Anastasia Kopsaftopoulou

Background/Objectives: Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL) affect young women, with cure rates exceeding 80%. Treatment-related gonadal insufficiency is recognized for its impact on fertility, yet fertility preservation remains underutilized, and prospective data are limited. The aim of this study is to prospectively evaluate gonadal function in women ≤40 years old with lymphoma undergoing chemotherapy. Methods: Ovarian reserve and endocrine ovarian function were evaluated by sequential measurements of follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), progesterone, and estradiol at diagnosis, during, and after chemotherapy. Results: 81 female patients ≤40 years old were enrolled, including 53 with HL and 28 with NHL (16 with PMBCL). HL patients had significantly lower AMH values for their respective age group compared to all other diagnoses (p = 0.05), which was more striking for patients ≤30 years old (p = 0.039), indicating pre-existing reduced ovarian reserve in HL. In HL, both FSH and AMH levels indicate gonadal dysfunction for at least six months post-chemotherapy, with AMH serving as a more sensitive biomarker than FSH. For PMBCL patients treated with R-DA-EPOCH, AMH suppression was noticed, with no evidence of recovery up to 18 months post-treatment. At all time points, the PMBCL patients had significantly lower AMH values compared to the HL patients (AMH6: p = 0.03, AMH12 and AMH18: p = 0.05). AMH emerged as the most sensitive marker of ovarian damage, with pretreatment levels <7 pmol/L predicting impaired ovarian reserve in HL patients. Conclusions: For HL, the pretreatment cut-off of 7 pmol/L could discriminate patients with ovarian insufficiency post-treatment, whereas no statistically significant predictive association was identified in PMBCL. These findings require validation in larger cohorts.

The prognostic value of NPM1 ‐mut Measurable Residual Disease (MRD) has been increasingly recognized. However, real‐world data validating the prognostic impact of NPM1 ‐mut MRD remains limited. The aim of this study was to assess the prognostic value of NPM1 ‐mut MRD and to explore optimal MRD thresholds for relapse prediction. One hundred forty‐one patients with newly diagnosed NPM1 ‐mut AML, from the Hellenic AML‐Registry, in CR/CRi after the second cycle of induction and with bone marrow (BM) MRD assessment by RT‐qPCR, were included in our study. Allogeneic stem cell transplantation (allo‐SCT) in CR1 was not associated with any difference in RFS or OS between patients who achieved < 0.1% mutNPM1/ABL after the second cycle of chemotherapy, suggesting that this cut‐off may effectively stratify relapse risk and possibly guide optimal use of allo‐SCT. End‐of‐treatment (EOT) and during follow‐up MRD assessment exhibited equally significant prognostic value, with high‐level MRD positivity (≥ 0.1% mutNPM1/ABL ) requiring early intervention to avoid imminent relapse, while those with undetectable or very low‐level MRD (< 0.01% mutNPM1/ABL ) being able to be safely monitored with no further intervention. Patients with low‐level MRD positivity (≥ 0.01% and < 0.1%) require close MRD monitoring due to the substantial risk for progression to high‐level MRD positivity. Overall, our results confirm the prognostic value of MRD assessment in BM samples at certain time points, with the cut‐off of 0.1% after two cycles of chemotherapy enabling risk stratification and possibly informing transplant decisions, and during follow‐up the cut‐off of 0.01% being able to predict the 6‐month relapse risk and guide further clinical management.

Background/Objectives: The National Cancer Institute introduced the intensified R-da-EPOCH regimen in primary mediastinal large B-cell lymphoma (PMLBCL) to improve outcomes while minimizing radiotherapy use. However, there is no randomized comparison of R-da-EPOCH vs. R-CHOP-21. The objective of this study was to compare R-da-EPOCH with R-CHOP-21 in consecutive patients with PMLBCL of a single, large referral center, where the R-da-EPOCH escalation schedule was strictly followed. Methods: We retrospectively analyzed all 35 consecutive patients who received R-da-EPOCH (2017–2022) compared to 35 consecutive patients treated with R-CHOP-21 arm at the same Department, starting from the most recent patient and going backwards (2005–2017). Results: R-da-EPOCH was given strictly in 33/35 (94%) patients. The 5-year freedom from progression (FFP) was 91% vs. 69% (p = 0.027). The 5-year event-free survival (EFS) was 84% vs. 69% (p = 0.124). The 5-year overall survival (OS) was 97% vs. 80% (p = 0.063). Among R-CHOP-21-responders, 20/29 (69%) received RT compared to 2/34 (6%) R-da-EPOCH-responders. In multivariate analysis, R-da-EPOCH remained better than R-CHOP-21 in terms of FFP [hazard ratios (HRs) 0.21–0.26, all p < 0.05] and was associated with very favorable HR for EFS and OS. Conclusions: Optimally delivered R-da-EPOCH minimized the use of RT in a real-life setting and provided superior outcomes than R-CHOP-21.

