Therapy For Hodgkin Lymphoma Research Articles

Optimizing the role of brentuximab vedotin in classical Hodgkin lymphoma therapy.

The US Food and Drug Administration approval of brentuximab vedotin (BV) in 2011 marked an important milestone in the management of classical Hodgkin lymphoma (HL). Although initially approved for use in the relapsed or refractory setting, its high efficacy and favorable toxicity profile led to numerous studies evaluating BV in the front-line, second-line, and posttransplant settings. BV is now approved for use (in combination with chemotherapy) as frontline treatment of advanced-stage patients and as maintenance therapy following autologous stem cell transplant. Additional studies demonstrate its promise as second-line therapy and for elderly patients, as well. Although studies have demonstrated its promise in multiple settings, the ideal timing for use of BV is evolving. Studies evaluating individualized treatment strategies will ultimately define the optimal place for BV in HL treatment.

Chronic Lymphocytic Leukemia (CLL) Transformed into Hodgkin Lymphoma (HL): Clinical Characteristics and Outcomes from a Large Multi-Center Collaboration

Chronic Lymphocytic Leukemia (CLL) Transformed into Hodgkin Lymphoma (HL): Clinical Characteristics and Outcomes from a Large Multi-Center Collaboration

The Development and Validation of an Electronic Health Record (EHR)-Based Algorithm for Identifying Treatment Failure in Newly Diagnosed Hodgkin Lymphoma (HL) Treated in a US Community Oncology Setting

IntroductionMost existing cancer registries do not fully capture relapse or progression of cancer. Further, clinical trials for upfront treatment typically withdraw patients from study at the time of treatment failure and only collect minimal information about approaches to and outcomes with salvage therapy. As such, patient outcomes other than mortality often are available only through formal chart review, which is resource intensive. For HL, although many patients are successfully cured, a sizeable subset of patients experience treatment failure. Most of the data describing failure arises from prospective clinical trials, despite most patients receiving treatment in the community setting. Therefore, data from the community setting are needed to understand the experience of real-world patients and to inform and improve the quality of care in oncology practices. To facilitate observational research and quality improvement projects on HL treatment failure, we examined an EHR-based algorithm for identifying treatment failure in HL.MethodsAll HL patients who initially presented with advanced stages II-IV disease between 2007-2012 at Kaiser Permanente Southern California (KPSC) were identified using KPSC's cancer registry. An algorithm for identifying treatment failure was proposed by study oncologists. Treatment failure was defined as relapse after complete remission of > 60 days' duration or disease progression on active treatment. The algorithm was defined as meeting one of the following: (1) Initiation of any second chemotherapy regimen, including use of brentuximab vedotin, or PD-1 inhibitor beyond initial regimen; or (2) stem cell transplantation (SCT). Data needed to construct the algorithm were collected from KPSC's EHR, including the chemotherapy database and transplant registry. The algorithm was applied to all HL cases up to 4 years after diagnosis, as most HL relapses occur within this timeframe. Manual chart reviews were performed for all potential treatment failure cases identified by the algorithm, and for one-third of randomly-selected HL cases not captured by the algorithm. Each case was abstracted by trained study staffed and reviewed for quality control by two study oncologists.ResultsOf the 470 HL patients newly diagnosed during the study period (91% diagnosed at age 18 and older, 57% male), the algorithm identified 80 as potential treatment failure cases. Chart review confirmed 75 of 80 as actual treatment failure. The algorithm misclassified relapse for 5 cases who had emergence of a second malignancy for which therapy was instituted after the completion of initial therapy for HL. The positive predictive value (PPV) was 94% (95% confidence interval: 89%-99%). The negative predictive value (NPV) based on the review of 127 patients not captured by the algorithm was 100%. Based on the high PPV and NPV, our review suggested both a high sensitivity and specificity of the algorithm.ConclusionThis EHR-based algorithm, based on receipt of second-line therapy beyond initial treatment and SCT, was highly effective in capturing relapse or disease progression cases among HL patients in this integrated health care delivery system. Application of this algorithm will allow for better long-term follow up for novel agents in observational studies, which is critical for understanding the cost-effectiveness of therapeutic agents in real-world patients. External validation using data from other health care settings or sources such as claims data will be useful to further confirm the generalizability of this algorithm. Altogether, this algorithm could assist practices in the identification and prospective tracking of the relapsed/refractory HL patient population for clinical and non-clinical outcomes, such as cost, health-related quality of life, and sequelae of treatment. DisclosuresChao:Seattle Genetics: Research Funding. Xu:Seattle Genetics: Research Funding. Cannizzaro:Seattle Genetics: Research Funding. Rodday:Seattle Genetics: Research Funding. Feliciano:Seattle Genetics: Employment, Equity Ownership. Kumar:Seattle Genetics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Tesaro: Research Funding; Abbvie: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Novartis: Consultancy; Acerta: Consultancy; Bayer: Consultancy. Parsons:Seattle Genetics: Research Funding.

