EPD versus others, respectively (P < .001)., Conclusion: In real-world, EPD is observed in more than one-fifth of patients, and it remains an unmet clinical need. Daratumumab-based therapies and ASCT significantly reduce the probability of EPD, while R2-ISS could serve as a useful prognostic tool for recognizing this population and guide therapeutic decisions., Competing Interests: Disclosure EK: Janssen Cilag, Amgen, Abbvie, Pfizer, GSK, Takeda, Sanofi, Karyopharm: Honoraria, Research Funding, EK: Consultancy: Janssen, Pfizer, Amgen Honoraria: Janssen, Pfizer, Takeda, Genesis Pharma, Amgen MG; Honoraria: Janssen, Genesis Pharma, Amgen, Karyopharm, Sanofi, GSK, Takeda, DD: Pfizer Research Funding, DF: Honoraria: Janssen, Sanofi. MM: Honoraria: Janssen, MG: Honoraria: Janssen, Genesis Pharma, Amgen, Karyopharm, Sanofi, GSK, Takeda, MAD: Honoraria: Takeda, BMS, Amgen, Beigene, Janssen. DF; Honoraria: Janssen, ET: Consultancy: Janssen, Amgen, Genesis Pharma, Celgene, Takeda, Sanofi; Honoraria: Novartis, Janssen, Takeda, Genesis Pharma, Amgen, Celgene, Sanofi, BMS, GSK. The other authors declare no conflicts of interest., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Poly(ADP-ribose) polymerase inhibitors (PARPi) target the DNA repair pathways and have been established in epithelial ovarian cancer (EOC) as maintenance therapy inducing prolonged survival. However, recently published data showed that PARPi may increase the risk of therapy-related myeloid neoplasms (t-MN) including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Herein, we investigated the incidence, characteristics, and management of t-MN among EOC patients after exposure to PARPi in a Greek Cancer Center. We analyzed 112 consecutive EOC patients treated with PARPi with a median age of 58 years (range 28-84). Olaparib and Niraparib were used in 90 and 22 patients, respectively. The median number of previous chemotherapy lines and duration of treatment with PARPi were 2 (range 1-9) lines and 12 (range 2-24) months, respectively. The incidence of t-MN among patients treated with PARPi was 3.57% (4/112). Patients with t-MN were distributed as follows: t-MDS: 1, t-MDS/AML: 1, t-AML: 2. We observed adverse cytogenetic features in t-MN patients leading to dismal prognosis. In conclusion, in accordance with previous real-world reports, we confirm a notable risk for t-MN in EOC patients treated with PARPi. As PARPi are an emerging therapy for many neoplasms, there is an unmet clinical need to identify patients who are considered at high risk for developing t-MN post-therapy with PARPi in order to introduce potential preventive strategies., (© 2024 UICC.)

Central nervous system (CNS) involvement is a rare and aggressive complication of multiple myeloma (MM). We identified 54/4352 MM patients (1.2%), who developed CNS-MM between 2000 and 2022. A matched-control group of MM patients without CNS-MM was used for comparisons. Median age was 63 years. Median time to CNS-MM was 28 months; 6/54 experienced CNS-MM at MM diagnosis. Abnormal lactate dehydrogenase (LDH), high-risk cytogenetics, and extramedullary involvement (EMI), that is, soft tissue plasmacytomas and/or plasma cell leukemia (PCL), were more frequent in CNS-MM versus controls (p < .05); 13/54 had PCL at CNS-MM. The majority had leptomeningeal infiltration (LMI) (66%); 26% had CNS-MM without systemic myeloma; EMI was the strongest predictor for CNS-MM (OR: 6.3). Median overall survival (OS) of CNS-MM patients versus controls was 43 months (95% CI: 32-54) versus 60 months (95% CI: 38-82) (p < .001); treatment of CNS-MM included mainly bortezomib/thalidomide/chemotherapy whereas 20% received novel drugs/immunotherapy combinations; 28 patients underwent cerebrospinal fluid infusions; EMI was the strongest negative predictor for post CNS-MM OS (p = .005; HR: 2.9). Treatment after 2016 predicted significantly for OS (p = .002; HR: 0.27). Median post CNS-MM OS was 4 months (95% CI: 2.6-5.4); in patients treated after 2016 median OS was 12 months. In conclusion, we have demonstrated in this large real-world series that survival of CNS-MM remains poor; however, there is a positive impact of treatment after 2016, related to the efficacy of modern anti-myeloma therapy; EMI significantly increases the probability to develop CNS-MM and the risk of post CNS-MM death, indicating a potential need for CNS prophylaxis for those patients., (© 2024 Wiley Periodicals LLC.)

