T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of STAT3 are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of STAT3/STAT5B, treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8⁺CD57⁺ group. Remarkably, patients included in the CD4⁺ group had a higher association with solid tumors (p = 0.037). STAT3 mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying STAT3 mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment (p = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of STAT3. We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of STAT3, and for the first time analyzes survival compared to a matched general Spanish population.

We analyzed 171 patients with asymptomatic IgM monoclonal gammopathies (64 with IgM monoclonal gammopathy of undetermined significance—MGUS and 107 with smoldering Waldenström macroglobulinemia - SWM) who had a bone marrow (BM) evaluation performed at diagnosis. Abnormal free-light chain ratio (53% vs. 31%) and MYD88 mutation prevalence (66% vs. 30%) were higher in patients with SWM. No other differences were found among groups. With a median follow-up of 4.3 years, 14 patients progressed to Waldenström macroglobulinemia, 1 to amyloidosis, and 28 died without progression. The MYD88 mutation was found in 53% of patients (available in 160 patients). Multivariate analysis showed that immunoparesis (subhazard ratio—SHR 10.2, 95% confidence interval—CI: 4.2–24.8; p < 0.001) and BM lymphoplasmacytic infiltration ≥ 20% (SHR: 6, 95% CI: 1.6–22.1; p = 0.007) were associated with higher risk of progression. We developed a risk model based on these two risk factors. In the absence of both variables, an ultra-low risk group was identified (SHR 0.1, 95% CI 0.02–0.5; p = 0.004), with 3% and 6% of cumulative incidence of progression at 10 and 20 years, respectively. Bootstrap analysis confirmed the reproducibility of these results. This study finds immunoparesis and BM infiltration as biomarkers of progression as well as a low-risk group of progression in asymptomatic IgM monoclonal gammopathies.

Background: Follicular lymphoma (FL) is the second most common B-cell lymphoma in Western countries, typically presenting as an indolent disease with prolonged overall survival. Despite favorable initial responses to therapy, most patients experience relapse, and early progression is associated with poor outcomes. Methods: This guideline provides evidence-based recommendations from the Spanish GELTAMO group on the diagnosis, staging, treatment, and follow-up of FL. A systematic literature review was conducted, and recommendations were graded according to the GRADE system. Results: Histopathological diagnosis should be based on excisional biopsy. PET-CT is recommended for staging and response evaluation. For localized disease, involved-site radiotherapy (ISRT) remains the treatment of choice. In asymptomatic patients with advanced-stage disease and low tumor burden, a watch-and-wait approach is appropriate, although rituximab monotherapy is also acceptable. For advanced-stage disease with high tumor burden, immunochemotherapy with anti-CD20 antibodies (rituximab or obinutuzumab) combined with CHOP, CVP, or bendamustine is recommended, followed by maintenance therapy. Management of relapsed disease is tailored based on tumor burden, treatment history, and timing of relapse. Although novel immunotherapies (CAR-T therapy and bispecific antibodies) are emerging as promising options, autologous stem cell therapies may still be a valid option in young patients with early relapse who are sensitive to immunochemotherapy. Conclusions: FL is a heterogeneous disease requiring individualized management strategies. Recent advances in immunotherapy and molecular diagnostics are reshaping the therapeutic landscape. These updated GELTAMO recommendations aim to provide practical guidance for optimal FL management in clinical practice.

Lysinuric protein intolerance (LPI) is a rare inborn error of metabolism (IEM), classified as an inherited aminoaciduria, caused by mutations in the SLC7A7 gene, leading to a defective cationic amino acid transport. The metabolic adaptations to the demands of pregnancy and delivery cause significant physiological stress, so those patients affected by IEM are at greater risk of decompensation. A 28-year-old woman with LPI had experienced 3 early miscarriages. While pregnancy was finally achieved, diverse nutritional and medical challenges emerged (food aversion, intrauterine growth restriction, bleeding risk, and preeclampsia suspicion), which put both the mother and the fetus at risk. Moreover, the patient requested a natural childbirth (epidural-free, delayed cord clamping). Although the existence of multiple safety concerns rejected this approach at first, the application of novel strategies made a successful delivery possible. This case reinforces that the woman’s wish for a non-medicated, low-intervention natural birth should not be automatically discouraged because of an underlying complex metabolic condition. Achieving a successful pregnancy is conceivable thanks to the cooperation of interdisciplinary teams, but it is still important to consider the risks beforehand in order to be prepared for possible additional complications.