Metabolic Tumor Volume and Soluble Cytokines Levels in Newly Diagnosed Hodgkin Lymphoma: What It Brings into the Staging Precision?

Background: Frontline therapy of Hodgkin lymphoma (HL) is strictly stage-adapted. Staging systems used are based on historical variables which only indirectly reflects tumor load (Ann Arbor stage) or lymphoma cytokine activity (systemic symptoms, erytrocyte sedimentation rate). With new, abbreviated interim PET-tailored chemotherapy schemes (2+2) and reduced radiotherapy protocols, there is a clinical need for precise staging tools. Last years have brought new insight into the prognostic role of metabolic quantitative PET parameters and HL-associated biomarkers. Total metabolic tumor volume (TMTV) measured using fluoro-deoxyglucose PET (FDG-PET) was found to be a predictor of therapy failure after frontline treatment (Kanoun 2014). Interestingly, TMTV was found capable of identifying poor responders within one (intermediate) staging group (Akhtari, 2018; Cottereau 2018). Serum concentrations of thymus and activation-regulated chemokine (TARC) and other cytokines have been proved to have prognostic significance in the patients treated both in the frontline and relapse setting (Moskowitz, 2015; Guidetti 2017). A relationship between pretreatment TMTV, baseline cytokines levels, and current staging systems has not been analyzed yet.Aim: To analyzed quantitative metabolic PET parameters and selected soluble biomarkers in the context of the staging systems used in the U.S. and EuropeMethods: We have analyzed a prospectively enrolled cohort of forty-eight patients with HL who were diagnosed in two large university medical centers from 5/2015 to 2/2018. All pts have undergone pretreatment FDG-PET/CT with quantitative analysis of TMTV, Total Lesion Glycolysis (TLG), Maximum Standardized Uptake Volume (SUVmax.) and the Largest Tumor Diameter (LD) and were sampled for cytokine analysis within 16 (median) days from the PET/CT. We have analyzed a set of four serum biomarkers: CD30 (sCD30), CD163 (sCD163), TARC, and interleukin 6 (sIL6), which were measured using ELISA assays.Results: A cohort consisted of 22 males and 26 females with median age of 42 years (range 21-75). Histology subtype was known in all but one case: nodular sclerosis in 23, mixed cellularity 15, lymphocyte-rich in 5 and nodular-lymphocyte predominant (NLPHL) in four. Ann Arbor stages were as follows: I in 5, II in 20, III in 13 and IV in 10 of the pts with systemic symptoms in 20 (42%) of them. All pts were classified according to the German Hodgkin Study Group (GHSG) and NCCN staging systems. GHSG stages - limited, intermediate and advanced were seen in 8 (17%), 10 (21%) and 30 (62%) pts, respectively. NCCN stages were distributed into early favorable in 8 (17%), early unfavorable in 17 (35%) and advanced in 23 (48%) of the pts. Chemotherapy was applied in all but four pts using: BEACOPPesc, combined BEACOPP+ABVD, ABVD and ABV/COPP protocols in 7, 15, 16 and six pts respectively. Of four pts without chemo one case was treated with local radiotherapy and three with WaW (all of them with NLPHL). Treatment response was known in 41 (85%) of the cases with CR, PR, and PD in 33 (80.5%), 6 (14.6%) and two (4.9%) pts, respectively. Relationships between disease stages and PET-parameters are summarized in Table 1. Briefly, metabolic tumor burden (TMTV, TLG) identified two markedly different groups: low and intermediate/high risk. Similarly, cytokines levels were significantly lower in low-risk patients compared to those with intermediate-high risk (Table 2). Treatment outcome did not correlate either with GHSG nor NCCN stage. We found correlation of sIL-6 (p=0.03) but not sCD30 (p=0.09), sCD163 (p=0.14) and TARC (p=0.57) with CR achievement. In terms of PET-parameters the high TMTV>104 cm3 (P=0.046) and TLG>798 (P=0.003) were associated with not achieving of CR with NPV, PPV and test accuracy of 94.4, 22.0, 58.5 for TMTV and 100%, 36,4%, 66% for TLG, respectively.Conclusion: Adequate frontline treatment policy is vital for achieving an optimal balance between efficacy and toxicity. Current staging systems have a weak correlation with metabolic tumor burden: one-third of those recognized as advanced stage have the low burden, and vice versa about a half of intermediate-risk pts have high tumor burden. Combination of TMTV/TLG and cytokines can be currently used for decision making in borderline stage cases and probably could serve as a backbone for a new staging system in the future.Acknowledgment: IGA_LF_2018_004, MH CZ-DRO (FNOL, 00098892) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The translational science of hodgkin lymphoma.

