As survival times of multiple myeloma (MM) patients continue to improve, second primary malignancies (SPM) have become an increasingly relevant long-term risk among MM survivors. Population studies since the 1950s have consistently observed an increased incidence of hematologic SPMs, specifically acute leukemia, among MM survivors. Prolonged treatment with alkylators, especially melphalan, was associated with an increased hematologic SPM risk; likewise, autologous stem cell transplantation appeared to minimally increase SPM risk. Immunomodulatory drugs, specifically lenalidomide, was associated with an increased SPM incidence, although most studies concluded that the benefits of therapy outweighed any risks of SPM. Newer anti-myeloma therapy such as proteasome inhibitors and monoclonal antibodies did not appear to increase SPM risk although robust long-term follow-up is lacking. This review discusses current understanding regarding SPMs among survivors of MM, how different host-, disease- and treatment-related factors contribute to SPM incidence and highlights emerging screening guidelines and prognosis for SPMs.

The cumulative incidence, risk factors, rate of subsequent venous thromboembolism (VTE) and bleeding and impact on mortality of isolated upper extremity deep vein thrombosis (UE DVT) in acute leukemia are not well-described. The California Cancer Registry, used to identify treated patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) diagnosed between 2009 and 2014, was linked with the statewide hospitalization database to determine cumulative incidences of UE DVT and subsequent VTE and bleeding after UE DVT diagnosis. Cox proportional hazards regression models were used to assess the association of UE DVT on the risk of subsequent pulmonary embolism (PE) or lower extremity deep vein thrombosis (LE DVT) and subsequent bleeding, and the impact of UE DVT on mortality. There were 5,072 patients identified: 3,252 had AML and 1,820 had ALL. Three- and 12-month cumulative incidences of UE DVT were 4.8% (95% confidence interval [CI]: 4.1-5.6) and 6.6% (95% CI: 5.8-7.5) for AML and 4.1% (95% CI: 3.2-5.1) and 5.9% (95% CI: 4.9-7.1) for ALL, respectively. Twelve-month cumulative incidences of subsequent VTE after an incident UE DVT diagnosis were 5.3% for AML and 12.2% for ALL. Twelve-month cumulative incidences of subsequent bleeding after an incident UE DVT diagnosis were 15.4% for AML and 21.1% for ALL. UE DVT was associated with an increased risk of subsequent bleeding for both AML (hazard ratio [HR]: 2.07; 95% CI: 1.60-2.68) and ALL (HR: 1.62; 95% CI: 1.02-2.57) but was not an independent risk factor for subsequent PE or LE DVT for either leukemia subtype. Isolated incident UE DVT was associated with increased leukemia-specific mortality for AML (HR: 1.42; 95% CI: 1.16-1.73) and ALL (HR: 1.80; 95% CI: 1.31-2.47). UE DVT is a relatively common complication among patients with AML and ALL and has a significant impact on bleeding and mortality. Further research is needed to determine appropriate therapy for this high-risk population.

Basal bodies are essential microtubule-based structures that template, anchor, and orient cilia at the cell surface. Cilia act primarily in the generation of directional fluid flow and sensory reception, both of which are utilized for a broad spectrum of cellular processes. Although basal bodies contribute to vital cell functions, the molecular contributors of their assembly and maintenance are poorly understood. Previous studies of the ciliate Tetrahymena thermophila revealed important roles for two centrin family members in basal body assembly, separation of new basal bodies, and stability. Here, we characterize the basal body function of a centrin-binding protein, Sfr1, in Tetrahymena. Sfr1 is part of a large family of 13 proteins in Tetrahymena that contain Sfi1 repeats (SFRs), a motif originally identified in Saccharomyces cerevisiae Sfi1 that binds centrin. Sfr1 is the only SFR protein in Tetrahymena that localizes to all cortical row and oral apparatus basal bodies. In addition, Sfr1 resides predominantly at the microtubule scaffold from the proximal cartwheel to the distal transition zone. Complete genomic knockout of SFR1 (sfr1Δ) causes a significant increase in both cortical row basal body density and the number of cortical rows, contributing to an overall overproduction of basal bodies. Reintroduction of Sfr1 into sfr1Δ mutant cells leads to a marked reduction of cortical row basal body density and the total number of cortical row basal bodies. Therefore, Sfr1 directly modulates cortical row basal body production. This study reveals an inhibitory role for Sfr1, and potentially centrins, in Tetrahymena basal body production. IMPORTANCE Basal bodies and centrioles are structurally similar and, when rendered dysfunctional as a result of improper assembly or maintenance, are associated with human diseases. Centrins are conserved and abundant components of both structures whose basal body and centriolar functions remain incompletely understood. Despite the extensive study of centrins in Tetrahymena thermophila, little is known about how centrin-binding proteins contribute to centrin's roles in basal body assembly, stability, and orientation. The sole previous study of the large centrin-binding protein family in Tetrahymena revealed a role for Sfr13 in the stabilization and separation of basal bodies. In this study, we found that Sfr1 localizes to all Tetrahymena basal bodies and complete genetic deletion of SFR1 leads to overproduction of basal bodies. The uncovered inhibitory role of Sfr1 in basal body production suggests that centrin-binding proteins, as well as centrins, may influence basal body number both positively and negatively.

