Macon, William R.

Key Points HGBL-DH/TH makes up 8% of de novo DLBCL, with HGBL-DH/TH with BCL2 rearrangement being a GCB phenomenon. Restricting FISH testing to tumors with dual protein expression and GCB subtype results in testing <15% of tumors, but missing ∼35% of HGBL-DH/TH.

Cutaneous reactions to red tattoo pigment rarely manifest as pseudolymphomatous reactions. We describe an exceedingly rare case of red tattoo‐related T‐cell predominant pseudolymphoma microscopically mimicking mycosis fungoides. Careful clinicopathological correlation was required to obtain the correct diagnosis and aid in an effective treatment course.

Summary This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma ( DLBCL ) after failure of front line anthracycline‐based immunochemotherapy ( IC ). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource ( MER ) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B‐cell lymphoma ( PMBL ) patients treated with front‐line anthracycline‐based IC were followed for relapse. Patients with relapse on follow‐up and subsequently retreated were included in this analysis. 1039 patients received anthracycline‐based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years ( OS 4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (auto HCT ) with OS 4 from auto HCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS 4 of 47% but those with a transient or no response to initial therapy had OS 4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo auto HCT . The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL .

SummaryHistological transformation (HT) of follicular lymphoma (FL) to an aggressive lymphoma after chemotherapy remains a key issue. The incidence of HT after radioimmunotherapy (RIT) is unknown. This single institution study analysed the risk of HT in FL after treatment with yttrium‐90 ibritumomab tiuxetan in 115 consecutive patients treated during 1987–2012. RIT was administered for progressive FL in 111 (97%) patients and as first‐line therapy in the remaining 4. 28% (n = 32) had HT, occurring at a median of 60 months from diagnosis and 20 months after RIT. 48% (12/25) of patients who received fludarabine developed HT. The estimated 10‐year risk of HT in the fludarabine and non‐fludarabine groups was 67% and 26% respectively (P = 0·015). Only prior fludarabine was significantly associated with predicting the risk of HT after RIT. 8% (9/115) of patients developed therapy‐related myelodysplastic syndrome/acute myeloid leukaemia (tMDS/AML) at a median of 41·4 months (range, 5–89). The estimated 10‐year risk of tMDS/AML in non‐fludarabine treated patients (n = 90) versus fludarabine treated (n = 25) was 13% and 29%, respectively. The estimated overall risk of FL undergoing HT at 10 years without fludarabine exposure appears similar to patients reported in the literature that have not received RIT. Patients with prior purine‐analogue therapy are at significantly higher risk of HT.

AbstractRelapsed indolent lymphoma often becomes refractory to standard chemoimmunotherapy and requires new therapeutic strategies. Targeting the PI3K/mTOR pathway in several types of lymphoma has shown preclinical and clinical efficacy providing the rationale to test this strategy in the treatment of relapsed/refractory indolent lymphomas. We investigated in a phase II open label clinical trial the efficacy and safety of single agent everolimus, an inhibitor of mTORC1, in patients with relapsed/refractory indolent lymphomas. Eligible patients received oral everolimus 10 mg daily on a 28 day‐cycle schedule. The primary endpoint was to evaluate the overall response rate (ORR) and safety of single‐agent everolimus in this patient population. Fifty‐five patients with indolent lymphoma were accrued. The median age was 67 years (range: 33‐85) with a median of five prior therapies (range: 1‐10). The ORR was 35% (19/55; 95% CI: 24‐48%), with complete response unconfirmed in 4% (2/55), and partial response in 31% (17/55). The ORR was 61% (14/23) in the patients with FL. The median time to response was 2.3 months (range: 1.4‐14.1), median duration of response of 11.5 months (95%‐CI: 5.7‐30.4), and a median progression‐free survival of 7.2 months (95%‐CI: 5.5‐12.5). The most common toxicity was hematologic with grades 3‐4 anemia, neutropenia, and thrombocytopenia documented in 15% (8/55), 22% (12/55), and 33% (18/55), respectively. There were no cases of febrile neutropenia, and eight patients discontinued therapy because of adverse events. Everolimus monotherapy is a valid therapeutic option in the relapsed and/or refractory indolent non‐Hodgkin lymphoma patients and is well tolerated.