Hodgkin Lymphoma (HL) is an unusual B-cell lymphoma because the malignant cells exist as a minority population in a densely cellular microenvironment. The microenvironment is comprised predominately of inflammatory and immune cells with fibrosis in some cases. There are multiple dysregulated signalling pathways that sustain HL within this microenvironment, such as the Nuclear factor-κB and Janus kinase/signal transducers and activators of transcription pathways. Advances in genomic medicine have enabled a better characterisation of the rare tumour cells and improved our understanding of the signalling mechanisms that exist between the malignant cell and its microenvironment. Current therapy for HL produces excellent clinical outcomes in most younger patients. However, problems with current treatment approaches include poorer outcomes in the elderly, toxicity of highly-effective combination chemotherapy regimens and relapse in high-risk patients. Better understanding of disease biology aids in upfront prognostication of patients, defines new methods for treatment monitoring and assists in the recognition of novel targets for therapy. Biology-driven therapies, including anti-CD30 antibody conjugates, cellular immunotherapies and immune modulation, particularly with checkpoint inhibitors, have changed treatment algorithms for relapsed/refractory patients. Future challenges exist in incorporating immune-based therapies earlier in treatment algorithms to reduce toxicity and prevent relapse for patients with HL.

Trends in Insurance Coverage of Proton Therapy for Hodgkin Lymphoma Involving the Thorax

Trends in Insurance Coverage of Proton Therapy for Hodgkin Lymphoma Involving the Thorax

Radiotherapy for Hodgkin Lymphoma: Reducing Toxicity While Maintaining Efficacy.

Radiation therapy (RT) for Hodgkin lymphoma has changed dramatically over the past couple of decades, from the very large extended-field RT with prophylactic treatment of all the major lymph node regions to the very limited involved-site RT with treatment only of the initially macroscopically involved lymphoma volume in the combined modality setting. Technological developments in imaging, treatment planning, and treatment machines have enabled very significant reductions in radiation doses to normal organs without jeopardizing the coverage of the lymphoma. Hence, the risks of long-term adverse effects have become much smaller than those in the past. Radiation therapy for Hodgkin lymphoma is now a highly individualized treatment, tailored to each patient. The risks of this limited RT should be weighed against the risks of long-term toxicity of possible additional systemic treatment up-front and at relapse in order to select the optimal treatment combination for each individual patient.

Treatment-Resistant Hodgkin Lymphoma: Defining the Role of Autologous Transplantation.

