ALBERT

Description: The February–March 2014 deployment of the National Aeronautics and Space Administration (NASA) Airborne Tropical Tropopause Experiment (ATTREX) provided unique in situ measurements in the western Pacific tropical tropopause layer (TTL). Six flights were conducted from Guam with the long-range, high-altitude, unmanned Global Hawk aircraft. The ATTREX Global Hawk payload provided measurements of water vapor, meteorological conditions, cloud properties, tracer and chemical radical concentrations, and radiative fluxes. The campaign was partially coincident with the Convective Transport of Active Species in the Tropics (CONTRAST) and the Coordinated Airborne Studies in the Tropics (CAST) airborne campaigns based in Guam using lower-altitude aircraft (see companion articles in this issue). The ATTREX dataset is being used for investigations of TTL cloud, transport, dynamical, and chemical processes, as well as for evaluation and improvement of global-model representations of TTL processes. The ATTREX data are publicly available online (at https://espoarchive.nasa.gov/).

Description: Most patients with follicular lymphoma (FL) achieve a complete response (CR) after treatment, but eventually most of them, particularly those with stage IV, relapse due to minimal residual disease (MRD). The t(14;18) gives rise to a rearrangement of the bcl-2 oncogene that constitutes an excellent target for detection of MRD by polymerase chain reaction (PCR). One hundred ninety-four previously untreated patients with indolent FL and detectable bcl-2 rearrangement were studied. The PCR assay was used to detect bcl-2–rearranged cells in blood and marrow before and after treatment. Molecular response rate was 37%, 53%, 56%, and 66% at 3 to 5, 6 to 8, 9 to 14, and 15 to 18 months from the start of therapy, respectively. Although molecular response was higher among clinical CRs, one third of partial responders at 3 to 5 months also achieved a molecular response. Patients who achieved a molecular response during the first year of treatment had a significantly longer failure-free survival (FFS) than those who did not (4-year FFS: 76% v 38%, respectively; P 〈 .001). Similar results were also observed in the subset of patients in clinical CR 1 year after treatment. By multivariate analysis, β2-microglobulin (β2-M; P 〈 .01), and molecular response (P 〈 .001) were the most important variables associated with outcome. When we combined β2-M and molecular response, three prognostic groups emerged: (1) low β2-M and molecular responders, (2) low β2-M and nonresponders or high β2-M and responders, and (3) high β2-M and nonresponders. The 4-year FFS of these 3 groups were 86%, 65%, and 23%, respectively. Finally, patients who achieved molecular response and sustained it had better FFS than those who either reverted back to PCR-positive or who never achieved molecular response. Serial PCR analysis to determine the molecular response in FL correlates well with outcome especially when combined with pretreatment β2-M.

Description: Background: Recent reports from prospective clinical trials of R-containing chemotherapy in DLBCL patients suggest that gender, weight and/or BMI influence clinical outcomes. Pharmacokinetic studies by the German High Grade Lymphoma Study Group have shown that R clearance is relatively slow in elderly women compared to men, leading to higher levels and prolonged exposure and hence better clinical outcomes in elderly females. Specifically, it has been suggested that elderly men are underdosed, based on faster R clearance (Muller et al., 2012; Pfreundschuh et al., 2014). Regarding BMI as a predictor of clinical outcome, analysis of the US Veterans Administrative database showed an association between increased BMI and improved survival in DLBCL patients (Carson et al., 2012), while the ECOG clinical trial (E4494) for elderly DLBCL patients failed to reveal a significant association of BMI with clinical outcomes, or a gender difference related to BMI in failure-free survival (Hong et al., 2014). To further investigate these associations, we studied the effect of gender, BMI as well as body surface area (BSA, the actual dosing parameter), and potential interactions among these factors on long-term clinical outcomes for elderly DLBCL patients in the National Comprehensive Cancer Network (NCCN) non-Hodgkin lymphoma database. Methods: De novo DLBCL patients with age 〉 60 yrs. were identified from the NCCN adult DLBCL cohort. Patients were diagnosed between June 2000 and December 2010. All received R as part of first-line therapy. Outcomes evaluated included progression free survival (PFS) and overall survival (OS) at 3 years based on patient gender, age and BMI/ BSA at presentation. Gender was stratified based on BMI (18.5-25, 〉25) or BSA (2), and Kaplan-Meier estimates were calculated. Associations with disease progression and survival were additionally adjusted for the International Prognostic Index (IPI) in the multivariable Cox regression analyses. Results: Of the 1,386 DLBCL patients who received R, 627 were elderly with age 〉60 yrs. The majority of elderly men were either overweight or large: only 13% had BMI

