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Evaluating patterns of care for early-stage low-grade follicular lymphoma in the rituximab era
Abstract
Radiotherapy (RT) utilization for early-stage, low-grade follicular lymphoma (FL) is low despite treatment guideline recommendations. We compare treatment trends for early-stage FL in the era of involved-site RT and rituximab. We identified 11,645 patients in the National Cancer Database (NCDB) with stage I–II, grade 1–2 nodal or extranodal FL diagnosed 2011–2017, with median follow-up of 44 months. From 2011 to 2017, RT utilization rates decreased from 33.4% to 22.4%, observation decreased from 65.3% to 49.7%, chemoimmunotherapy increased from 0.5% to 15.0%, immuno-monotherapy increased from 0.6% to 10.2%, and RT + systemic therapy increased from 0.6% to 2.5%. RT utilization remains low in the involved-site RT and rituximab era.
Follicular lymphoma is the most common indolent lymphoma accounting for approximately 20%-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Whilst outcomes are mostly favorable, the spectrum of clinical phenotypes includes high-risk groups with significantly inferior outcomes. This review discusses recent updates in risk stratification and treatment approaches from upfront treatment for limited and advanced stage follicular lymphoma to the growing options for relapsed, refractory disease with perspectives on how to approach this from a personalized lens. Notable gaps remain on how one can precisely and prospectively select optimal treatment for patients based on varying risks, with an anticipation that an increased understanding of the biology of these different phenotypes and increasing refinement of imaging- and biomarker-based tools will, in time, allow these gaps to be closed.
Between 1998 and 2009, a total of 295 patients (median age 58, 53% females) with newly diagnosed early-stage follicular lymphoma (FL) were managed at Memorial Sloan Kettering Cancer Center. Approximately half of patients (137, 46%) underwent initial observation and half (158, 54%) immediate treatment: radiation alone (n = 108), systemic treatment alone (n = 29), or combined modality treatment (n = 21). Median follow-up was 8.4 years (range 0.3–17.2), and 10-year overall survival (OS) was 87.2%. OS was similar between initially-observed and immediately-treated patients (hazard ratio [HR]: 1.25, 95% CI: 0.67–2.36, p = 0.49). For patients receiving radiation alone, 5-year OS was 98.0%. Patients selected for systemic therapy alone had high-risk baseline features and had shorter OS than patients treated with radiation alone (HR 3.38, 95% CI 1.29–8.86, p = 0.01). Combined modality treatment did not yield superior survival compared with radiation alone (P > 0.05) but was associated with better progression-free survival (HR 0.36, 95% CI 0.14–0.90, p = 0.03). The rate of transformation increased steadily over time and was 4.2% at 5 years and 10.8% at 10 years. This modern-era analysis rationalized the role of initial observation in patients with early-stage FL although patients receiving radiation therapy also demonstrate excellent outcome.
SARS‐CoV‐2 infection can cause severe pneumonia (COVID‐19). There is evidence that patients with comorbidities are at higher risk of a severe disease course. The role of immunosuppression in the disease course is not clear. In the present report, we first describe two cases of persisting SARS‐CoV‐2 viraemia with fatal outcome in patients after rituximab therapy.
Purpose:
Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era.
Patients and methods:
We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes.
Results:
Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis.
Conclusion:
Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.
To obtain a deeper understanding of poor responses to COVID-19 vaccination in patients with lymphoma, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies postvaccination, compared with 100% of controls. When evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible.
Significance:
In a large cohort of patients with B-cell lymphoma, time since anti-CD20 treatment was an independent predictor of neutralizing antibody response to COVID-19 vaccination. Comparing patients who received anti-CD20 treatment before or after vaccination, we demonstrate that vaccinating first can generate an antibody response that endures through anti-CD20-containing treatment. This article is highlighted in the In This Issue feature, p. 85.
Coronavirus disease 2019 (COVID-19) infection results in both acute mortality and persistent and/or recurrent disease in patients with hematologic malignancies, but the drivers of persistent infection in this population are unknown. We found that B-cell lymphomas were at particularly high risk for persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity. Further analysis of these patients identified discrete risk factors for initial disease severity compared with disease chronicity. Active therapy and diminished T-cell counts were drivers of acute mortality in COVID-19–infected patients with lymphoma. Conversely, B cell–depleting therapy was the primary driver of rehospitalization for COVID-19. In patients with persistent SARS-CoV-2 positivity, we observed high levels of viral entropy consistent with intrahost viral evolution, particularly in patients with impaired CD8+ T-cell immunity. These results suggest that persistent COVID-19 infection is likely to remain a risk in patients with impaired adaptive immunity and that additional therapeutic strategies are needed to enable viral clearance in this high-risk population.
