Evidence for external beam radiotherapy in mediastinal Hodgkin and non-Hodgkin lymphoma - systematic review.

INTRODUCTION AND OBJECTIVE: Proton beam therapy (PBT) provides the opportunity for a more localized delivery of high energy protons and may reduce the damage to healthy tissues and vital organs. The aim of this review was to assess the effects of proton therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma treated with mediastinal irradiation. REVIEW METHODS: A systematic search of EMBASE, MEDLINE via OVID and Cochrane Library was conducted in May 2022 according to PRISMA guidelines to identify relevant data on the efficacy and toxicity of proton beam therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: Of 566 screened abstracts (430 after de-duplication) 11 studies with a total of 529 patients were included. All studies were case series published between 2011-2021. Median range of follow-up time was 15-63.6 months. The overall survival (OS) for 2 years varied from 91% - 98% for 5 of the included studies. Three of the included studies had favourable outcomes with 2-year progression-free survival (PFS) ranging from 73% - 94%. Skin reaction, oesophagitis and fatigue were found to be the most common grade 1 and grade 2 toxicities. No acute or late grade 4 and higher toxicities/adverse events were observed. SUMMARY: There are data indicating that PBT may to be an effective treatment against mediastinal Hodgkin and non-Hodgkin lymphoma. Because all the studies were case series, the authors of this review have little confidence in the evidence. There remains a need for well-designed randomized controlled trials to inform about the optimal approach to proton irradiation in HL and NHL.

Prediction model of radiotherapy outcome for Ocular Adnexal Lymphoma using informative features selected by chemometric algorithms.

BACKGROUND: Ocular Adnexal Lymphoma (OAL) is a non-Hodgkin's lymphoma that most often appears in the tissues near the eye, and radiotherapy is the currently preferred treatment. There has been a controversy regarding the prognostic factors for systemic failure of OAL radiotherapy, the thorough evaluation prior to receiving radiotherapy is highly recommended to better the patient's prognosis and minimize the likelihood of any adverse effects. PURPOSE: To investigate the risk factors that contribute to incomplete remission in OAL radiotherapy and to establish a hybrid model for predicting the radiotherapy outcomes in OAL patients. METHODS: A retrospective chart review was performed for 87 consecutive patients with OAL who received radiotherapy between Feb 2011 and August 2022 in our center. Seven image features, derived from MRI sequences, were integrated with 122 clinical features to form comprehensive patient feature sets. Chemometric algorithms were then employed to distill highly informative features from these sets. Based on these refined features, SVM and XGBoost classifiers were performed to classify the effect of radiotherapy. RESULTS: The clinical records of from 87 OAL patients (median age: 60 months, IQR: 52-68 months; 62.1% male) treated with radiotherapy were reviewed. Analysis of Lasso (AUC = 0.75, 95% CI: 0.72-0.77) and Random Forest (AUC = 0.67, 95% CI: 0.62-0.70) algorithms revealed four potential features, resulting in an intersection AUC of 0.80 (95% CI: 0.75-0.82). Logistic Regression (AUC = 0.75, 95% CI: 0.72-0.77) identified two features. Furthermore, the integration of chemometric methods such as CARS (AUC = 0.66, 95% CI: 0.62-0.72), UVE (AUC = 0.71, 95% CI: 0.66-0.75), and GA (AUC = 0.65, 95% CI: 0.60-0.69) highlighted six features in total, with an intersection AUC of 0.82 (95% CI: 0.78-0.83). These features included enophthalmos, diplopia, tenderness, elevated ALT count, HBsAg positivity, and CD43 positivity in immunohistochemical tests. CONCLUSION: The findings suggest the effectiveness of chemometric algorithms in pinpointing OAL risk factors, and the prediction model we proposed shows promise in helping clinicians identify OAL patients likely to achieve complete remission via radiotherapy. Notably, patients with a history of exophthalmos, diplopia, tenderness, elevated ALT levels, HBsAg positivity, and CD43 positivity are less likely to attain complete remission after radiotherapy. These insights offer more targeted management strategies for OAL patients. The developed model is accessible online at: https://lzz.testop.top/.