Autologous hematopoietic stem cell transplant (AHCT) remains the current standard of care for patients with relapsed or refractory Hodgkin lymphoma (HL) after frontline chemotherapy. However, treatment paradigms for HL are rapidly changing with positron emission tomography-adapted therapy, as well as the incorporation of brentuximab vedotin and checkpoint inhibitors into frontline, salvage, and maintenance therapy for HL. Patients who relapse or are refractory to these novel agents are likely to have different responses and outcomes with AHCT than the 3-year event-free survivals of 50% historically reported with AHCT for patients failing conventional combination chemotherapy. This article reviews the current data on the efficacy of AHCT, pretransplant prognostic markers, pretransplant salvage regimens, peritransplant radiation therapy, and posttransplant maintenance therapy in classic HL. Future research should reexamine the efficacy, timing, risk factors, pretransplant salvage regimens, and maintenance approaches posttransplant in the era of brentuximab vedotin and checkpoint inhibitors for HL.

Risk-adapted therapy for pediatric Hodgkin lymphoma (HL) results in lower risk of late effects: a report from the Childhood Cancer Survivor Study (CCSS).

10510Background: The goal of multi-modal, risk-adapted therapy for HL is to increase cure rates while decreasing risk for late effects; this is particularly important for children due to their vuln...

Survival by age in children and adolescents with Hodgkin lymphoma: A pooled analysis of Children’s Oncology Group (COG) trials.

7543 Background: The National Cancer Institute defines adolescent/young adult as 15-39y. Guidelines from ASCO and Friends of Cancer Research call for including children ≥12y on late phase trials spanning children and adults. We examined whether, in children and adolescents receiving response-based therapy for Hodgkin lymphoma (HL), age ≥12y would define a group with inferior outcomes compared to younger patients. Methods: This was a pooled analysis of individual patient-level data from three COG Phase 3 trials for intermediate, low, high-risk HL (AHOD0031, AHOD0431, AHOD0831). 5-yr event free survival (EFS) and overall survival (OS) by age were estimated via Kaplan Meier method. Cox regression models examined the influence of age on EFS and OS, adjusted for race/ethnicity, sex, insurance, histology, Ann Arbor stage, B symptoms, bulk, study, and radiation therapy (RT). Results: We included 2071 of 2155 patients, 1-21y enrolled from 2002 -2012. Mean age at diagnosis was 14.6y (±3.5) with 54% ≥15y (N = 1121) and 81% ≥12y (N = 1684). At median follow-up of 6.9 years, patients < 15y had statistically significantly better EFS ( < 15y: 85% vs. ≥15y: 80%, p = 0.02). A difference in EFS was noted in those < 12y vs. ≥12y (87% vs. 81%, p = 0.0503). OS was significantly better in patients < 15y vs. ≥15y (98% vs. 95%, p = 0.006), but did not differ in < 12y vs. ≥12y (99% vs. 97%, p = 0.136). Cumulative incidence of second malignant neoplasm did not differ by age category. In multivariable models, older age was an independent predictor of treatment failure in both age categories (Table). Conclusions: With contemporary, response-based therapy on COG trials, adolescents ≥12 and ≥15y had worse EFS than younger groups. This suggests that children ≥12y may benefit from therapy escalation and inclusion in late phase trials of novel agents incorporating antibody drug conjugates or checkpoint inhibitors. Multivariable cox model of 5-yr EFS and OS by age group. 5-yr EFS 5-yr OS HR 95% CI p-value HR 95% CI p-value < 12 years (R: ≥12) 0.71 (0.51, 0.98) 0.04 0.51 (0.2, 1.34) 0.17 < 15 years (R: ≥15) 0.74 (0.59, 0.93) 0.01 0.39 (0.2, 0.76) 0.006 HR: hazard ratio; 95%CI: 95% confidence interval; R: reference group

Hodgkin lymphoma therapy in practical health care: analysis of the hospital register of city clinical hospital named after S.P. Botkin

Hodgkin lymphoma therapy in practical health care: analysis of the hospital register of city clinical hospital named after S.P. Botkin

Predictors of Hypothyroidism in Hodgkin Lymphoma Survivors After Intensity Modulated Versus 3-Dimensional Radiation Therapy

