Radiation for hematologic malignancies: from cell killing to immune cell priming

Over the past half-century, the role of radiotherapy has been revolutionized, in part, by a shift from intent to directly kill cancer cells to the goal of priming anti-tumor immune responses that attack both irradiated and non-irradiated tumors. Stimulation of anti-tumor immunity depends on the interplay between radiation, the tumor microenvironment, and the host immune system, which is a burgeoning concept in cancer immunology. While the interplay of radiotherapy and the immune system has been primarily studied in solid tumors, we are beginning to understand this interplay in hematological malignancies. The intent of this review is to lead readers through some of the important recent advances in immunotherapy and adoptive cell therapy, highlighting the best available evidence in support of incorporating radiation therapy and immunotherapy into the treatment of hematological malignancies. Evidence is presented regarding how radiation therapy ‘converses’ with the immune system to stimulate and enhance anti-tumor immune responses. This pro-immunogenic role of radiotherapy can be combined with monoclonal antibodies, cytokines and/or other immunostimulatory agents to enhance the regression of hematological malignancies. Furthermore, we will discuss how radiotherapy facilitates the effectiveness of cellular immunotherapies by acting as a “bridge” that facilitated CAR T cell engraftment and activity. These initial studies suggest radiotherapy may help catalyze a shift from using chemotherapy-intensive treatment to treatment that is “chemo-free” by combining with immunotherapy to target both the radiated and non-irradiated disease sites. This “journey” has opened the door for novel uses of radiotherapy in hematological malignancies due to its ability to prime anti-tumor immune responses which can augment immunotherapy and adoptive cell-based therapy

Proton therapy for adults with mediastinal lymphomas: The international lymphoma radiation oncology group guidelines

Among adult lymphoma survivors, radiation treatment techniques that increase the excess radiation dose to organs at risk (OARs) put patients at risk for increased side effects, especially late toxicities. Minimizing radiation to OARs in adults patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the deciding factor for the choice of treatment modality. Proton therapy may help to reduce the radiation dose to the OARs and reduce toxicities, especially the risks for cardiac morbidity and second cancers. Becauseproton therapymay have some disadvantages, identifying the patients and the circumstances that may benefit the most from proton therapy is important. We present modern guidelines to identify adult lymphoma patients who may derive the greatest benefit from proton therapy, along with an analysis of the advantages and disadvantages of proton treatment. (Blood. 2018;132(16):1635-1646)

An international multicenter retrospective analysis of patients with extranodal marginal zone lymphoma and histologically confirmed central nervous system and dural involvement

Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. The clinical features, treatment, and prognosis are not well characterized. We performed a multicenter retrospective study of CNS MZL. Twenty-six patients were identified: half with primary and half with secondary CNS involvement. The median age was 59 years (range 26-78), 62% female and 79% with ECOG performance status ≤ 1. The most common disease site was the dura (50%). Treatment was determined by the treating physician and varied substantially. After a median follow up of 1.9 years, the estimated 2-year progression-free (PFS) and overall survival (OS) rates were 59% and 80%, respectively. Secondary CNS MZL was associated with 2-year OS of 58%. CNS MZL is rare, but relative to other forms of CNS lymphoma, outcomes appear favorable, particularly among the subset of patients with dural presentation and primary CNS presentation

Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas

AbstractMore active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days −8 to −3). Gemcitabine was infused continuously at 10 mg/m2/minute over 4.5 hours (days −8 and −3). Busulfan dosing targeted 4000 μM-minute/day (days −8 to −5). Melphalan was infused at 60 mg/m2/day (days −3 and −2). Patients with CD20+ tumors received rituximab (375 mg/m2, days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography–positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation

ACR Appropriateness Criteria® Hodgkin Lymphoma-Favorable Prognosis Stage I and II

This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy

ACR Appropriateness Criteria® Recurrent Hodgkin Lymphoma

This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decisionmaking associated with the management of recurrent Hodgkin lymphoma