A Systematic Review of Clinical Applications of Anti-CD20 Radioimmunotherapy for Lymphoma.

PURPOSE: The clinical efficacy of anti-CD20 radioimmunotherapy (RIT) is due to a combination of extracellular mechanisms involving immune-mediated cytotoxicity, and intracellular mechanisms related to inhibition of CD20 signaling and DNA damage from ionizing radiation. In 2002, the first RIT was approved by the U.S. Food and Drug Administration for the treatment of patients with indolent B-cell follicular non-Hodgkin lymphoma (NHL). The 2 approved agents, 90 Y-ibritumomab tiuxetan (90Y-IT, Zevalin, Acrotech Biopharma) and 131 I-tositumomab (131-IT, Bexxar, GlaxoSmithKline) both target CD20. The aim of this study was to review the clinical applications and supporting clinical trial data of anti-CD20 RIT for lymphoma. METHODS: A review of published articles and abstracts on the clinical efficacy and safety of 90Y-IT and iodine I 131 tositumomab was performed. RESULTS: The clinical efficacy and safety of anti-CD20 RIT have been demonstrated in numerous clinical trials and case series. Agents have produced significant responses in patients with follicular NHLs and in off-label applications. Importantly, RIT has demonstrated promising findings in high-risk lymphomas and heavily pretreated and refractory patient populations. Associated toxicity profiles are noted as tolerable, acceptable, and most often reversible. CONCLUSIONS: In the 2 decades since its approval, anti-CD20 RIT continues to demonstrate efficacy, particularly with a proportion of patients maintaining long-term remissions. The combination of prolonged efficacy, tolerability, and treatment convenience makes RIT a reasonable alternative to other systemic therapies. It is recommended that further research on RIT should focus on biomarkers of long-term response, pretargeting, and sequencing of RIT in the treatment course.

Incorporating radiation with anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory non-Hodgkin lymphoma: A multicenter consensus approach.

Anti-CD19 chimeric antigen receptor T-cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B-cell non-Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life-threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre-existing sites of disease present pre-CART. Radiation therapy stands as a promising peri-CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease-free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post-CART disease alters the pattern of relapse and improves local recurrence-free and progression-free survivals. Salvage radiotherapy for relapsed post-CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri-CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART.

Is oligometastatic disease an applicable and useful concept in haematologic malignancies? A narrative review of radiation therapy standards, modern techniques, and innovations.

PURPOSE: Haematologic malignancies are particular in that they can generally be cured, even when distant metastases are present at diagnosis, unlike solid malignancies. Systemic treatments, including chemotherapy, targeted therapies, and immunotherapy, are the standard of care with excellent results. The considerable progress made in the management of these diseases in the last 20years has redefined the role of radiation therapy as minor in many clinical situations. We propose a literature review of data, showing that radiation therapy still has a role in curative, salvage, and palliative therapy situations. MATERIAL AND METHODS: A document and literature search was carried out in the following databases: Medline and ClinicalTrial.gov, for the terms "radiotherapy", "haematologic malignancies", "Hodgkin lymphoma", "non-Hodgkin lymphoma", "CAR T cells", "multiple myeloma", "solitary plasmocytoma", "intensity-modulated radiotherapy", "extracranial stereotactic body radiation therapy" and "proton therapy references". RESULTS: Haemopathological malignancies include a wide range of diseases and radiation therapy indications have been assessed over the past 20years. Currently, radiation therapy is indicated for localized disease (solitary plasmocytoma), as an adjuvant (Hodgkin lymphoma), in palliative settings, or after systemic treatment in relapsed patients (chimeric antigen receptor [CAR] T-cells) with a low recurrence burden, which can therefore be considered "oligorecurrence". Radiation therapy, through total body irradiation, has important indications, thanks to its immunomodulatory and/or myeloablative effects. Moreover, recent technological developments have made possible significant improvement in safety, contributing to radiation therapy being positioned in the treatment strategy of several indications. CONCLUSIONS: Given the effectiveness of systemic treatments in hematologic malignancies, the oligometastasis stage is of little importance. A curative intent after local radiation therapy, even advanced stage, is possible, both with residual disease for advanced Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, or solitary plasmocytoma, and even without evidence of disease after chemotherapy for Hodgkin or non-Hodgkin lymphoma. The role of new treatments, such as CAR T cells, allows us to consider radiation therapy after systemic treatment of relapsed diseases with low volume recurrence, which can be considered oligorecurrence.

