TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman’s disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman’s disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Background: Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin’s lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results. Methods: We designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen’s expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)). Results: We found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19⁻ relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen. Conclusions: Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.

Background: The majority of patients with acute promyelocytic leukemia (APL) manifest a specific chromosomal translocation t(15;17)(q22;q21), characterized by the fusion of RARA and PML genes. However, a proportion of APL cases are due to variant translocations, being t(11;17) (q23;q21) the most common amongst them. With the major exception of ZBTB16-RARA t(11;17) APL, these variant APL cases present similar morphological features as classic APL and are characterized by a lack of differentiation response to retinoids. Case summary: We describe the case of variant APL with the ZBTB16-RARA fusion gene, showing a distinct morphology of classical APL, characterized by crystalline intracytoplasmic inclusions in both peripheral blood (PB) and bone marrow (BM) patients’ blasts. Our patient was treated with two courses of intensive chemotherapy, initiating maintenance treatment with all-trans retinoic acid (ATRA) on day twenty-eight of the second course. Our patient achieved complete remission (CR) once the intensive chemotherapy was combined with ATRA.Conclusions: This is the second case described of APL with t(11;17) that showed crystalline intracytoplasmic inclusions. The finding of these morphological features may suggest the presence of a variant translocation with RARA, being that both cases described are related to the presence of t(11;17). Despite induction treatment with intensive chemotherapy that included a seven-day continuous treatment with cytarabine (200 mg/m²), plus daily idarubicin (12 mg/m²) during the first three days, our patient did not achieve complete remission (CR) until scheduled 3 + 7 regimen combined with ATRA treatment was established. This observation suggests that ATRA may be partially effective in some ZBTB16-RARA APLs.

T-cell lymphoblastic lymphoma is an uncommon lymphoid neoplasm in adults, although more frequent in children and teenagers, that often affects the mediastinum and bone marrow, requiring intensive chemotherapy protocols. Its prognosis is poor if a cure is not achieved with first-line treatments. We present a case report of a 19-year-old man diagnosed with this type of lymphoma due to significant respiratory distress and a mediastinal mass. He received treatment according to the hyper-CVAD regimen, with a complete metabolic response. However, seven months later a new mediastinal growth was observed, leading to salvage treatment with a combination of nelarabine and daratumumab. We observed not only refractoriness, but also leukemization, which prompted consideration of hematopoietic stem cell transplantation. Based on this case, we conducted a review of pharmacological treatment options for refractory or relapsed lymphoblastic lymphoma, as well as the role of radiotherapy in managing mediastinal disease. This case report highlights the limited evidence available regarding later-line treatments, with unusual reports regarding employing our combination of daratumumab and nelarabine, and emphasizes the importance of achieving cures in the first line of treatment.