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the right therapy, for the right patient. How do we reach this very appealing but also difficult target?

First, we must consider that the milestone of the heterogeneity concept lies in the possibility of having
representative samples of every single patient, collected in the diagnostic moment. These samples should be
able to show not only which different biological pathways are activated in that patient but also what
potential role they play in favoring the development of the disease. Since performing different biopsies of
different disease sites is hardly ever possible, we think that efforts should be made to improve diagnosis
through CTCs and cfDNA. By improving these techniques, we will be able to obtain large amounts of
information with a noninvasive sample of peripheral blood.

Second, we encourage clinical trials where targeted therapies are used up-front. Only in this way, we can
compare the newer and often less toxic molecules to the older chemotherapy schemes that still represent the
basis of FL initial therapy. Ideally, if we could promptly and reliably identify the patients who are more
likely to be POD24-positive, we could design appropriate frontline treatment strategies that minimize the
risk of early relapse.

Another extremely relevant matter is how to define the most appropriate succession of treatments, given all
of the innovative agents that are available nowadays, in order to obtain the best possible results from each of
them without exposing patients to unnecessary toxicity.

Ongoing clinical experience with PI3Ki, for instance, has unveiled their scarce manageability, particularly
when compared to newer agents such as tazemetostat, together with unsatisfactory response rates compared
to immunotherapies such as BsAbs and CAR T-cells.

BsAbs, differently from autologous CAR T-cells, are “off-the-shelf” products, and therefore a potentially
more convenient choice for symptomatic patients who would have trouble waiting for the manufacturing
process of CAR T-cells to be completed. Moreover, the absence of lymphodepleting chemotherapy and their
favorable safety profile make them a more promising option for older or unfit patients. The association
between BsAb and other target agents, such as lenalidomide or the anti-CD79b antibody-drug conjugated,
polatuzumab vedotin (NCT05169658, NCT03671018, and NCT03533283), shows promising results in B-
[107]
cell NHL, also in those who failed CAR T-cell treatment.

Consequently, in the near future, third-line therapy of FL could be dominated by CAR T-cells, whenever
possible to use them depending on the characteristics of the disease (aggressiveness, CD19 antigen
expression), and BsAbs, which could become the option of choice in symptomatic, older, or unfit patients
not suitable for chemotherapy conditioning or who cannot wait for the T-cell manufacturing procedures.

Randomized trials comparing HDT and ASCT with immunotherapies (CAR T-cells and BsAbs) could also
help clarify the actual role of transplantation in FL patients at first relapse, which would be especially
relevant for POD24-positive patients who are at the highest risk of being chemoresistant.

To conclude, even if for now it is probably still a dream, the hope for the future is to build new diagnostic
strategies capable of identifying the right therapeutic choice for every single patient. In this way, hopefully,
we will be able to spare the less effective therapies for that single patient a priori. Moreover, by using only
targeted therapies, we will also avoid chemotherapy’s intolerable traditional side effects.