Page 23 - 2022_01-Haematologica-web

Individualized first-line management of FL
ies of aggressive lymphoma whereas FL has a different disease biology and pattern of relapse. For post-induction PET-negative patients in first remission destined to have a long survival and for whom most relapses will occur after more than 3 years, the cumulative radiation exposure and the increase of life-time incidence of cancer attributable to radiation exposure66 do not argue for prolonged imag- ing surveillance, aside from considerations of increased expense and heightened anxiety. Thus, the limited value of surveillance imaging in detecting asymptomatic non- Hodgkin lymphoma relapse earlier, relative to symptom- driven investigations is now generally acknowledged even if not investigated in a randomized controlled man- ner.
A recent retrospective study analyzing the effect of sur- veillance imaging on relapse detection and OS concluded that the majority of relapses after first remission are ini- tially suggested by clinical signs and symptoms and relapse detection through routine surveillance imaging in asymptomatic patients carries no additional survival advantage over imaging in the case of clinical concerns.67 Although PET-CT is more sensitive than CT-scan for asymptomatic surveillance imaging in FL, it has a lower specificity compared to CT-scan, leading to invasive biopsies and heightening anxiety and cost burden. There is now evidence for recommendations limiting imaging surveillance to examinations that significantly change treatment and/or demonstrate prognostic value. Thus PET-CT at the end of induction and CT scanning every 6 months during the 2 years following induction therapy enable the detection of POD24 patients at risk of early FL- related death. After that, imaging investigations should be limited to confirmation of relapse in the presence of concerning clinical signs and symptoms. Molecular mon- itoring for minimal residual disease is not recommended outside of clinical trials.
Ongoing unmet needs in follicular lymphoma
The estimated prolonged survival of most patients diagnosed with FL in 2021 represents one of the greatest oncology advances in the new millennium. However, this advance is based primarily on the introduction of com- bined immunochemotherapy induction and maintenance and/or re-treatment with a failure to demonstrate superi- ority of a lenalidomide-rituximab “chemo-free” approach. While collaborative efforts have studied imaging and molecular markers of response, we still struggle to clearly identify at diagnosis the individual patient destined to have an inferior response for whom therapies used in relapse warrant testing in the first-line setting. With per- haps the future exception of EZH2 inhibitors, a greater understanding of the mutational landscape has not even- tuated in the hoped for precision medicine in FL. The bio- logical plausibility of efficacy of BCL-2 and BTK inhibitors has not translated into meaningful clinical ben- efit and the phophoinositidine-3 kinase inhibitors have remained firmly as therapies for later relapse. Rather, we are currently focused on the potential to harness the power of chimeric antigen receptor T cells and bi-specific antibody therapies in patients with multiply relapsed/refractory disease with hope that success with these cellular therapies will warrant their study in the management of early relapses. Our current focus on the
unmet need for the early progressing (POD24) population is appropriate. Patients who have remained event free for 24 months after immunochemotherapy have an age- and gender-matched survival comparable to that of the gener- al population.34 However, for such patients destined to have a “functional cure”, a clear unmet is the develop- ment of appropriate trial designs that move beyond PFS as the sole primary endpoint. Perhaps it is time to devel- op, in parallel, a composite health utility measure that incorporates both efficacy and toxicity of therapy for such patients with FL.
Impact of the SARS-CoV-2 pandemic on the care of patients with follicular lymphoma
Coronavirus disease 2019 (COVID-19) has become a global health problem. Despite the arrival of vaccines, SARS-CoV-2 infection disproportionately affects our patients. Those with hematologic malignancies are at higher risk of death from COVID-19.68 Indolent lym- phoma was an independent predictor of mortality (HR=2.19, 95%CI: 1.07-4.48) in a retrospective Italian study.69 Initial data support expectations that the rate of SARS-CoV-2 IgG seroconversion after vaccination is lower in patients receiving an anti-CD20 monoclonal antibody.70 The profound impact of rituximab was recent- ly highlighted in patients with chronic lymphocytic leukemia in whom none of 22 patients exposed to ritux- imab in the 12 months preceding vaccination responded to the mRNA vaccines.71 Circulating rituximab (and obin- utuzumab) is found 3 to 6 months after four weekly infu- sions of the monoclonal antibody and rituximab induces B-cell depletion72 which recovers 9 to 12 months after the last infusion.73 Treatment with bendamustine, which lowers the CD4+ T-lymphocyte count for several months starting as early as after one cycle,64 has also recently been suggested as a determinant of severe COVID-1974 and likely also jeopardizes post-vaccination immune respons- es. General recommendations for FL patients to continue wearing a face mask and maintain social distancing as well as vaccination of all close contacts remain important. For patients with FL not requiring immediate therapy, rit- uximab could be withheld at least until there is some con- fidence that the patients exhibit SARS-Cov-2 post-vacci- nation immunization, and that their contacts and the community as a whole have likewise received vaccina- tion. For symptomatic patients, vaccination could be attempted before treatment initiation for those able to wait at least 2 to 3 months. For patients requiring treat- ment, the greater immunosuppression, particularly T-cell depletion, associated with bendamustine suggests that this drug should be avoided. The question of mainte- nance antibody treatment is challenging since induction immunochemotherapy alone likely results in an inability of patients to become immunized for at least 1 year after the last infusion of the antibody. Maintenance therapy prolongs this problem by at least 2 years. In the COVID era the long-term PRIMA follow-up data warrant a closer look.2 While the median PFS of patients not receiving rit- uximab maintenance was only 4.1 years there was a median 9.3 years for time to next chemotherapy in this arm. In future years, booster vaccines, herd immunity and monoclonal antibody therapies for acute COVID-19 may make SAR-CoV-2 infection less of a threat, but vac-
haematologica | 2022; 107(1)
15