To identify predictors of hypothyroidism after chemoradiation therapy for Hodgkin lymphoma (HL) and to compare outcomes after intensity modulated radiation therapy (IMRT) with those after 3-dimensional (3D) conformal radiation therapy (CRT). Ninety patients who underwent involved-site IMRT in 2009 through 2014 were evaluated for treatment-induced hypothyroidism, defined as elevated thyroid-stimulating hormone or decreased free thyroxine levels (or both). Receiver operating characteristic curve analysis identified individuals at low versus high risk based on dosimetric variables. Dosimetric cutoff points were verified with an external data set of 50 patients who underwent 3D-CRT. In the IMRT group, most patients (75 [83%]) had stage II HL, and the median prescribed dose was 30.6Gy; in the 3D-CRT group, 32 patients (64%) had stage II HL, and the median prescribed dose was 32.0Gy. No differences were found in the proportions of patients with bilateral (P=.982) or unilateral (P=.074) neck involvement between the 2 groups.Hypothyroidism rates were marginally higher in the IMRT group, with estimated 3-year rates of freedom from hypothyroidism of 56.1% in the 3D-CRT group and 40% in the IMRT group (P=.057). Univariate analysis showed that smaller thyroid volume and higher thyroid dose were associated with hypothyroidism in both groups (P<.05). In the IMRT group, the percentage of the thyroid gland volume receiving ≥25Gy (V25) and the absolute volume of the thyroid gland spared from 25Gy (VS25Gy) were the strongest predictors of hypothyroidism (P=.001 and P<.001, respectively).Cutoff points of 63.5% (V25) and 2.2mL (VS25Gy) classified patients as high risk (80%-82%) or low risk (37%-44%) (P<.001). Use of a thyroid avoidance structure reduced the incidence of hypothyroidism (P<.05) in the IMRT group. The percentage of the thyroid receiving 25Gy and the volume of the thyroid spared from 25Gy predicted the risk of hypothyroidism after either IMRT or 3D-CRT for HL. IMRT may confer a higher risk than 3D-CRT unless a treatment avoidance structure is used during planning.

Emerging role of novel therapies in Hodgkin lymphoma: proceed with caution.

Based on very high response rates in the relapsed and refractory setting, brentuximab vedotin and the programmed cell death protein 1 (PD-1) inhibitors, nivolumab and pembrolizumab, have quickly been incorporated into clinical trials for first- and second-line therapy of Hodgkin lymphoma. Preliminary data show that brentuximab vedotin alone is not adequate therapy for newly diagnosed Hodgkin lymphoma in older patients, but modestly decreases the risk of relapse when combined with adriamycin, vinblastine, and dacarbazine in patients with previously untreated advanced-stage disease. In second-line therapy, combining brentuximab vedotin with conventional chemotherapy or with PD-1 inhibitors as pretransplant salvage is associated with high overall and complete response rates, although further follow up is needed to assess whether posttransplant outcomes are improved. Although these new drugs are well tolerated when given as single agents, unexpected toxicities have been encountered with combination regimens, specifically severe pulmonary toxicity with the bleomycin and brentuximab vedotin combination and frequent infusion-related reactions. There is concern with the use of PD-1 inhibitors as first-line therapy due to the theoretical potential for more frequent or severe immune-mediated toxicities in patients who have not received prior chemotherapy. Aside from these concerns, these new agents have the potential to improve outcomes for patients even further, bringing us closer to eradicating recurrent Hodgkin lymphoma.

Advanced-Stage Hodgkin Lymphoma in the East of England Cancer Network: A 10-Year Comparative Analysis of Outcomes for Patients Treated with ABVD or Escalated BEACOPP in the Non-Trial Setting Compared with Age-Matched Patients Treated in the Multinational RATHL Trial