Theranostics in Hematooncology.

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using ß-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

MRI-based long-term follow-up of indolent orbital lymphomas after curative radiotherapy: imaging remission criteria and volumetric regression kinetics.

We systematically analyzed the kinetics of tumor regression, the impact of residual lesions on disease control and the applicability of the Lugano classification in follow-up MRI of orbital non-Hodgkin lymphomas that were irradiated with photons. We retrospectively analyzed a total of 154 pre- and post-irradiation MRI datasets of 36 patients with low-grade, Ann-Arbor stage I, orbital non-Hodgkin lymphomas. Patients with restricted conjunctival involvement were excluded. Lymphoma lesions were delineated and volumetrically analyzed on T1-weighted sequences. Tumor residues were present in 91.2% of all cases during the first six months after treatment. Volumetric partial response rates (> 50% volume reduction) were 75%, 69.2%, and 50% at 12-24 months, 36-48 months and > 48 months after the end of treatment. The corresponding complete response (CR) rates according to the Lugano classification were 20%, 23.1% and 50%. During a median clinical follow-up of 37 months no significant differences in progression free survival (PFS) rates were observed between the CR and non-CR group (p = 0.915). A residual tumor volume below 20% of the pretreatment volume should be expected at long-term follow-up beyond one year after radiotherapy.

Radioimmunotherapy of Non-Hodgkin B-cell Lymphoma: An update.

Systemic radioimmunotherapy (RIT) is arguably the most effective and least toxic anticancer treatment for non-Hodgkin lymphoma (NHL). In treatment-naïve patients with indolent NHL, the efficacy of a single injection of RIT compares with that of multiple cycles of combination chemotherapy. However, 20 years following the approval of the first CD20-targeting radioimmunoconjugates 90Y-Ibritumomab-tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), the number of patients referred for RIT in western countries has dramatically decreased. Notwithstanding this, the development of RIT has continued. Therapeutic targets other than CD20 have been identified, new vector molecules have been produced allowing for faster delivery of RIT to the target, and innovative radionuclides with favorable physical characteristics such as alpha emitters have been more widely available. In this article, we reviewed the current status of RIT in NHL, with particular focus on recent clinical and preclinical developments.

Cure of Micrometastatic B-Cell Lymphoma in a SCID Mouse Model Using 213Bi-Anti-CD20 Monoclonal Antibody.

We studied the feasibility of using the α-emitting 213Bi-anti-CD20 therapy with direct bioluminescent tracking of micrometastatic human B-cell lymphoma in a SCID mouse model. Methods: A highly lethal SCID mouse model of minimal-tumor-burden disseminated non-Hodgkin lymphoma (NHL) was established using human Raji lymphoma cells transfected to express the luciferase reporter. In vitro and in vivo radioimmunotherapy experiments were conducted. Single- and multiple-dose regimens were explored, and results with 213Bi-rituximab were compared with various controls, including no treatment, free 213Bi radiometal, unlabeled rituximab, and 213Bi-labeled anti-HER2/neu (non-CD20-specific antibody). 213Bi-rituximab was also compared in vivo with the low-energy ß-emitter 131I-tositumomab and the high-energy ß-emitter 90Y-rituximab. Results: In vitro studies showed dose-dependent target-specific killing of lymphoma cells with 213Bi-rituximab. Multiple in vivo studies showed significant and specific tumor growth delays with 213Bi-rituximab versus free 213Bi, 213Bi-labeled control antibody, or unlabeled rituximab. Redosing of 213Bi-rituximab was more effective than single dosing. With a single dose of therapy given 4 d after intravenous tumor inoculation, disease in all untreated controls, and in all mice in the 925-kBq 90Y-rituximab group, progressed. With 3,700 kBq of 213Bi-rituximab, 75% of the mice survived and all but 1 survivor was cured. With 2,035 kBq of 131I-tositumomab, 75% of the mice were tumor-free by bioluminescent imaging and 62.5% survived. Conclusion: Cure of micrometastatic NHL is achieved in most animals treated 4 d after intravenous tumor inoculation using either 213Bi-rituximab or 131I-tositumomab, in contrast to the lack of cures with unlabeled rituximab or 90Y-rituximab or if there was a high tumor burden before radioimmunotherapy. α-emitter-labeled anti-CD20 antibodies are promising therapeutics for NHL, although a longer-lived α-emitter may be of greater efficacy.