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event‐free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1‐3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002‐2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re‐treatment, or death due to any cause. OS was compared to age‐and‐sex‐matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78‐4.88; Lyon SMR = 8.74, 95%CI: 5.41‐13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56‐0.94, Lyon SMR = 1.02, 95%CI: 0.58‐1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97‐25.02, Lyon SMR = 19.10, 95%CI:9.86‐33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31‐17.74, Lyon SMR = 7.22, 95%CI:4.13‐11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096–1101, 2016. © 2016 Wiley Periodicals, Inc.

Abstract Background. DLBCL is the most common non-Hodgkin lymphoma (NHL) subtype in western countries and is known to be clinically heterogeneous. Gene expression profiling has identified two major, biologically distinctive DLBCL subtypes on the basis of their cell-of-origin (COO): the germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. Recently, the InterLymph Subtypes Project identified medical history, lifestyle, and family history risk factors for DLBCL using a large pooled analysis of case-control studies. In this study we evaluated these same risk factors for etiologic heterogeneity as defined by DLBCL COO. Methods. For this analysis we used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2012, with 474 DLBCL cases and 2203 controls. COO was determined clinically using the Hans algorithm, which is based on immunohistochemistry markers using formalin-fixed, paraffin-embedded tumor tissue. Amongst DLBCL cases 107 were ABC, 207 were GCB, and 160 were missing subtype (tissue unavailable). Risk factor data, including body mass index (BMI), smoking, alcohol use, any allergy, asthma, blood transfusion, diabetes, rheumatoid arthritis, sun exposure, lived on a farm and family history of hematologic malignancy, were collected from self-administered questionnaires. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for ABC and GCB subtypes, adjusted for age and sex. Results. The mean age of cases was 60.4 years with 53% male; the mean age of controls was 61.6 years and 53% male. We identified a strong positive association for BMI with risk of ABC but not GBC DLBCL (p-heterogeneity 0.025). Compared to BMI 18.5-24.9 kg/m2, those with a BMI of 25.0-29.9 (OR = 1.65; 0.93-2.93) or 30+ (OR = 2.61; 1.48-4.62) were at increased risk of ABC DLBCL. There was no association for a BMI of 25.0-29.9 (OR = 0.91; 0.63-1.31) or 30+ (OR = 1.21; 0.83-1.76) with GCB DLBCL. There was no evidence of significant heterogeneity between ABC and GCB DLBCL for the other risk factors that we evaluated. Further adjustment of the BMI association for educational level, smoking, and alcohol only slightly attenuated these findings. Conclusions. We observed a strong positive association of BMI with ABC but not GCB DLBCL. In contrast, other evaluated risk factors showed no heterogeneity by COO. While BMI has not been clearly associated with NHL overall, there has been evidence for an association with DLBCL. The etiologic heterogeneity we observed for ABC DLBCL is notable as BMI is also a strong risk factor for multiple myeloma, another post-germinal center B-cell malignancy. While requiring replication, our findings suggest BMI may influence B-cell neoplasia through effect on post-germinal center pathways. Citation Format: Matthew K. Breitenstein, Megan M. O’Byrne, Andrew L. Feldman, Carrie A. Thompson, William R. Macon, Grzegorz S. Nowakowski, Stephen M. Ansell, Susan L. Slager, Thomas M. Habermann, James R. Cerhan. Body mass index shows etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1762.

Key Points The risk of transformation of NLPHL to DLBCL is 0.74 per 100 patient-years of follow-up. Risk factors for transformation include prior exposure to chemotherapy and splenic involvement at time of diagnosis.