Introduction: The majority of young patients presenting with advanced-stage Hodgkin lymphoma (HL) in the UK are managed with ABVD. However, from 2009, escalated BEACOPP (escBEACOPP) was introduced as a treatment option in certain UK cancer centres. Within the East of England Cancer Network (EECN), 6 hospitals introduced escBEACOPP as a treatment option, while 2 hospitals continued to use ABVD as standard first-line therapy for all patients. During this time period, recruitment to the RATHL (Response Adjusted Therapy for Hodgkin Lymphoma) trial was also a first-line treatment option across the UK and 4 of the EECN centres. Analysing data from all patients treated in the EECN centres and the RATHL trial has therefore enabled outcomes of patients treated with either escBEACOPP or ABVD within a non-trial setting to be compared to patients treated with ABVD in a clinical trial.Methods: We performed a retrospective multicentre analysis of patients treated for advanced-stage HL, aged 16-59 years, diagnosed between 2004-2014 in the EECN and compared outcomes with age and international prognostic score (IPS)-matched patients in the RATHL trial.Results: Over this 10-year period, 250 patients were diagnosed with advanced-stage HL in the EECN; 202 commenced treatment with ABVD (23 within RATHL), 44 escBEACOPP, 3 other regimens, and 1 died before treatment. Five-year progression-free survival (PFS) for all patients was 82% and overall survival (OS) was 93%. In RATHL, 1088 patients aged 18-59 years commenced treatment with ABVD, with 5-year PFS of 81% and OS of 95%. Within the EECN, there was a clinician-patient preference to treat higher-risk patients (IPS 3+) with more intensive therapy; a higher proportion of escBEACOPP patients were IPS 3+ (IPS 3+: escBEACOPP 75% vs. ABVD 39%, p<0.0001).ABVD-treated EECN patients had highly similar 5-year PFS and OS rates compared with age-matched RATHL patients (PFS 80% vs 81%; HR: 1.1 (95% CI: 0.8-1.5), p=0.60: OS 93% vs 95%; HR: 1.5 (95% CI: 0.8-2.7), p=0.21; Figure 1A-B). Despite being enriched with higher-risk patients, the 5-year PFS for all escBEACOPP-treated EECN patients was superior to ABVD in both the EECN and RATHL cohorts (PFS 95% vs 80% (EECN); HR 0.2 (95% CI: 0.1-0.9), p=0.04; Figure 1C; Table 1), but there was no significant OS advantage (5-year OS 97% vs. 93% (EECN); HR 0.4 (95% CI: 0.0-2.8), p=0.34; Figure 1D; Table 1). However, subgroup analysis of higher-risk (IPS 3+) patients found that escBEACOPP-treated EECN patients had both a 5-year PFS and OS advantage when compared with IPS 3+ ABVD-treated EECN patients (PFS 97% vs 74%; HR 0.1 (95% CI: 0.0-0.8), p=0.03; OS 100% vs 85%; p=0.03). However, when these higher-risk escBEACOPP patients were compared with IPS 3+ patients from RATHL, the significance of the OS advantage was lost (Table 1).Despite similar relapse/refractory rates for IPS 3+ ABVD-treated patients in the EECN and RATHL datasets, the OS for relapsed/refractory patients was inferior in the EECN. One explanation could be the time period over which the EECN data was collected, as the majority (7/9) of higher-risk ABVD-treated EECN patients who died from progressive disease died prior to 2011, when brentuximab vedotin was unavailable to treat relapsed HL in the UK.Conclusion: Our data support recently published European data showing that first-line HL patients treated in the non-trial setting achieve similar outcomes to those treated in contemporary clinical trials. Our data also reflect prospective trial results which show a first-remission PFS, but not OS, advantage for advanced-stage HL patients treated with escBEACOPP compared with ABVD, but suggest that higher-risk patients might benefit disproportionately from more intensive first-line therapy with escBEACOPP. However, improved access to more effective salvage treatments for relapsed/refractory patients may have diminished any OS benefit from the use of first-line escBEACOPP in higher-risk patients. [Display omitted] DisclosuresFollows:Abbvie: Other: advisory board and lecturing; Janssen: Other: advisory board and lecturing; Gilead: Other: advisory board and lecturing; Roche: Other: advisory board and lecturing.

Reduced Mortality Risk in the Recent Era in Early-Stage Hodgkin Lymphoma Patients Treated With Radiation Therapy With or Without Chemotherapy