Risk and prognosis of secondary breast cancer after radiation therapy for non-Hodgkin lymphoma: a massive population-based analysis.

PURPOSE: One of the best ways to control non-Hodgkin lymphoma (NHL) locally is radiation therapy (RT), which is a crucial component of care for many patients. There has not been any research on the risk and prognosis of secondary breast cancer (SBC) in females with NHL receiving RT. METHODS: In our study, females with NHL as their initial cancer diagnosis were included from 1975 to 2018 in the Surveillance, Epidemiology and End Results (SEER) database. Using Fine and Gray's competing risk regression assess the cumulative incidence of SBC. The standardized incidence ratios (SIR) and radiation-attributed risk (RR) for SBC were assessed using Poisson regression analysis. We evaluated the overall survival (OS) of SBC patients using the Kaplan-Meier technique. RESULTS: Of the 41,983 females with NHL, 10,070 received RT and 320 (3.18%) developed SBC. 31,913 females did not receive RT and 805 (2.52%) developed SBC. RT was significantly related with a greater chance of acquiring SBC in the Fine-Gray competing risk regression (adjusted hazard ratios (HR) = 1.14; 95% confidence intervals (CI), 1.09-1.30; P = 0.011). When an NHL diagnosis was made at an older age, the dynamic SIR and RR for SBC also declined over time. Regarding general survivability, there was not statistically significant (P = 0.970) after propensity score matching (PSM). CONCLUSIONS: RT is an independent risk factor for SBC in females with NHL. Special attention should be paid to the monitoring of breast cancer indicators in them, especially young.

Cardiovascular risk factors, radiation therapy, and myocardial infarction among lymphoma survivors.

BACKGROUND: Mediastinal radiation is associated with increased risk of myocardial infarction (MI) among non-Hodgkin lymphoma (NHL) survivors. OBJECTIVE: To evaluate how preexisting cardiovascular risk factors (CVRFs) modify the association of mediastinal radiation and MI among a national population of NHL survivors with a range of CVRFs. MATERIAL AND METHODS: Using Danish registries, we identified adults diagnosed with lymphoma 2000-2010. We assessed MI from one year after diagnosis through 2016. We ascertained CVRFs (hypertension, dyslipidemia, and diabetes), vascular disease, and intrinsic heart disease prevalent at lymphoma diagnosis. We used multivariable Cox regression to test the interaction between preexisting CVRFs and receipt of mediastinal radiation on subsequent MI. RESULTS: Among 3151 NHL survivors (median age 63, median follow-up 6.5 years), 96 were diagnosed with MI. Before lymphoma, 32% of survivors had ≥1 CVRF. 8.5% of survivors received mediastinal radiation. In multivariable analysis, we found that mediastinal radiation (HR = 1.96; 95% CI = 1.09-3.52), and presence of ≥1 CVRF (HR = 2.71; 95% CI = 1.77-4.15) were associated with an increased risk of MI. Although there was no interaction on the relative scale (p = 0.14), we saw a clinically relevant absolute increase in risk for patients with CVRF from 10-year of MI of 10.5% without radiation to 29.5% for those undergoing radiation. CONCLUSION: Patients with CVRFs have an importantly higher risk of subsequent MI if they have mediastinal radiation. Routine evaluation of CVRFs and optimal treatment of preexisting cardiovascular disease should continue after receiving cancer therapy. In patients with CVRFs, mediastinal radiation should only be given if oncologic benefit clearly outweighs cardiovascular harm.

Radiotheranostic Agents in Hematological Malignancies.

