Citations

Abstract Background. The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma. Methods. Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated. Results. A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age <60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS. Conclusion. Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy. Implications for Practice: Patients with salivary gland extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) have an excellent prognosis, particularly those with associated Sjögren's disease. A wide range of available therapies may provide similar durable rates of disease control and survival. Therefore, an important goal in selection of therapy should be to minimize morbidity from treatment. When determining initial therapy for these patients, practitioners should consider the potential side effects and long-term toxicities of treatment.

Abstract Background. Non-steroidal anti-inflammatory drugs (NSAIDs) and statin drugs have been suggested as protective agents against the development of non-Hodgkin lymphoma (NHL), but data are limited, particularly for NHL subtypes. Further, some in vitro, animal and epidemiologic data suggest there may be a synergistic effect of these two agents in cancer prevention, but there has been no test of this hypothesis in NHL. Methods. We evaluated the use of NSAIDs and statins in a clinic-based study of 1683 newly diagnosed cases and 2168 frequency matched controls enrolled from 2002-2012. Regular use (at least once/week for at least one year) of low dose (baby) aspirin, standard or extra strength aspirin, ibuprofen, other NSAIDs (e.g., naproxen, etc), COX-2 inhibitors, as well as statins or other cholesterol lowering drugs, was ascertained using a self-administered questionnaire. Frequency, amount and duration of use were also collected. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, education, body mass index, smoking history, alcohol use, and history of rheumatoid arthritis and osteoarthritis. Pathologic classification of NHL subtypes was centrally reviewed, and subtype-specific NHL risks were estimated using polychotomous logistic regression for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, N = 495), diffuse large B-cell (DLBCL, N = 326), follicular (FL, N = 410) and marginal zone (MZL, N = 134) lymphomas. Results. The mean age of cases was 61.8 years and 59% were men, while the mean age of controls was 61.6 years and 53% were men. We observed an inverse association of low dose aspirin use with risk of NHL (OR = 0.82; 95% CI 0.70-0.96), with stronger associations for more pills per day, longer duration of use and greater number of pill-years. In contrast, we observed no evidence of an association with NHL risk with use of regular or extra-strength aspirin, ibuprofen, other NSAIDs, or COX-2 inhibitors, nor use of statins or other cholesterol-lowering drugs. When we modeled the joint use of low dose aspirin and statins, the strongest inverse association was observed for low dose aspirin use only, followed by use of both aspirin and statins; there was no association with statin use only and no evidence for any interaction of low dose aspirin and statins on NHL risk. For low dose aspirin, the strongest inverse trends were observed for DLBCL, followed by FL and MZL, while there were no consistent associations for CLL/SLL. Conclusions. We found a strong inverse association of low dose aspirin use with risk of NHL and the subtypes of DLBCL, FL, and MZL, but no association for regular/extra strength aspirin, other NSAIDs or statin use. While confirmation is needed, our findings for low dose aspirin but not use of other NSAIDs suggest that anti-platelet or other effects of low dose aspirin may be of etiologic significance in lymphomagenesis. Citation Format: James R. Cerhan, Megan M. O'Bryne, Grzegorz S. Nowakowski, Timothy G. Call, Carrie A. Thompson, Tait D. Shanafelt, William R. Macon, Neil E. Kay, Thomas M. Habermann, Susan L. Slager, Mark Liebow. Aspirin and other nonsteroidal anti-inflammatory drugs, statins, and risk of non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 877. doi:10.1158/1538-7445.AM2015-877