Involvement of female genital track (FGT) by diffuse large B cell lymphoma (DLBCL) represents an extremely rare diagnosis. Especially data regarding early-stage disease (i.e., IE, IIE) is very limited. Importantly, previous studies showed controversial results about the risk of central nervous system (CNS) relapse in this entity. Herein, we describe one of the largest reported real-world series of patients with early-stage FGT DLBCL aiming to investigate the clinicopathological characteristics, response to therapy and survival outcomes in the era of immunochemotherapy. We analyzed 21 consecutive patients with biopsy proven DLBCL from uterus or ovary classified as stage IE or IIE out of 1905 newly diagnosed DLBCL patients (1.1%). Uterine and ovarian localization was observed in 14 and seven patients, respectively. Median age was 66 years (range 33-96); 9/21 (43%) were <55 years. Regarding Cell of Origin DLBCL subtype, Germinal Center B-cell subtype was found in seven patients, non-GCB in 10 and non-classified in 4 patients. Median follow-up was 57 months and 5-year overall survival, lymphoma specific survival and Freedom from Progression were 78%, 89% and 90%, respectively. There was no correlation of patients' characteristics with survival parameters. Interestingly, none of the patients experienced CNS relapse. Our results indicate that localized FGT DLBCL exhibits a good prognosis and may not increase the risk for secondary CNS involvement., (© 2024 John Wiley & Sons Ltd.)

Introduction: Human leukocyte antigen (HLA) polymorphisms have been associated with the development of various autoimmune diseases, as well as malignant neoplasms. Non-Hodgkin lymphomas (NHLs) are a heterogenous group of lymphoid malignancies in which a genetic substrate has been established and is deemed to play a crucial role in disease pathogenesis. This study aimed to identify whether variations in the HLA gene region were associated with diffuse large B-cell lymphoma (DLBCL) risk and prognosis., Methods: We defined HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1, HLA-DQB1) alleles in 60 patients with DLBCL and compared the results to those found by 236 healthy adult donors from the bone marrow bank of Northern Greece. HLA typing was performed by two molecular methods, Sequence - Specific Oligonucleotide HLA typing (SSO) and Sequence - Specific Primer HLA typing (SSP), from white blood cells recovered from peripheral blood. The phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 between patients and controls were compared with the 2-sided Fisher's exact test. Results with p -value <0.05 were considered statistically significant. Odds Ratios with 95% Confidence Intervals were calculated to further strengthen the results. The 2-sided Fisher's exact test was also applied to alleles found only in one of the two groups, while the odds ratios together with the confidence intervals were corrected with Haldane-Anscombe method., Results: Among the studied HLA polymorphisms, the frequency HLA-C*12 allele was significantly lower in patients with DLBCL compared with control subjects (6.7% vs. 34.7%, OR = 0.16, 95% CI: 0.04-0.44). Frequency of HLA-B*39 was significantly lower in patients with DLBCL compared with controls, but due to the low frequency of this polymorphism in the studied population and small sample size, determinations regarding the significance of this findings were limited. Survival analysis revealed that the presence of HLA-C*12 was not associated with improved or worsened overall and progression-free survival. No statistically significant associations were observed in the phenotypic frequencies of HLA-A, HLA-DQB1, HLA-DRB1 and the rest of HLA-B alleles between the control and DLBCL groups., Discussion: Collectively, our results provide valuable insight regarding the role of HLA variations on DLBCL risk. Further studies are required to consolidate our findings and ascertain the clinical implications of these genetic variations on DLBCL management and prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Diamanti, Fylaktou, Verrou, Vlachaki, Sinakos, Katodritou, Ouranos, Minti and Gioula.)