Radioimmunotherapy (RIT) is a cancer treatment that combines radiation therapy with tumor-directed monoclonal antibodies (Abs). Although RIT had been introduced for the treatment of CD20 positive non-Hodgkin lymphoma decades ago, it never found a broad clinical application. In recent years, researchers have developed theranostic agents based on Ab fragments or small Ab mimetics such as peptides, affibodies or single-chain Abs with improved tumor-targeting capacities. Theranostics combine diagnostic and therapeutic capabilities into a single pharmaceutical agent; this dual application can be easily achieved after conjugation to radionuclides. The past decade has seen a trend to increased specificity, fastened pharmacokinetics, and personalized medicine. In this review, we discuss the different strategies introduced for the noninvasive detection and treatment of hematological malignancies by radiopharmaceuticals. We also discuss the future applications of these radiotheranostic agents.

FDG PET/CT and Dosimetric Studies of 177Lu-Lilotomab Satetraxetan in a First-in-Human Trial for Relapsed Indolent non-Hodgkin Lymphoma-Are We Hitting the Target?

PURPOSE: [177Lu]Lu-lilotomab satetraxetan, a novel CD37 directed radioimmunotherapy (RIT), has been investigated in a first-in-human phase 1/2a study for relapsed indolent non-Hodgkin lymphoma. In this study, new methods were assessed to calculate the mean absorbed dose to the total tumor volume, with the aim of establishing potential dose-response relationships based on 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) parameters and clinical response. Our second aim was to study if higher total tumor burden induces reduction in the 177Lu-lilotomab satetraxetan accumulation in tumor. PROCEDURES: Fifteen patients with different pre-dosing (non-radioactive lilotomab) regimens were included and the cohort was divided into low and high non-radioactive lilotomab pre-dosing groups for some of the analyses. 177Lu-lilotomab satetraxetan was administered at dosage levels of 10, 15, or 20 MBq/kg. Mean absorbed doses to the total tumor volume (tTAD) were calculated from posttreatment single-photon emission tomography (SPECT)/computed tomography (CT) acquisitions. Total values of metabolic tumor volume (tMTV), total lesion glycolysis (tTLG) and the percent change in these parameters were calculated from FDG PET/CT performed at baseline, and at 3 and 6 months after RIT. Clinical responses were evaluated at 6 months as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD). RESULTS: Significant decreases in tMTV and tTLG were observed at 3 months for patients receiving tTAD ≥ 200 cGy compared to patients receiving tTAD < 200 cGy (p = .03 for both). All non-responders had tTAD < 200 cGy. Large variations in tTAD were observed in responders. Reduction in 177Lu-lilotomab satetraxetan uptake in tumor volume was not observed in patients with higher baseline tumor burden (tTMV). CONCLUSION: tTAD of ≥ 200 cGy may prove valuable to ensure clinical response, but further studies are needed to confirm this in a larger patient population. Furthermore, this work indicates that higher baseline tumor burden (up to 585 cm3) did not induce reduction in radioimmunoconjugate accumulation in tumor.

Anti-CD37 radioimmunotherapy with 177Lu-NNV003 synergizes with the PARP inhibitor olaparib in treatment of non-Hodgkin's lymphoma in vitro.

BACKGROUND AND PURPOSE: PARP inhibitors have been shown to increase the efficacy of radiotherapy in preclinical models. Radioimmunotherapy results in selective radiation cytotoxicity of targeted tumour cells. Here we investigate the combined effect of anti-CD37 ß-emitting 177Lu-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin's lymphoma cell lines. MATERIALS AND METHODS: The combined effect of 177Lu-NNV003 and olaparib was studied in seven cell lines using a fixed-ratio ray design, and combination index was calculated for each combination concentration. mRNA was extracted before and after treatment with the drug combination. After RNA-sequencing, hierarchical clustering was performed on basal gene expression profiles and on differentially expressed genes after combination treatment from baseline. Functional gene annotation analysis of significant differentially expressed genes after combination treatment was performed to identify enriched biological processes. RESULTS: The combination of olaparib and 177Lu-NNV003 was synergistic in four of seven cell lines, antagonistic in one and both synergistic and antagonistic (conditionally synergistic) in two, depending on the concentration ratio between olaparib and 177Lu-NNV003. Cells treated with the combination significantly overexpressed genes in the TP53 signalling pathway. However, cluster analysis did not identify gene clusters that correlate with the sensitivity of cells to single agent or combination treatment. CONCLUSION: The cytotoxic effect of the combination of the PARP inhibitor olaparib and the ß-emitting radioimmunoconjugate 177Lu-NNV003 was synergistic in the majority of tested lymphoma cell lines.

