Discussion
Our retrospective study reports TLS incidence in a real-life cohort of
patients with advanced stage disease and aggressive histology of B-cell
lymphoma. The majority of patients (75%) exhibited a high IPI score,
which was associated with a low 2-year OS probability of 33% for the
cohort. We employed the well-established Cairo and Bishop criteria to
define LTLS [18], even though different algorithm management of TLS
were recently proposed [20]. Our study primarily included patients
classified as being at high risk for TLS occurrence, as per the defined
criteria [1]. Accordingly, a fractionated rituximab approach was
implemented as the initial strategy for TLS prevention in agreement with
the guidelines of our Institution. The overall occurrence of TLS in our
study was 7% including 1% CTLS and 6% LTLS, aligning with findings
from other reports [6,7, 20–27]. Notably, the occurrence of TLS had
no significant impact on overall survival.
In our study population, the prevalence of TLS was higher among BL
patients, constituting 57% of all TLS cases. Preliminary findings from
the EudraCT2013-004394-27 BL cohort (n=89) indicated a TLS
incidence of 2.3% (2/89) [19]. Conversely, the LMBA02 trial, which
included only 14% of patients aged 60 or above, did not report any
cases of TLS resulting in renal failure higher than grade 2 [28]. In
a cohort comprising 113 patients with BL who underwent treatment with
the DA-EPOCH-R regimen, the occurrence of TLS was documented at a rate
of 5% [23]. This observation is consistent with prior studies where
BL patients were included as subsets within diverse histological
subtypes [6,7, 24–27]. Within the smaller subset of BL patients in
our cohort (n=13), we observed no instances of CTLS but four cases of
LTLS. Indeed, the occurrence of LTLS is scarcely reported. A study
conducted on a cohort of 102 lymphoma patients documented an incidence
of 42% for LTLS and 6% for CTLS. Within this investigation, nine cases
of BL were observed, with six instances of LTLS and one case of CTLS,
which concurs with our own observation of frequent occurrences of LTLS
among BL patients [22]. Moreover, the TLS incidence in the subset of
DLBCL and HGBCL patients in our cohort was comparable to an
international dataset of DLBCL patients treated with DA-EPOCH-R or
R-CHOP [21]. Notably, only 40% of the patients included in this
comparative dataset had a high IPI score, as compared to 74% in the
current cohort. These findings imply that employing fractionated
rituximab as an initial debulking strategy resulted in a low incidence
of TLS, similar to the observations made in other cohorts consisting of
younger patients with less advanced-stage lymphoma.
The standardization of approaches for preventing TLS remains a
challenge. A recent Cochrane review highlighted the effectiveness of
urate-lowering agents in normalizing uric acid levels, but their impact
on renal failure and mortality remains uncertain [29]. Within our
study, 26% of patients received rasburicase, and it was observed that
the occurrence of TLS was higher in this subset. This was indicative of
an exceptional risk for TLS development within this subset, as the
administration of rasburicase was not mandatory but based on the
individual patient TLS risk score in our study. This underscores that
urate-lowering agents are just one component of the comprehensive TLS
management strategy. Notably, tumor-debulking approaches are
concurrently employed. A \soutprophase pre-phase regimen administered
before the initial cycle of immuno-chemotherapy, commonly utilizing
steroids alone or in combination with vincristine or cyclophosphamide,
is widely employed in acute lymphoblastic leukemia and high-risk B-cell
lymphoma [7, 24][31–34]. This strategy has demonstrated
efficacy in reducing TLS and therapy-related mortality [27, 28,
31–36]. In our cohort, the majority of patients (82%) received a
steroid pre-phase, which may have contributed to the observed low
incidence of TLS following subsequent administration of fractionated
rituximab. These results underscore the importance of implementing a
comprehensive strategy for managing TLS in patients with high-risk
B-cell lymphoma.
To the best of our knowledge, our real-life study represents a
pioneering investigation into the potential of fractionated rituximab as
a preemptive strategy for reducing the occurrence of TLS. Our findings
indicate that implementing a comprehensive approach involving
urate-lowering agents, a steroid pre-phase, and fractionated rituximab
tailored to individual patient risk profiles could result in a minimal
incidence of CTLS in high-risk B-cell lymphoma patients. Furthermore,
the question of fractionating the dosage of anti-CD20 agents to not only
mitigate TLS but also address infusion-related side effects such as
cytokine release syndrome is of particular importance in the current era
of novel targeted therapies and T-cell engager therapies. Indeed, the
use of anti-CD20 pre-phase regimens becomes imperative when utilizing
novel anti-CD20/CD3 bispecific engagers like glofitamab [40]. In
summary, our findings suggest that the fractionation of the initial
rituximab dose holds promise as a valuable strategy to mitigate the
risks of both TLS and IRR in B-cell malignancies characterized by a
significant tumor burden. These results highlight the need for further
investigations through large-scale prospective studies.