The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara-Ixa-dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide-based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow-up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second-line treatment with Dara-Ixa-dex in patients with RRMM pre-treated with a lenalidomide-based regimen resulted in rapid responses along with a favorable effect on bone metabolism., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Competing Interests: ET is a HemaSphere Editor. The authors have no conflicts of interest to disclose.

We evaluated the efficacy and prognostic impact of bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) versus previous anti-myeloma therapies, that is, bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria, that is, circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86) out of 3324 myeloma patients (3%), registered in our database between 2001 and 2021, were studied; 37% had cPCS 5%-19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective responses. Treatment with VRd/DBQ strongly correlated with a higher complete response rate (41% vs. 17%; p = .008). After a median follow-up of 51 months (95% CI: 45-56), 67 patients died. Early mortality was 3.5%. Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ versus BSC/CT (25 months, 95% CI: 13.5-36.5 vs. 13 months 95% CI: 9-16.8; p = .03). Median overall survival (OS) was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ versus BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p < .001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/μL, independently predicted OS (p < .05). Our study has demonstrated that in the real-world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL., (© 2023 Wiley Periodicals LLC.)

During the COVID-19 pandemic, different SARS-CoV-2 variants of concern (VOC) with specific characteristics have emerged and spread worldwide. At the same time, clinicians routinely evaluate the results of certain blood tests upon patient admission as well as during hospitalization to assess disease severity and the overall patient status. In the present study, we searched for significant cell blood count and biomarker differences among patients affected with the Alpha, Delta and Omicron VOCs at admission. Data from 330 patients were retrieved regarding age, gender, VOC, cell blood count results (WBC, Neut%, Lymph%, Ig%, PLT), common biomarkers (D-dimers, urea, creatinine, SGOT, SGPT, CRP, IL-6, suPAR), ICU admission and death. Statistical analyses were performed using ANOVA, the Kruskal-Wallis test, two-way ANOVA, Chi-square, T-test, the Mann-Whitney test and logistic regression was performed where appropriate using SPSS v.28 and STATA 14. Age and VOC were significantly associated with hospitalization, whereas significant differences among VOC groups were found for WBC, PLT, Neut%, IL-6, creatinine, CRP, D-dimers and suPAR. Our analyses showed that throughout the current pandemic, not only the SARS-CoV-2 VOCs but also the laboratory parameters that are used to evaluate the patient's status at admission are subject to changes.

Background: Carfilzomib, an irreversible proteasome inhibitor approved for the treatment of relapsed/refractory Multiple Myeloma (MM) has been associated with Thrombotic Microangiopathy (TMA). Several pathogenetic mechanisms of carfilzomib-induced TMA have been proposed; however, recently, there has been a shift of focus on the potential contribution of complement dysregulation. Our aim was to explore whether patients with carfilzomib-induced TMA harbor germline variants of complement-related genes, which have been characterized as risk factors for TMA., Methods: We retrospectively recruited consecutive MM patients with carfilzomib-induced TMA and compared them to MM patients who received ≥4 cycles of carfilzomib and did not develop signs/symptoms of TMA, in a 1:2 ratio. Genomic DNA from peripheral blood was analyzed using next generation sequencing (NGS) with a complement-related gene panel; ADAMTS13 activity and soluble C5b-9 were measured using ELISA., Results: Complement-related variants were more common in patients with carfilzomib-induced TMA compared to non-TMA controls, regardless of patient and treatment characteristics; ADAMTS13 activity and C5b-9 were compatible with the phenotype of complement-related TMA., Conclusions: We confirmed the previous findings that implicated complement-related genes in the pathogenesis of carfilzomib-induced TMA. Most importantly, by incorporating a control group of non-TMA MM patients treated with carfilzomib-based regimens and functional complement assays, we enhanced the credibility of our findings.