Treatment Outcomes of Low-grade Lymphoma of the Orbit.

AIMS: Radiation therapy can be used with curative intent in patients with low-grade orbital non-Hodgkin's lymphoma (NHL) stages IE and IVE (limited to the bilateral orbits). This study evaluated local control and survival outcomes of patients with unilateral or bilateral orbital lymphoma treated in a provincial population. MATERIALS AND METHODS: The study subjects were 176 patients with low-grade orbital or conjunctival lymphoma referred for management from 1980 to 2016. Demographic, tumour and treatment characteristics were abstracted by chart review. Recurrence-free survival (RFS) and overall survival were assessed with competing risks analysis and Gray's test. RESULTS: The median follow-up was 8.5 years (range 0.4-29.5 years). The median age at diagnosis was 65 years (range 20-97 years). The most common histological subtype was mucosa-associated lymphoid tissue (MALT) (73%). Stage IVE accounted for 20.5% of the cohort. Orbital radiation therapy was used in 122 patients with stage IE (87%) and 12 patients with stage IVE (28%). The median dose was 25 Gy (range 2-35 Gy). Other treatments were antibiotics (seven patients), chemotherapy (10 patients), radioimmunotherapy (six patients), surgery (three patients) and observation (16 patients). Within the group treated with orbital external beam radiation therapy (EBRT) there were no local recurrences. Among those with stage IE NHL, EBRT was associated with improved local RFS (P ≤ 0.001) but did not have an impact on contralateral or distant RFS. In patients with stage IVE NHL limited to the bilateral orbit, bilateral EBRT was associated with improved RFS (P = 0.012) but did not affect distant recurrences or overall survival. CONCLUSION: There were no local recurrences after EBRT for stage IE and IVE orbital low-grade NHL. The treatments offered over the study period varied, but only EBRT for stage IVE disease improved RFS. This supports EBRT as the preferred primary treatment for patients with localised orbital low-grade lymphoma, including those with bilateral disease.

Dosimetric Approaches for Radioimmunotherapy of Non-Hodgkin Lymphoma in Myeloablative Setting.

Radioimmunotherapy (RIT) is a safe and active treatment available for non-Hodgkin lymphomas (NHLs). In particular, two monoclonal antibodies raised against CD20, that is Zevalin (90Y-ibritumomab-tiuxetan) and Bexxar (131I-tositumomab) received FDA approval for the treatment of relapsing/refractory indolent or transformed NHLs. RIT is likely the most effective and least toxic anticancer agent in NHLs. However, its use in the clinical setting is still debated and, in case of relapse after optimized rituximab-containing regimens, the efficacy of RIT at standard dosage is suboptimal. Thus, clinical trials were based on the hypothesis that the inclusion of RIT in myeloablative conditioning would allow to obtain improved efficacy and toxicity profiles when compared to myeloablative total-body irradiation and/or high-dose chemotherapy regimens. Standard-activity RIT has a safe toxicity profile, and the utility of pretherapeutic dosimetry in this setting can be disputed. In contrast, dose-escalation clinical protocols require the assessment of radiopharmaceutical biodistribution and dosimetry before the therapeutic injection, as dose constrains for critical organs may be exceeded when RIT is administered at high activities. The aim of the present study was to review and discuss the internal dosimetry protocols that were adopted for non-standard RIT administration in the myeloablative setting before hematopoietic stem cell transplantation in patients with NHLs.

Radiotherapy of lymphomas.

Radiotherapy for Hodgkin lymphomas has evolved a lot over time, but still plays an important role, almost always in addition to chemotherapy, for the management of the early stages. The major objective is to preserve the quality of life of patients who will be cured from this disease in the vast majority of cases. Also, the personalization of the indications for the purpose of de-escalating toxicity is very refined and is essentially based on the pre- and pertherapeutic assessment by FDG-PET. The indications for radiotherapy are more limited for non-Hodgkin lymphomas, but the same principles are found, regardless of the histological type. We present the update of the recommendations of the French society of oncological radiotherapy for radiotherapy of lymphomas, which remains a very evolving field in terms of therapeutic strategy and evaluation.