To determine the effect of treatment changes over time on all-cause mortality risk in patients with early-stage Hodgkin lymphoma (HL) after radiation therapy. The long-term survivorship of those with HL necessitates quantification of the late risk of mortality from HL and other causes. An institutional review board-approved retrospective study was conducted using a multi-institutional database of 1541 stage I and II HL patients treated from 1968 to 2007 with radiation therapy alone or combined-modality treatment. The analytic methods included cumulative incidence function, Kaplan-Meier estimates and log-rank tests for overall survival (OS) differences, and Cox proportional hazards modeling. The median age at diagnosis was 27 years. At a median follow-up of 15.2 years (35% of patients with >20 years of follow-up), 395 patients had died of all causes, including 85 HL, 168 second malignancy (25 hematologic and 143 nonhematologic), 70 cardiovascular, and 21 pulmonary deaths. The cumulative incidence of non-HL mortality had surpassed HL mortality at 8.3 years. For patients treated from 1968 to 1982, 1983 to 1992, and 1993 to 2007, the 15-year OS rates were 78%, 85%, and 88%, respectively (P=.0016). On Cox proportional hazards analysis, age, B symptoms, and number of disease sites were significantly associated with all-cause mortality in the first decade of follow-up, with a trend toward significance for radiation field extent. The all-cause mortality risk was significantly lower for patients treated in the most recent era during the first decade of follow-up, likely due to improved HL therapy resulting in a higher cure rate and lower treatment-related toxicity from smaller radiation fields. Current efforts toward radiation treatment reduction might further reduce the long-term mortality risk for these patients.

Impact of Consolidation Radiation Therapy in Stage III-IV Hodgkin Lymphoma After Complete Metabolic Response by Gallium or PET-CT

The role of consolidation radiation therapy (RT) in advanced Hodgkin lymphoma (HL) is controversial, in part due to conflicting results from randomized trials. These studies were conducted in the pre-positron emission tomography (PET) era and many did not utilize the ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). The role of consolidation RT after ABVD, in the setting of a complete response (CR) by metabolic imaging such as PET, is not well defined. We therefore analyzed our institutional experience over a 20 year period. This institutional review board-approved study reviewed all patients who received chemotherapy (ChT) alone or combined modality therapy (CMT) for advanced HL at our institution between 1992 and 2012. Patients were not randomized but allocated to ChT or CMT at physician’s discretion. Only patients achieving a CR by PET or gallium scan were included. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A multivariate analysis (MVA) for both PFS and OS using a Cox proportional hazards model was also performed. One hundred twenty-seven patients initiated chemotherapy for advanced HL during the time period. Exclusions included: primary refractory disease (n = 24), positive post-chemotherapy PET (n = 3), no functional imaging (n = 4), died during chemotherapy (n = 5), concurrent AML (n = 1). Thus, 90 patients were identified (44 ChT alone; 46 CMT). Bulky disease was present in 18% and 28% of ChT alone and CMT cohorts, respectively (P = 0.26). Chemotherapy (median 6 cycles, range 4-8) was ABVD in 80%. Post-chemotherapy imaging was PET in 71% and gallium in 29%. Median RT dose was 21 Gy (range, 13-31). RT fields varied but primarily included all sites of original involvement. CMT patients were younger (34 vs. 49 years, P = 0.002), more often had stage III disease (65% vs. 45%, P = 0.06), and a lower International Prognostic Score (2 versus 3, P = 0.04) compared with patients treated with ChT alone. With a median follow-up of 50 months, 5-year PFS (88% vs. 65%, P<0.001) and OS (97% vs. 78%, P = 0.002) favored CMT. PFS (83% vs. 42%) and OS (92% vs. 60%) at 10 years also favored CMT. On MVA, age < 45 years (HR = 4.26, 95% CI = 1.5-15.6) and CMT (HR = 3.19, 95% CI = 1.1-10.7) were independently associated with improved PFS. Age <45 years (P < 0.001) and CMT (HR = 4.5, 95% CI = 1.06-32) were also independently associated with improved survival. There were no deaths in patients <45 years. Secondary malignancies developed in 4 ChT alone patients and 5 CMT patients. Cardiac events occurred in 2 ChT alone patients (both CHF) and 5 CMT patients (2 MI, 3 CHF). Low-dose consolidation RT improved PFS and OS in our series of advanced HL patients achieving a CR to chemotherapy by PET or gallium scan. CMT remains an effective treatment strategy with acceptable toxicity in the ABVD-era.

Breast Cancer Risk After Radiation Therapy for Hodgkin Lymphoma: Influence of Gonadal Hormone Exposure

Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk. We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports. We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause <30years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR, 0.13; 95% CI, 0.03-0.51) than did women with menopause ≥50years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<.001). Among women with early menopause (<45years), hormone replacement therapy (HRT) use for ≥2years did not increase BC risk (OR, 0.86; 95% CI, 0.32-2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve. BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship.