Background Venous thromboembolism (VTE) is a known complication in patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and non-Hodgkin's lymphoma (NHL). However, the cumulative incidence, risk factors, rate of subsequent VTE and impact on mortality of upper extremity deep vein thrombosis (UE DVT) in these diseases is not well-described. Methods Using the California Cancer Registry, we identified patients with a first primary diagnosis of AML, ALL and NHL from 2005-2014 and linked these patients with the statewide hospitalization and emergency department databases to identify an incident UE DVT event using specific ICD-9-CM codes. Patients with VTE prior to or at the time of malignancy diagnosis or who were not treated with chemotherapy were excluded. We determined the cumulative incidence of first UE DVT, adjusted for the competing risk of death. We also examined the cumulative incidence of subsequent VTE (UE DVT, lower extremity deep vein thrombosis (LE DVT) and pulmonary embolism (PE)) and major bleeding after incident UE DVT. Using Cox proportional hazards regression models, stratified by tumor type and adjusted for other prognostic covariates including sex, race/ethnicity, age at diagnosis, neighborhood, sociodemographic status and central venous catheter (CVC) placement, we identified risk factors for development of incident UE DVT, the effect of incident UE DVT on PE and/or LE DVT development, and impact of incident UE DVT on cancer specific survival. The association of CVC placement with incident UE DVT was not assessed in acute leukemia patients, as all who undergo treatment were assumed to have a CVC. Results are presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results Among 37,282 patients included in this analysis, 6,213 had AML, 3,730 had ALL and 27,339 had NHL. The 3- and 12-month cumulative incidence of UE DVT was 2.6% and 3.6% for AML, 2.1% and 3% for ALL and 1.0% and 1.6% for NHL respectively (Figure 1A). Most (56-64%) incident UE DVT events occurred within the first 3 months of malignancy diagnosis. African Americans (HR 1.66; CI 1.22-2.28) and Hispanics (HR 1.35; CI 1.10-1.66) with NHL had an increased risk of incident UE DVT compared to non-Hispanics Whites. NHL patients with a CVC had over a 2-fold increased risk of incident UE DVT (HR 2.05; CI 1.68-2.51) compared to those without a CVC. UE DVT was a risk factor for development of PE or LE DVT in ALL (HR 2.53; CI 1.29-4.95) and NHL (HR 1.63; CI 1.11-2.39) but not in AML. The 12-month cumulative incidence of subsequent VTE after an incident UE DVT diagnosis was 6.4% for AML, 12.0% for ALL and 7.6% for NHL. 46-58% of subsequent VTEs occurred within the first 3 months of incident UE DVT diagnosis. The majority of subsequent VTEs were UE DVT which had a 12-month cumulative incidence of 4.6% for AML, 6.6% for ALL and 4.0% for NHL (Figure 1B). The 12-month cumulative incidence of subsequent LE DVT was 1.3% for AML, 1.6% for ALL and 1.9% for NHL (Figure 1C). The 12-month cumulative incidence of subsequent PE was 0.4% for AML, 4.1% for ALL and 1.8% for NHL (Figure 1D). The 12-month cumulative incidence of major bleeding after an UE DVT diagnosis was 29% for AML, 29% for ALL and 20% for NHL. Common major bleeding events included gastrointestinal (GI) bleeds, epistaxis and intracranial hemorrhage. GI bleeding was the most common major bleeding event among all three malignancies (14.2% in AML, 9.6% in ALL and 12.4% in NHL). The rate of intracranial hemorrhage was 6% in AML, 3.5% in ALL and 1.7% in NHL. A diagnosis of incident UE DVT was associated with an increased risk of cancer-specific mortality in all three malignancies (HR 1.38; CI 1.16-1.65 in AML, HR 2.16; CI 1.66-2.82 in ALL, HR 2.38; CI 2.06-2.75 in NHL). Conclusions UE DVT is an important complication among patients with AML, ALL and NHL, with the majority of UE DVT events occurring within the first 3 months of diagnosis. The most common VTE event after an index UE DVT was another UE DVT, although patients also had subsequent PE and LE DVT. UE DVT was a risk factor for development of PE or LE DVT in ALL and NHL, but not in AML. Major bleeding after an UE DVT was high in all three malignancies (>20%), with GI bleeds being the most common. UE DVT in patients with AML, ALL and NHL is associated with increased risk of mortality. Disclosures: Wun: Janssen: Other: Steering committee; Pfizer: Other: Steering committee.

