Central Nervous System Involvement in Aggressive ATLL: Can We Predict the Risk in a Devastating Complication? Epidemiology and Clinical Features from Latin America. a Collaborative Study from Grupo De Estudio Latino-Americano De Linfoproliferativo (GELL) & T-Cell Brazil Project (TCBP)
Authors: Zing Natalia Pin Chuen , Fischer Thais , Miranda Eliana , Dias Maria Almeida , Gonzaga Yung , Baptista Renata Lyrio R , Amarante Guilherme D , Schaffel Rony , Nogueira Frederico Lisboa , Bortucchi Davimar , Santucci Rodrigo , Brasil Sergio , Cecyn Karin Z , Figueiredo Vera , Castro Nelson S , Rabelo Yana S , Silva Gilnara Fontinele , Hallack Neto Abrahão Elias , Giacon Patricia , Matedi Milene , Cle Diego Vila , Pereira Juliana , Barroso Fernando , Souza Renata R , Quintero Henry , Castro Denisse , Beltran Brady E , Enriquez Daniel J , Vasquez Jule F , Roche Claudia , Artiles Daniel , Valverte Fabiola , Villela Luis Mario , Oliver Ana Carolina , Korin Laura , Roa Macarena , Peña Camila , Torres Viera Maria Alejandra , Von Glasenapp Alana , Quiroz Alfredo , Samanez-Figari Cesar , Rios Jimenez Rosa Oliday , Paredes Sally , Edelman Saul Eduardo , Bermack Casey , Meza Kelly , Valcarcel Bryan , De Souza Carmino , Malpica Luis , Chiattone Carlos 
Published: December 2024

Introduction
Adult T-cell leukemia/lymphoma (ATLL) is a mature, peripheral T-cell neoplasm caused by HTLV-1. The cumulative lifetime risk of developing ATLL is estimated as 4-7% among HTLV-1 carriers. Four subtypes have been described using the Shimoyama criteria: acute, lymphomatous, chronic, and smoldering. Acute and lymphoma subtypes are highly aggressive diseases and carry a dismal prognosis, characterized by shorter survival rates and a high risk of central nervous system involvement (iCNS) compared to other peripheral T-cell lymphomas. Currently, the treatment of ATLL remains challenging, lacking a universally accepted standard of care. Our recent study on PTCL epidemiology and outcomes in Latin America (Thais et al 2023 ASH Meeting) highlighted ATLL (18%) as the second most frequent subtype of PTCL, likely influenced by our distinct viral epidemiology.
Objective
The objective of the present study is to assess the prevalence, clinical features, risk factors, and outcomes of iCNS in ATLL in Latin America.
Methodology
We compiled data of patients aged ≥18 years with newly diagnosed ATLL from the retrospective registry of the GELL (n=208, 2000-2023, retrospective) and TCBP (n=83, 2015-2022, ambispective). Clinical information included coded patient and site identifiers, gender, age, date of diagnosis, sites of disease including extranodal presentation (location and number) and Ann Arbor stage. Initial therapy response; follow-up (remission, progression or relapse); subsequent therapies and outcomes were also recorded. Our primary endpoints were overall survival (OS) and progression-free survival (PFS). REDcap Platform (by Vanderbilt) was used to collect and store data and for descriptive analysis the IBM-SPSS version 24 was applied. Kaplan-Meier method estimated the OS, whereas Log-Rank tests to compare its curves. This trial is registered at Clinical trials (NCT03207789).
Results
We enrolled 291 patients. In this exploratory analysis the prevalence of iCNS in ATLL was 7.9% (23/291), considering only aggressive forms (acute- 40% and 60%-lymphomatous). Patients' characteristics were similar between those without and with iCNS. There was a high frequency of advanced stage (90% vs 82%); ECOG ≥ 2 (45% vs 43%); B symptoms (74% vs 56%); elevated LDH (84% vs 78%); and IPI ≥3 (82% vs 65%) in the iCNS group. Considering the inclusion of both aggressive subtypes, treatment was heterogeneous including: IFN+AZT (74%) - for acute subtypes, and CHOP (52%), CHOEP (26%) and EPOCH (2%), for lymphoma subtypes. Less than 30% of patients with and without iCNS achieved complete response at end of first treatment. Two clinical features were identified as possibly associated to iCNS: median age at diagnosis (55 [20-95] vs 44 [23-65]; p&lt;0.0001) and extra nodal involvement ≥ 2 (32% vs. 65%, p=0.005).
We reassure the dismal outcomes in the entire cohort of ATLL with 60 months OS and PFS of 16% [95% CI: 12-20%] and 9% [95% CI: 5-13%], respectively; with median time of OS and PFS of 7 months (6-9) and 5 months (4-6), respectively. iCNS did not have an impact on survival outcomes (60 months OS 14% iCNS (n=23) vs 16% no iCNS (n=254), p=0.91; PFS 12% vs 9% no iCNS, p=0.61;) despite being a devastating complication. Outcomes in patients with lymphoma subtypes were slightly better than acute (60 months OS 19% vs 10%, p&lt;0.0001; PFS 12% vs 5%, p&lt;0.0001, respectively).
Conclusion
Unlike other lymphoma subtypes, iCNS in ATLL does not appear to significantly impact outcomes. This paradoxical finding underscores the complexity of ATLL and may reflect the limitations of existing treatment options and the absence of standardized therapeutic protocols for this aggressive malignancy. The lack of significant survival difference, despite the severity of iCNS, points to an urgent need for innovative therapies and more effective treatment strategies. Our analysis identified median age at diagnosis and extranodal involvement as potential risk factors for iCNS, suggesting avenues for future prospective studies to further elucidate their role in disease progression. Given the high prevalence of ATLL in Latin America, there is a unique opportunity to advance our understanding of this disease through region-specific research. Collaborative efforts in this region could pave the way for breakthroughs in the management of ATLL and potentially offer insights applicable on a global scale.