Radiation Therapy Oncology Group Research Articles

Background: Community-acquired respiratory viruses such as influenza (Flu), human metapneumovirus (hMPV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV) are leading causes of morbidity and mortality after hematopoietic cell transplant (HCT) or solid organ transplant (SOT). While these viruses may begin in the upper respiratory tract, ~50% of cases progress to the lower respiratory tract, potentially leading to more severe conditions such as pneumonia, bronchiolitis, bronchiolitis obliterans, and chronic lung allograft dysfunction. ALVR106 is an allogeneic, off-the-shelf, polyclonal, multi-respiratory virus T-cell therapy specific for Flu, hMPV, PIV, and RSV. ALVR106 is generated by exposing peripheral blood mononuclear cells to peptide mixtures followed by ex vivo expansion in presence of activating cytokines. The expanded T cells are Th1-polarized, polyfunctional, and selectively able to kill viral target cells. ALVR106 cells have not shown alloreactivity, attesting to their selectivity and safety for use in HCT or SOT. Methods: In this first-in-human, placebo (PBO)-controlled, dose-ranging trial, HCT or SOT recipients 17 years or older with upper or mild lower respiratory tract infections (URTI/LRTI) caused by Flu, hMPV, PIV, or RSV were randomized in a 3:1 ratio to receive ALVR106 or PBO. Four doses of ALVR106 ranging from 1 × 10 5 cells/kg to 2 × 10 6 cells/kg were planned to be given to 4 cohorts of 4 patients each. Patients receive up to 2 infusions of ALVR106 or PBO once every 14 days and will be followed for up to 1 year. The primary objective was safety as measured by treatment emergent adverse events (AEs), AEs of special interest (acute and chronic graft vs host disease (GvHD), cytokine release syndrome (CRS), infusion related reactions (IRR), and progressive dyspnea), and clinical laboratory abnormalities from baseline (BL) through 12 weeks after the last infusion. Secondary endpoints included evaluation of antiviral activity by qualitative PCR assay by nasal swab and a composite endpoint through D28 which included change from BL in Radiation Therapy Oncology Group Lung Toxicity Scale Grade and viral detection from nasal swab. Patients with an improvement in symptoms or undetectable virus were considered partial responders (PR); those with improved symptoms and undetectable virus were complete responders (CR), and those whose condition did not improve or worsen from BL were non-responders (NR). To assess functional T-cell immune reconstitution and frequency of circulating virus-specific T cells, IFN-g virus-specific ELISpot analysis was performed on serial blood samples over time. ELISpot results will be presented. Preliminary study results presented herein will be unblinded at the time of data presentation. Results: 16 patients were dosed: four in Cohorts (C) 1 and 2, five in C3, and three in C4. Table shows BL demographics, disease characteristics, and blinded results for safety and antiviral activity by composite endpoint. Cohorts 2, 3, and 4 had at least 1 patient with mild LRTI at BL, no patients in C1 had LRTI. All patients received at least 1 infusion. No patients with Flu were enrolled. In these blinded results, no differences were seen in rate or severity of AEs among cohorts. Four patients (25%) had AEs possibly related to treatment (ALVR106 or PBO); all were Grade 1 (mild) in severity. These related events were reported in 1 patient each: diarrhea, ear pressure, neutrophil count decrease, and 1 patient had pyrexia, cGvHD oral, and aGvHD skin. Eight patients (50%) had serious AEs (SAEs), none related to treatment. One patient (6%) in C3 had G2 progressive dyspnea not related to treatment. One patient (6%) in C1 had Grade I aGVHD skin and cGVHD oral; both were considered possibly related to treatment (ALVR106 or PBO). No patients had Grade II-IV aGVHD, cGVHD, IRR, or CRS. No clinically significant changes from BL or trends over time in lab abnormalities or vital signs were seen. At Day 28, all patients in C1 and C2 had undetectable respiratory virus via nasal swab, except 1 patient in C1 who missed D28 visit due to COVID-19; 4/5 (80%) in C3 were undetectable; and 2/3 (67%) in C4 were undetectable. Conclusion: In this ongoing trial-the first-in-human, double-blind, PBO-controlled trial of virus-specific T cell therapy in transplant recipients with respiratory infection-ALVR106 was safe and well tolerated, supporting its continued evaluation in HCT and SOT recipients.