Abstract 3724: PDL1 protein expression and tumor mutation burden in hematologic malignancies: correlation with Hodgkin and high grade lymphoma

Abstract Background: The success of anti PD–1 therapy in Hodgkin lymphoma has led to clinical trials in other types of lymphomas. However, there is limited data on PD–L1 expression in acute leukemias. In this study, we analyzed PD–L1 protein expression and tumor mutational burden in various hematologic malignancies including leukemias, lymphomas and myelomas. Methods: In the IHC cohort, formalin fixed paraffin embedded sections from 92 hematologic malignancies including acute myeloid and lymphoblastic leukemia (AML, ALL), Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), low-grade non-Hodgkin lymphoma (LGNHL) and myeloma were immunostained using the FDA approved PD-L1 IHC 22C3 pharmDx assay [monoclonal mouse anti-PD–L1 antibody (DAKO clone 22C3)]. Any perceptible partial or complete membrane staining in all viable tumor cells was scored as follows: &amp;lt;1%-negative, 1-49%-low level and &amp;gt;50%-high level PD-L1 expression. In the second cohort of 2064 cases, comprehensive genomic profiling (CGP) was performed using a hybrid–capture, adaptor ligation assay to a mean depth of &amp;gt;672X. Tumor mutation burden (TMB) was calculated from a minimum of 1.11MB of sequenced DNA as previously described and reported as mutations/MB. High PD–L1 expression was noted in 100% of HL. DLBCL showed significantly higher PD–L1 positivity compared to LGNHL (p=0.01). No correlation for PD–L1 expression was noted between AML and ALL (p = 0.2). On CGP analysis of the second cohort, TMB was significantly higher in DLBCL as compared to LGNHL (p&amp;lt;0.0001). Conclusion: The high PD-L1 expression in both HL and DLBCL and high TMB in DLBCL may be linked to enhanced responsiveness to check point inhibitor therapy in these cancers. PD-L1 expression and TMB are relatively infrequent and at low levels in acute leukemias. Additionally, novel anti PD–1/PD–L1 therapeutic strategies are worthy of consideration for both advanced stage refractory/relapsed acute myeloid and lymphoblastic leukemias. Results: PD-L1 expression and TMB are tabulated below.PD-L1 IHCTMB (mutations/MB)Tumor typenLow PositiveHigh PositiveTotal Positive (%)n&amp;gt;=10.0&amp;gt;=20.0AML21505/21 (24%)50%0%ALL3212012/32 (38%)10%0%HL1001010/10 (100%)368%8%DLBCL10448/10 (80%)25344%15%LGNHL10202/10 (20%)930%0%Myeloma9202/9 (22%)NANANA Citation Format: Lina Abdul Karim, Peng Wang, Jose de Guzman, Brandi Higgins, Joeffrey Chahine, Christine Sheehan, Bhaskar Kallakury, Jeffrey S. Ross. PDL1 protein expression and tumor mutation burden in hematologic malignancies: correlation with Hodgkin and high grade lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3724. doi:10.1158/1538-7445.AM2017-3724

How to Approach a Patient With Limited Stage Hodgkin Lymphoma Who Remains PET Positive at the End of Chemotherapy: Radiation Therapy?

The use of 18-F fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography has emerged as a crucial tool for response-adapted therapy in Hodgkin lymphoma (HL). Although more studies have focused on the predictive value of an interim or early PET obtained after 2 cycles of chemotherapy, there are indications that the end of therapy PET might even be more predictive of outcome. The optimal treatment of patients with limited stage HL who are PET-positive after chemotherapy is unknown. Here we review the prognostic significance of end of treatment PET in early stage HL, the role of consolidative radiotherapy in patients who have FDG-PET avidity at the end of chemotherapy, and discuss the place of salvage chemotherapy and autologous transplantation in these patients.

Response-adapted therapy in Hodgkin lymphoma.

Journal supplement: 14th International Conference on Malignant Lymphoma Palazzo dei Congressi, Lugano (Switzerland) 14-17 June, 2017