Significance
We describe the largest cohort of persistent symptomatic COVID-19 infection in patients with lymphoid malignancies and identify B-cell depletion as the key immunologic driver of persistent infection. Furthermore, we demonstrate ongoing intrahost viral evolution in patients with persistent COVID-19 infection, particularly in patients with impaired CD8+ T-cell immunity.
This article is highlighted in the In This Issue feature, p. 1
Background
The optimal radiotherapy dose for indolent non-Hodgkin lymphoma is uncertain. We aimed to compare 24 Gy in 12 fractions (representing the standard of care) with 4 Gy in two fractions (low-dose radiation).
Methods
FoRT (Follicular Radiotherapy Trial) is a randomised, multicentre, phase 3, non-inferiority trial at 43 study centres in the UK. We enrolled patients (aged >18 years) with indolent non-Hodgkin lymphoma who had histological confirmation of follicular lymphoma or marginal zone lymphoma requiring radical or palliative radiotherapy. No limit on performance status was stipulated, and previous chemotherapy or radiotherapy to another site was permitted. Radiotherapy target sites were randomly allocated (1:1) either 24 Gy in 12 fractions or 4 Gy in two fractions using minimisation and stratified by histology, treatment intent, and study centre. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Patients, treating clinicians, and investigators were not masked to random assignments. The primary endpoint was time to local progression in the irradiated volume based on clinical and radiological evaluation and analysed on an intention-to-treat basis. The non-inferiority threshold aimed to exclude the chance that 4 Gy was more than 10% inferior to 24 Gy in terms of local control at 2 years (HR 1·37). Safety (in terms of adverse events) was analysed in patients who received any radiotherapy and who returned an adverse event form. FoRT is registered with ClinicalTrials.gov, NCT00310167, and the ISRCTN Registry, ISRCTN65687530, and this report represents the long-term follow-up.
Findings
Between April 7, 2006, and June 8, 2011, 614 target sites in 548 patients were randomly assigned either 24 Gy in 12 fractions (n=299) or 4 Gy in two fractions (n=315). At a median follow-up of 73·8 months (IQR 61·9–88·0), 117 local progression events were recorded, 27 in the 24 Gy group and 90 in the 4 Gy group. The 2-year local progression-free rate was 94·1% (95% CI 90·6–96·4) after 24 Gy and 79·8% (74·8–83·9) after 4 Gy; corresponding rates at 5 years were 89·9% (85·5–93·1) after 24 Gy and 70·4% (64·7–75·4) after 4 Gy (hazard ratio 3·46, 95% CI 2·25–5·33; p<0·0001). The difference at 2 years remains outside the non-inferiority margin of 10% at −13·0% (95% CI −21·7 to −6·9). The most common events at week 12 were alopecia (19 [7%] of 287 sites with 24 Gy vs six [2%] of 301 sites with 4 Gy), dry mouth (11 [4%] vs five [2%]), fatigue (seven [2%] vs five [2%]), mucositis (seven [2%] vs three [1%]), and pain (seven [2%] vs two [1%]). No treatment-related deaths were reported.
Interpretation
Our findings at 5 years show that the optimal radiotherapy dose for indolent lymphoma is 24 Gy in 12 fractions when durable local control is the aim of treatment.
Funding
Cancer Research UK.
Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.
6619
Background: Low-grade follicular lymphoma (FL) can present as localized stage I to II disease in up to one-third of patients. Upfront involved-site radiation therapy (RT) to 24-30Gy is the preferred first-line management strategy for these patients. However, the National LymphoCare Study found that less than one quarter of patients with early-stage, low-grade FL received upfront RT, while more than half received either chemoimmunotherapy or observation. Methods: We performed a cost-effectiveness analysis using a Markov state-transition model to simulate the progression of early-stage, low-grade FL in a cohort of 60-year-old men. The following first-line treatments were compared: RT, observation, rituximab induction (RI), rituximab and bendamustine (BR), and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Patients who relapsed received second-line therapies that were dependent on their first-line treatment: RT for RI and observation, RCHOP for RT and BR, and BR for RCHOP. Disease-progression probabilities and other model inputs were from published trials. Results: First-line RT followed by RCHOP for relapses had a quality-adjusted life expectancy (QALE) of 11.4 years, superior to first-line observation, RI, BR, and RCHOP strategies. First-line RT strongly dominated observation, BR, and RCHOP. Compared with RI, first-line RT resulted in an incremental cost-effectiveness ratio of $2,740 per quality-adjusted life year. The probability of dying from other causes, the probability of a complete response to RT, and the probability of relapse had the greatest impact on both cost and effectiveness expected values. Conclusions: In contrast to current practice patterns, first-line RT is the most effective upfront treatment for patients with early-stage, low-grade FL. Further, first-line RT paired with RCHOP for relapses is a cost-effective treatment paradigm, relative to other strategies. [Table: see text]