Background Limited stage (stage I−II) disease is an uncommon presentation of mantle cell lymphoma (MCL), and its optimal management remains controversial. A British Columbia study (Leitch, Ann Oncol, 2003) and a Surveillance, Epidemiology and End Results (SEER) study (Murthy, Clin Lymphoma Myeloma Leuk, 2014) suggested the importance of radiotherapy (RT). A National Cancer Database (NCDB) study in the pre-BTK inhibitor (BTKi) era showed that chemotherapy (Chemo) plus RT (Chemo+RT) improved overall survival (OS) compared to Chemo or RT alone (Gill, Int J Radiat Oncol Biol Phys, 2015). However, a retrospective International Lymphoma Radiation Oncology Group study (Dabaja, Ann Oncol, 2017) reported comparable OS with Chemo+RT vs Chemo or RT alone. The potential differences in OS with different frontline therapy modalities may be modified by subsequent therapies for relapsed or refractory (R/R) disease. In this study, we used the NCDB data to analyze frontline treatment patterns and outcomes of limited stage MCL in the pre-BTKi vs BTKi eras. Methods The NCDB was queried to identify patients with stage I−II MCL diagnosed in 2004−2020. Because the first BTKi ibrutinib was approved by the FDA for R/R MCL in November 2013, we defined 2004−2013 as pre-BTKi era and 2014−2020 as BTKi era. Frontline treatment modalities were categorized to RT alone, Chemo alone, or Chemo+RT. Survival analysis was performed using the Kaplan-Meier method and the Cox proportional hazards model. Results Among 32,746 patients with newly diagnosed MCL in 2004−2020, 3,836 (11.7%) presented with stage I−II disease, with 2,428 having treatment information available. For patients diagnosed in the pre-BTKi era (n = 2005), 195 (9.7%) received RT alone, 1472 (73.4%) received Chemo alone, and 338 (16.9%) received Chemo+RT. For patients diagnosed in the BTKi era (n = 423), 45 (10.6%) received RT alone, 320 (75.7%) received Chemo alone, and 58 (13.7%) received Chemo+RT. Patients in the RT alone group were older (P &lt;0.001) and had more females (P &lt;0.001), but there were no statistically significant differences in Charlson-Deyo score, international prognostic index, or treating facility type (academic vs non-academic). For patients with stage I disease, in the pre-BTKi era, patients treated with Chemo+RT (n = 182) had improved OS compared to those treated with RT alone (n = 141) or Chemo alone (n = 647), with a 5-year OS of 75.4% vs 71.8% vs 61.4% (P &lt;0.001). Similar results were observed in the BTKi-era, with a 5-year OS of 83.6% vs 69.5% vs 62.9% (P &lt;0.001) for patients treated with Chemo+RT (n = 31), RT alone (n = 30), or Chemo alone (n = 130), respectively. After adjusting for age and sex, Chemo+RT was associated with improved OS compared to Chemo alone (pre-BTKi era, HR = 0.59, 95% CI = 0.46−0.75, P &lt;0.001; BTKi era, HR = 0.34, 95% CI = 0.14−0.79, P = 0.013), but not compared to RT alone (pre-BTKi era, HR = 0.62, 95% CI = 0.23−1.68, P = 0.343; BTKi era, HR = 0.77, 95% CI = 0.56−1.05, P = 0.10) (Figure 1A). For patients with stage II disease, in the pre-BTKi era, patients treated with Chemo+RT (n = 156) had improved OS compared to those treated with RT alone (n = 54) or Chemo alone (n = 825), with a 5-year OS of 70.0% vs 47.3% vs 58.4% (P &lt;0.001). In the BTKi-era, patients treated with Chemo+RT (n = 27) or RT alone (n = 15) both had improved OS compared to those treated with Chemo alone (n = 190), with a 5-year OS of 77.2% vs 78.8% vs 61.9% (P = 0.004) . After adjusting for age and sex, Chemo+RT was associated with improved OS compared to Chemo alone in BTKi era only (pre-BTKi era, HR = 0.85, 95% CI = 0.67−1.07, P = 0.165; BTKi era, HR = 0.49, 95% CI = 0.25−0.95, P = 0.034), but not compared to RT alone (pre-BTKi era, HR = 0.78, 95% CI = 0.53−1.13, P = 0.185; BTKi era, HR = 0.97, 95% CI = 0.35−2.67, P = 0.952) (Figure 1B). Conclusions Treatment pattern for limited stage MCL has not changed significantly from the pre-BTKi era to the BTKi era, with approximately 15% of patients receiving Chemo+RT, 10% RT alone and 75% Chemo alone. In the BTKi era, Chemo+RT appeared to be associated with better OS compared to Chemo alone but not compared to RT alone. Interpretation of the results requires caution because (1) patient numbers are small in Chemo+RT and RT alone groups, (2) longer follow-up may be needed, and (3) selection of therapy was not random, eg, patients receiving Chemo alone may have had higher disease burden such as bulky disease and/or non-contiguous stage II involvement but these details are not available in NCDB.

Radiation Therapy Oncology Group Research Articles

Articles published on Radiation Therapy Oncology Group

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Treatment Pattern and Survival Outcome of Limited Stage Mantle Cell Lymphoma: A National Cancer Database Analysis in Pre-BTK Inhibitor Vs BTK Inhibitor Era

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