Discussion
This study is the first to estimate and emphasize on the frequency
(12.5%) and the clinical utility of L-TGL determination at DLBCL
diagnosis using systematic SEP. We demonstrated that L-TGL has a strong
negative impact on the overall and infectious-related mortality rates.
The higher AG ratio in L-TGL than in H-TGL patients suggests that the
pronounced decrease in TGL levels and the associated clinical outcomes
in the L-TGL subgroup may be 1) first, independent of the other possible
associated unspecific causes and 2) second, mostly and directly related
to one of our two hypotheses: either a pre-existent but previously
undiagnosed PID on which DLBCL developed or an SID directly induced by
the DLBCL condition. Finally, for both hypotheses, considered alone or
in combination, the ability of a chemotherapy-induced SID to worsen, or
reveal a greater susceptibility to infections in L-TGL patients is
probable but remains unquantifiable in the context of the design of the
present study. Our population was close to what has been described in
France during this period of time, with a median age of 69 years,
representing 35 to 40% of patients with lymphoma.(23,24)
At DLBCL diagnosis SEP is not unanimously recommended according to the
international workgroup guidelines for malignant lymphoma(13–15),
however from the results in our study we propose SEP to be performed at
diagnosis. In our study, there were no significant differences between
the two subgroups regarding inflammatory parameters, as assessed using
CRP level, and albuminemia, suggesting that the decrease in TGL may not
be secondary to metabolic/inflammatory causes or to increased loss of
immunoglobulins but is probably directly related to low gamma-globulin
production. In the same manner, since neither the Ann Arbor staging
classification, IPI, nor the chemotherapy regimen were significantly
different between the two groups, the increase in the overall and
specific infection-related death rates may be attributed to the decrease
in TGL in L-TGL subgroup. We didn’t exclude neither Richter syndrome nor
associated CNS involvement DLBCL subtypes that could exhibited worst
malignant prognosis, because the first were identified only in H-TGL
subgroup and both subtypes didn’t show overall highest mortality rate in
this study. Therefore, we may consider that this study drew up an
overall picture of all subtypes of DLBCL. Moreover, showing that L-TGL
patients exhibited a lower survival rate than all other possible
subgroups of DLBCL, including patients who did not get a SEP at
diagnosis, we further confirmed the importance of TGL assessment.
The main limitations of this study include its retrospective design with
some missing data, including mainly immunoglobulin isotype levels,
absence of systematic and reliable assessment of previous infections,
and monitoring of TGL in the follow-up for the entire cohort.
Consequently, two main secondary objectives could not be reached in this
study: determination of an approach for eventual CVID diagnosis criteria
and a differentiation scheme for the two causes of L-TGL considered
herein, namely, primary or DLBCL-related secondary immunodeficiencies.
We assumed that combining analyses of both DLBCL and TGL outcomes under
chemotherapy should partially help to differentiate these two causes of
decrease in TGL for each patient. Indeed, complete or partial remission
of DLBCL and concomitant increase in TGL under chemotherapy would
support a DLBCL-related SID. Conversely, in cases of a lack of response
or early death, no conclusion could be drawn, since chemotherapy would
induce a further decrease in TGL for an unknown duration.
To conclude, while epidemiological data on lymphoma treatment strategies
are optimistic and have seen improvements in survival throughout the
years. This study, using a simple, widely and easily available
biological test, seems to show that L-TGL patient subgroup exhibits
worse prognosis with higher overall and infection-related mortality
risks than H-TGL subgroup. Therefore, this study argues for the need to
systematically perform at least SEP at lymphoma and especially at DLBCL
diagnosis and emphasizes on the need of further studies to confirm these
results especially in prospective studies: 1) to determine nosological
and prognostic distinctions between possible previously undiagnosed PIDs
and DLBCL-related SIDs using, for example, next-generation sequencing
methods to uncover molecular defects of humoral PIDs(22,25) and to
assess the timing of a possible TGL recovery after chemotherapy in
relation to lymphoma outcomes; 2) to assess the possible clinical
benefit of immunoglobulin supplementation for SIDs, or prophylactic
antibiotics, taking into account advances in chemotherapy and management
strategies in Onco-Haematology.