Abstract Background: Protein kinase Cβ (PKCβ) is critical for B-cell signaling and survival and overexpression of PKCβ in DLBCL is associated with inferior survival. ENZA, an oral serine/threonine kinase inhibitor, targets PKCβ. Here we report immunohistochemical (IHC) and fluorescence in-situ hybridization (FISH) correlative analyses. Methods: PRELUDE (NCT00332202) was a phase III, double-blind maintenance study of 758 pts with DLBCL who were randomized 2:1 to ENZA 500 mg daily (1125-mg loading dose) (n = 504) or PBO (n = 254), respectively, following CR to induction therapy with R-CHOP. The primary endpoint was disease-free survival (DFS). Overall survival (OS) and assessment of biomarkers specific to ENZA and DLBCL were secondary endpoints. Pre-treatment formalin-fixed, paraffin-embedded samples were assessed via IHC staining in a blinded manner (Eric Hsi) for cell of origin (COO) using Hans’ algorithm. In addition, IHC was performed for c-MYC, BCL2, BCL6, FOXP1, and MUM1 (10% increments/% tumor cells stained), markers relevant to ENZA, including PKCβ2. FISH was performed to identify translocations involving c-MYC, BCL2, and BCL6. Cox regression was used to determine statistical associations between efficacy outcomes and dichotomized markers, adjusting for treatment and additional baseline covariates. All tests of association were conducted at a 2-sided α = 0.05. Results: There was no difference in 4-year DFS (70% vs 71%) or OS (81% vs 82%) between ENZA and PBO arms, respectively. A total of 243 (32%) pts had ≥1 evaluable sample available for IHC and FISH. There was no difference in outcome for pts based on COO (GCB vs non-GCB). Independent of treatment, significant associations were observed for BCL2 (pre-specified cutpoint 20%) and MUM1 (cutpoint 30%) with OS, and FOXP1 (cutpoint 80%) by IHC with DFS (HR [95% CI]: 2.19 [1.01-4.73]), p = 0.031; 1.97 [1.04-3.71], p = 0.032; 1.74 [1.04-2.90], p = 0.032, respectively). Associations were not significant for other IHC markers, including c-MYC and BCL6. Low PKCβ2 (<50% expression) had numerically better (but not significant) DFS/OS vs high PKCβ2. Dual translocation lymphoma by FISH was identified in two pts (1.2%) each for c-MYC/BCL2 and c-MYC/BCL6, and one pt (0.6%) had a triple hit involving c-MYC/BCL2/BCL6. Conclusions: No difference in outcomes between treatment arms was observed for the trial. Independent of treatment, COO was not prognostic of outcomes. Pts with low PKCβ2 expression had numerically better DFS/OS compared with high PKCβ2 expression. Significant treatment-independent associations were observed for BCL2 and MUM1 with OS and for FOXP1 with DFS (low IHC expression corresponded to better outcomes). The small number of double hit and triple hit lymphomas seen in the study may reflect the enrollment of CR patients with more favorable biology. Citation Format: Eric D. Hsi, Kerry J. Savage, Sonali M. Smith, Fritz Offner, Scott P. Myrand, Thomas M. Habermann, Donald E. Thornton, Boris K. Lin, Tuan S. Nguyen, Oday Hamid, Michael Crump. Correlative results from PRELUDE, a phase III study of enzastaurin (ENZA) vs placebo (PBO) in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL) following a response to R-CHOP therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5303. doi:10.1158/1538-7445.AM2015-5303

Abstract Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow‐up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa‐associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty‐five per cent of the patients were female. The median age at diagnosis was 62 (range 28–88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression‐free survival ( p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long‐term disease‐free survival for patients with localized disease. Systemic treatment, including alkylating‐containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright © 2015 John Wiley & Sons, Ltd.

The World Health Organization classification of non‐Hodgkin lymphoma (NHL) was introduced in 2001. However, its incorporation into clinical practice is not well‐described. We studied the distribution of NHL subtypes in adults diagnosed from 1998 to 2011, evaluated time trends, geo‐demographic correlates, and changes in 5‐year overall survival (OS). We obtained data prospectively collected by the National Cancer Data Base, which covers 70% of US cancer cases. There were 596,476 patients diagnosed with NHL. The major subtypes were diffuse large B‐cell (32.5%), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 18.6%), follicular (17.1%), marginal zone (8.3%), mantle cell (4.1%), peripheral T‐cell not‐otherwise‐specified (1.7%), Burkitt (1.6%), hairy cell (1.1%), lymphoplasmacytic (1.1%), and NHL not‐otherwise‐specified (10.8%). Over the study period, the proportion of NHL not‐otherwise‐specified declined by half, while marginal zone lymphoma doubled. The distribution of major and rare NHL subtypes varied according to demographics but less so geographically or by type of treatment facility. We noted several novel findings among Hispanics (lower proportion of CLL/SLL, but higher Burkitt lymphoma and nasal NK/T‐cell lymphoma), Asians (higher enteropathy‐associated T‐cell and angioimmunoblastic T‐cell lymphomas), Blacks (higher hepatosplenic T‐cell lymphoma), and Native Americans (similar proportions of CLL/SLL and nasal NK/T‐cell lymphoma as Asians). With the exception of peripheral T‐cell not‐otherwise‐specified and hairy cell leukemia, 5‐year OS has improved for all the major NHL subtypes. Am. J. Hematol. 90:790–795, 2015. © 2015 Wiley Periodicals, Inc.