Background/Objective: The prognostic impact of additional cytogenetic aberrations and molecular abnormalities (such as MDS-related mutations, mutations in myeloid genes and the KRAS/NRAS mutations) in patients with NPM1- and/or FLT3-ITD-mutated AML remains elusive. Methods: This retrospective, multicentre study of real-world data aimed to investigate the impact of these mutations and cytogenetic abnormalities on the prognosis of patients with NPM1- and/or FLT3-ITD-mutated AML, treated with intensive chemotherapy. Results: In a cohort of 161 patients, the only parameters identified to affect the outcomes (EFS and OS) were the age of the patient, primary refractory disease, the presence of a NPM1 mutation and the use of allogenic stem cell transplantation (allo-SCT) within the first complete remission. More specifically, ages below the median conferred significantly improved outcomes, whereas primary refractory disease exhibited a negative correlation with the EFS and OS. Subsequent subgroup analysis, stratifying patients into three groups (Group 1: NPM1^mutated/FLT3^wt; Group 2: NPM1^mutated/FLT3^mutated; Group 3: NPM1^wt/FLT3^mutated). revealed that allo-SCT in CR1 improved the outcomes (EFS and OS) in Groups 2 and 3, but had no additional impact in Group 1. Conclusions: Age, primary refractory disease and allogenic stem cell transplantation in the first complete response were found to have a prognostic impact on outcomes, Interestingly, no significant association was detected between the poor prognostic cytogenetic abnormalities or the presence of additional mutations in myeloid genes, MDS-related genes or KRAS/NRAS genes and the outcomes in any group of patients.

Data on antibody response (AR) after vaccination against SARS-CoV2 in hematopoietic stem-cell transplantation setting (HSCT) were initially scarce, mainly due to the exclusion of such patients from approval studies. Shortly after the worldwide application of vaccination against SARS-CoV-2 in vulnerable populations such as patients with hematologic malignancies, limited single-center trials, including HSCT patients, were published. However, there was a great heterogeneity between them regarding the type of underlying malignancy, co-current treatment, type of vaccine, method of AR measurement, and time point of AR measurement. Herein, we present the results of a prospective study on AR after vaccination for SARS-CoV-2 using the BNT162b2 vaccine in a cohort of 54 HSCT recipients—mostly autologous from a single Unit—along with a broad review of the current literature. In our cohort, the AR positivity rate at 1 month was 80.8% and remained positive in 85.7% of patients at 3 months after vaccination. There were only nine non-responders, who were more heavily pretreated and more frequently hypogammaglobulinemic compared to responders. High antibody titers (AT), [AT ≥ 1000 U/mL], were detected in 38.5% and 30.6% of the patients at m₁ and m₃, respectively. A significant decline in AT between m₁ and m₃ was demonstrated—p < 0.0001; median AT₁ and AT₃ were 480.5 and 293 U/mL, respectively. A novel finding of our study was the negative impact of IgA hypogammaglobulinemia on response to vaccination. Other negative significant factors were treatment with anti-CD20 antibody at vaccination and vaccination within 18 months from HSCT. Our data indicate that HSCT recipients elicit a positive response to the BNT162b2 vaccine against SARS-CoV-2 when vaccinated at 6 months post-transplant, and vaccination should be offered to this patient population even within the post-pandemic COVID-19 era.

The significance of serum beta-2 microglobulin (sβ₂m) in Hodgkin lymphoma (HL) is controversial. We analyzed 915 patients with HL, who were treated with ABVD or equivalent regimens with or without radiotherapy. Sβ₂m levels were measured by a radioimmunoassay (upper normal limit 2.4 mg/L). Sequential cutoffs (1.8–3.0 by 0.1 mg/L increments, 3.5 and 4.0 mg/L) were tested along with ROC analysis. The median sβ₂m levels were 2.20 mg/L and were elevated (>2.4 mg/L) in 383/915 patients (41.9%). Higher sβ₂m was associated with inferior freedom from progression (FFP) at all tested cutoffs. The best cutoff was 2.0 mg/L (10-year FFP 83% vs. 70%, p = 0.001), which performed better than the 2.4 mg/L cutoff (“normal versus high”). In multivariate analysis, sβ₂m > 2.0 mg/L was an independent adverse prognostic factor in the whole patient population. In multivariate overall survival analysis, sβ₂m levels were predictive at 2.0 mg/L cutoff in the whole patient population and in advanced stages. Similarly, sβ₂m > 2.0 mg/L independently predicted inferior HL-specific survival in the whole patient population. Our data suggest that higher sβ₂m is an independent predictor of outcome in HL but the optimal cutoff lies within the normal limits (i.e., at 2.0 mg/L) in this predominantly young patient population, performing much better than a “normal versus high” cutoff set at 2.4 mg/L.