Does bridging radiation therapy affect the pattern of failure after CAR T-cell therapy in non-Hodgkin lymphoma?

PURPOSE: Analyze the pattern of disease failure after anti-CD19-directed chimeric antigen receptor T-cell therapy (CART) for non-Hodgkin lymphoma, assess the local control rate of bridging radiotherapy (bRT) and characterize in-field recurrences. METHODS: We retrospectively reviewed 120 patients with NHL who received CART between 2018 and 2020. Baseline characteristics and treatment outcomes were compared between patients who received bRT and those who did not (noRT). RESULTS: Of the 118 patients included, 14 (12%) received bRT, while 104 (88%) did not. bRT group had more localized and extranodal disease. bRT was delivered with a median dose of 20 Gy (range: 15-36) in 5 fractions (range: 3-24). Pattern of failure analysis revealed that progression involving pre-existing sites was the predominant pattern of failure in both the bRT and noRT groups (86% and 88%, respectively). Median duration of response was 128 days (range: 25-547) for bRT group and 93 days (range: 22-965) for noRT group (p = 0.78). In the bRT group, only 2/15 sites irradiated had infield recurrence and where characterized by bulky disease, SUVmax >20, elevated LDH at the time of CART infusion, and extranodal involvement. The bRT 1-year LC was 86%. Median duration of local response was 257 days (range: 25-630) for radiation-bridged sites. CONCLUSION: Majority of progressions after CART infusion involve pre-existing sites. Bridging RT prior to CART provides excellent in-field local control and durable response. Patients with bulky disease, SUVmax >20, elevated LDH, and extranodal involvement are likely at higher risk of in-field recurrence after bRT and may benefit from higher curative doses of bRT.

Selective salvage radiotherapy could provide favorable outcomes in patients with refractory or relapsed primary central nervous system lymphoma.

INTRODUCTION: To date, there is no relevant data supporting the role of salvage radiotherapy (sRT) in patients with refractory or relapsed primary central nervous system lymphoma (PCNSL). Herein, we aimed to investigate the impact of sRT in patients with refractory or relapsed PCNSL following upfront HD-MTX. METHODS: We retrospectively reviewed 89 patients who had refractory (n = 16) or recurrent disease after an initial favorable response (n = 73); among them, 41 were treated with sRT and 48 were treated without sRT (nRT). Event-free survival (rEFS) and overall survival (rOS) after first recurrence were considered from the date of recurrence to date of each event. RESULTS: Overall, the first failure was diagnosed at a median of 11.0 months [interquartile range (IQR), 5.6-26.4] after first treatment. More than half of the patients had recurrent disease involving initial tumor bed (n = 47), deep structure (n = 67), and multiple lesions (n = 58). Among 19 patients who were initially treated with 23.4 Gy of whole brain RT, 10 patients received sRT as a re-irradiation; other 31 patients in sRT group were RT naïve patients. There was no significant difference in tumor characteristics between sRT and nRT group. Overall and complete response after salvage treatment were 80% and 48%, respectively; sRT provided higher overall response rate than nRT (93% vs. 69%, p = 0.011). With a median follow-up of 14.3 months (IQR, 7.9-31.4), 2-year rEFS and rOS rates were 27% and 57%, respectively. There were no differences in rEFS and rOS according to sRT (sRT vs. nRT, 26% vs. 28%, p = 0.730; 63% vs. 50%, p = 0.690). Poor performance, recurrence interval < 8 months, and unfavorable response following salvage treatment were associated with inferior rEFS and rOS. Additionally, sRT and stem cell transplantation improved response rate independently after multivariate analysis for complete/partial response. CONCLUSIONS: We found favorable response rate and comparable survival outcomes following sRT compared with non-local treatments for patients with refractory/relapsed PCNSL. Further studies of patient selection could stratify patients who can benefit from sRT.