Abstract Objectives and Rationale: Structural variants (SV) including large copy number aberrations (CNV), translocations, inversions, and large insertions and deletions (INDEL) play a critical role in tumorigenesis and progression. In fact, we now know that tumors can be categorized according to the size of mutations harbored. In several cancers, including ovarian and breast cancer, the large structural mutations, rather than single site mutations, play a dominate role in tumor etiology. Therefore, it's critical to implement reliable algorithm for the detection of structural variants in DNA sequencing data. Mate-pair sequencing is a protocol specifically implemented for detection of the whole-genome level structural variants. It requires less sequencing depth therefor is cost effective, and enables the detection of CNVs, translocations, and inversions simultaneously. However, so far there has been no reliable bioinformatics pipeline for the analyses of the mate-pair sequencing data. Methods: Our novel algorithm, the SnowShoes-SV, is an exhaustive search algorithm designed specifically for mate-pair DNA sequencing data analyses. It calls the SVs based on disconcordant read pairs. The false SVs are filtered according to the following criteria: (i) the number of the supporting read pairs; (ii) the lack of reads from control data that implicate SV at the same region; (iii) the mappability and uniqueness of the region based on data from the ENCODE project; (iv) consistencies of the mapping orientations of the supporting read pairs; (v) the similar sizes between sequencing library and the two end read clusters. Results: Using a set of samples previously genotyped by aCGH, the SnowShoes-SV successfully detected all known CNVs and other SVs. It also identified copy number neutral translocations and inversions previously not identified by aCGH. In addition, the algorithm nominated novel SVs which are to be validated by PCR. Conclusions: SnowShoes-SV is a highly sensitive and specific algorithm for SV detection from the mate-pair DNA sequencing data. Citation Format: Yan W Asmann, Chen Wang, Brian M Necela, Xianfeng Chen, Jean-Pierre A Kocher, Matthew J Maurer, Thomas M Habermann, Susan L Slager, Andrew L Feldman, Anne J Novak, James R Cerhan, Edith A Perez, E Aubrey Thompson. An exhaustive algorithm for detecting copy number aberrations and large structural variants in whole-genome mate-pair sequencing data [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-07-03.

Key Points The mTOR pathway is constitutively activated in the TCL cells and is responsible for TCL proliferation. This is first trial to demonstrate that mTORC1 inhibitors (everolimus) have substantial antitumor activity (44% overall response rate) in patients with relapsed TCL.

Summary A persistently positive positron emission tomography ( PET ) scan during therapy for diffuse large B‐cell lymphoma ( DLBCL ) is predictive of treatment failure. A response‐adapted strategy consisting of an early treatment change to four cycles of R‐ ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R‐ CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET ‐positive patients received four cycles of R‐ ICE , PET ‐negative patients received two more cycles of R‐ CHOP . A ≥45% 2‐year progression‐free survival ( PFS ) for mid‐treatment PET ‐positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two‐year PFS was 70%; 42% [90% confidence interval (CI), 19–63%] for PET ‐positives and 76% (90% CI 65–84%) for PET ‐negatives. Three‐year overall survival ( OS ) was 69% (90% CI 43–85%) and 93% (90% CI 86–97%) for PET ‐positive and ‐negative cases, respectively. The 2‐year PFS for mid‐treatment PET ‐positive patients intensified to R‐ ICE was 42%, with a wide confidence interval due to the low proportion of positive mid‐treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.

Although transformation to Hodgkin lymphoma (HL) is a recognized complication in patients with chronic lymphocytic leukemia (CLL), its incidence, clinical characteristics and outcomes are not well defined. We used the Mayo Clinic CLL and Lymphoma Databases to identify CLL patients who developed biopsy‐proven HL (CLL/HL) on follow‐up, as well as cases of de novo HL (i.e., without prior CLL). Among 3887 CLL patients seen at Mayo Clinic from January 1995 through August 2011, 26 (0.7%) developed HL. In a nested cohort of 2,465 newly diagnosed CLL patients followed prospectively, the incidence of HL was 0.05%/year (10 year risk = 0.5%). The median overall survival (OS) from date of HL diagnosis in patients with CLL/HL was 3.9 years compared to not reached for de novo HL patients ( n = 709) seen during the same time interval ( P < 0.001). The shorter OS of CLL/HL patients persisted after adjusting for differences in age and Ann Arbor stage of disease. The International Prognostic score (IPS) developed for de novo HL stratified prognosis among CLL/HL patients with median survival of not reached, 6.2, 2.4, and 0.3 years ( P = 0.006) for those with IPS scores of ≤2, 3, 4, and ≥5, respectively. In summary, approximately 1 of every 200 CLL patients will develop HL within 10 years. Survival after HL diagnosis in patients with CLL is shorter than de novo HL patients. The IPS for de novo HL may be useful for stratifying survival in CLL/HL patients. Am. J. Hematol. 90:334–338, 2015. © 2015 Wiley Periodicals, Inc.

Key Points BCL2 mutations in FL correlate with activation-induced cytidine deaminase expression and frequently alter the amino acid sequence of the protein. Mutations in the BCL2 coding sequence at diagnosis are associated with shortened time to transformation and earlier death due to lymphoma.