Abstract: Introduction: While previous studies propose pesticide exposure to be a risk factor for non-Hodgkin lymphoma (NHL) development, results are inconclusive. In addition, the impact of pesticide exposure on NHL survival is not well-established. Therefore, we identified NHL patients from the California Cancer Registry and linked these patients with the statewide pesticide use reporting database to determine the impact of pesticide exposure on NHL-related incidence and outcomes. Methods: Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010-2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state mandated Pesticide Use Reporting (PUR) by census tract from 2012-2014. In addition, data from PUR was integrated into a geographic information system that employs land use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. SEER*Stat software was used to calculate NHL subtype incidence rates by census tract pesticide use level. Multivariable cox proportional hazards regression models were used to evaluate the impact of total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data on lymphoma-specific and overall survival. Results: Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Pesticide exposure was higher in Hispanic/Latino (46.5%) and non-Hispanic white (45.6%) then Asian/Pacific Islander (37.2%) and African American (34.9%) patients with NHL. Glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt exposure was reported in 34.1%, 26.0%, 10.6%, 14.0% and 12.8% of NHL patients, respectively. Pesticide exposure was not associated with increased NHL incidence by NHL subtype or subgroups defined by sociodemographic factors. Total pesticide exposure at time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival. Conclusion: In this large population-based study of neighborhood agricultural pesticide exposure, pesticide exposure was noted to be prevalent among patients diagnosed with NHL, with high pesticide exposure particularly observed in Hispanics/Latinos and non-Hispanic whites. However, pesticide exposure was not consistently associated with increased NHL incidence or worse NHL lymphoma-specific or overall survival. Disclosures: Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding.

Background

There is evidence indicating that pesticide exposure is a risk factor for non-Hodgkin lymphoma (NHL) development. However, the association between pesticide exposure and NHL survival is not well-established.

Methods

Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010 to 2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state-mandated Pesticide Use Reporting (PUR) by census tract from 2012 to 2014. In addition, data from PUR was integrated into a geographic information system that employs land-use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. Multivariable Cox proportional hazards regression models were used to evaluate the association between total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data and lymphoma-specific and overall survival.

Results

Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt exposure was observed in 34.1%, 26.0%, 10.6%, 14.0%, and 12.8% of NHL patients, respectively. Total pesticide exposure at the time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival.

Conclusions

Although we found no consistent associations between agricultural pesticide exposure at the neighborhood level and worse survival, these results provide a platform for designing future studies to determine the association between pesticide and NHL.

Purpose

Rituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described.

Patients and methods

We conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies.

Results

At a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B⁺ (GranB⁺) CD8⁺ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB⁺ CD8⁺ T-cell levels (% total lymphocytes).

Conclusions

Rituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB⁺ CD8⁺ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.