Central Nervous System Involvement Does Not Worsen Survival in Hematologic or Molecular Relapse of Adult Acute Lymphoblastic Leukemia Patients - Retrospective Analysis By the Czech Leukemia Study Group for Life (CELL)
Authors: Hrabovsky Stepan , Salek Cyril , Folber Frantisek , Horacek Jan M , Szotkowski Tomas , Koristek Zdenek , Lukas Jozef , Arpas Tomas , Bakesova Denisa , Cernan Martin , Bergerova Veronika , Sramek Jiri , Novak Jan , Doubek Michael 
Published: December 2024

Background
Intrathecal prophylaxis for central nervous system (CNS) relapse has been a standard part of adult acute lymphoblastic leukemia (ALL) treatment for years. However, the risk factors and outcomes associated with CNS relapses in adult ALL remain unclear, and there is no standardized treatment protocol for these patients. Given the rarity of CNS relapses, comprehensive data on this subject are lacking.
Methods
We conducted a retrospective analysis of risk factors and outcomes associated with CNS relapse in Czech adult ALL patients. Data were sourced from the ALL registry of the Czech Leukemia Study Group for Life (CELL), including patients from seven Czech and one Slovak hematology-oncology centers. All patients provided informed consent for data collection and scientific use.
Results
Data from 691 consecutive adult ALL patients diagnosed between May 2003 and June 2024 were available for the analysis. Thirty-three patients (4.8%) experienced thirty-seven CNS relapses. Of these, all but three cases (9.1%) were associated with concurrent bone marrow hematological (63.6%) or molecular (27.3%) relapse.
Increased white blood cell count (WBC) was identified as the only statistically significant independent risk factor for CNS relapse (median 35.0 (0.3-302) vs. 12.3 (0.3-830) ×109/L, p=0.05) in the time of diagnosis. Furthermore, no significant associations were found between CNS relapse rates and age, peripheral blasts percentage, CNS or other extramedullary infiltration, immunophenotype, aberrant cytogenetics, BCR::ABL1, or KMT2A-r in the time of diagnosis, although there was a trend towards higher CNS relapse rates in EGIL T-III (thymic/cortical) immunophenotype (5/45, 11.1% cases).
The type of initial therapy protocol (pediatric-inspired intensive, “adult-type” intensive, “adult-type” non-intensive, palliative) did not significantly influence CNS relapse rates (16/370, 4.3%; 5/116, 4.3%; 7/111, 6.3%; 3/53, 5.7%, respectively). Similarly, prophylactic neurocranium radiotherapy during induction did not significantly reduce CNS relapse rates compared to no radiotherapy (4/126, 3.2% vs. 25/524, 4.8%). Furthermore, neither allogeneic hematopoietic stem cell transplant (SCT), myeloablative conditioning, nor total body irradiation (TBI) reduced CNS relapse incidence (9/243, 3.7%; 7/192, 3.6%; 6/130, 4.6%, respectively).
Patients of this cohort experiencing a CNS-involved relapse were treated by a number of different intensive and non-intensive systemic immunochemotherapy regimens, intrathecal cytostatic drugs, monoclonal antibodies or radiotherapy. Survival analysis revealed comparable 5-year overall survival (OS) rates between patients with and without CNS involvement in the setting of hematologic (17.1% vs. 21.3%) or molecular (40.2% vs. 50.4%) bone marrow relapse. This trend persisted also in more consistent subgroup treated with the GMALL-based pediatric-inspired intensive protocol (N=369, 20.0% vs. 29.8%, 53.3% vs. 59.5%).
Conclusion
In concordance with other authors, increased WBC seems to be a consistent risk factor of subsequent CNS relapse in adult ALL. However, its practical utility is limited since it has previously been shown to be a risk factor for bone marrow relapse. Despite the relatively small sample size of our cohort, our findings suggest that CNS involvement in adult ALL relapse does not significantly impact overall survival, which is primarily influenced by the bone marrow tumor burden, i.e. molecular or hematologic relapse. Further validation of these findings in larger cohorts is warranted.