Description: Introduction: Aggressive MCL has a poor prognosis with a 21-40% complete remission (CR) after CHOP and a duration of response of only 10-16 months. More intense therapy could improve these statistics. Rituximab is effective in MCL and has minimal toxicity. Methods: A prospective phase II trial of R-HCVAD (considered to be one cycle) alternating every 21 days with R- M/A (considered to be another cycle) as described earlier (Ann Oncol. 13, suppl 2, 2002 #24). Prophylaxis with mesna, calcium leucovorin, prednisone eyedrops, G-CSF, antibacterial, antifungal, and antiviral therapy. CBC with differential and platelet counts X 2-3/week. Re-staging every 2 cycles including upper and lower endoscopies. Patients in complete remission (CR) after 6 courses of a planned 6-8 cycles were not offered consolidation with stem cell transplant. Post-treatment evaluation was performed every 3 months for 1 yr, every 4 months for 2 yrs, every 6 months for 2 years, then annually. Results: Of 100 patients registered, one was ineligible and two decided to not receive the treatment after registration, leaving 97 evaluable for analysis of response, survival and toxicity. An analysis of response after the first 6 cycles shows an 87% CR/CRu rate. With a median follow up of 40 months, the 3-year FFS and overall survival (OS) were 67% and 81%, respectively. Adverse factors for FFS were: Grade 4 hematologic toxicity was significant. Five patients died during treatment of sepsis (3), pulmonary hemorrhage (1), and unknown cause (1). Four patients developed myelodysplasia/acute myelogenous leukemia after treatment and while in CR and three have died, for a total of 8 deaths in the study (8%). Conclusion: R-HCVAD alternating with R-M/A without stem cell transplant is an effective regimen for treatment of aggressive untreated MCL, specially for patients ≤ 65 years old. Toxicity is as expected for an intense regimen. This encouraging data warrants continued follow-up and comparison with existing/new therapies in future trials.

Description: The malignant Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (HL) rarely survive outside their microenvironment, which is illustrated by the difficulty in establishing HRS-derived cell lines. Reactive B and T cells, monocytes, and eosinophils have been reported to express growth and survival factors such as CD30 ligand, CD40 ligand, RANK ligand, and BLyS that may support HRS cell survival. To examine the contribution of reactive B-cells to the survival of HRS cells in vivo, we hypothesized that depleting B-cells from the HL microenvironment by rituximab may deprive HRS cells from critical survival and resistance factors and thereby improving the efficacy of chemotherapy. To test this hypothesis, we evaluated the safety and efficacy of the novel combination of rituximab and ABVD (R-ABVD) chemotherapy in newly diagnosed patients with classical HL. Rituximab was given at 375 mg/m2 weekly for 6 weeks to rapidly deplete B lymphocytes, while ABVD was given at a standard dose and schedule. The first dose of rituximab was given concurrently with the first dose of ABVD (schedule A) or 3 weeks before the first dose of ABVD (schedule B). Patients with lesions larger than 5 cm received involved field radiation therapy at the end of R-ABVD. Patients were eligible if they were older than 16 years of age and had biopsy-confirmed classical HL irrespective of CD20 expression on HRS cells, bidimensionally measurable disease, adequate bone marrow reserve (ANC 〉 1,000/uL, Platelets 〉 100,000/uL) and adequate cardiac and renal functions. They were excluded if they had HIV infection, or were pregnant women. To date 70 newly diagnosed patients are enrolled, of whom 65 patients had at least 12 months of follow up and are evaluable for treatment response. The median age is 28 years (Range; 18–72 years). Patients had stage II (50%), stage III (31%), or stage IV (19%) disease. Using the IPS prognostic score model, 36 patients (55%) had a score of 2 or higher. With a median follow up of 32 months, the estimated event-free survival (EFS) for the entire group is 85% and the overall survival is 98%. EFS for patients with different IPS groups is shown in the table and is compared with the expected EFS for ABVD alone as reported by Hasenclever and Diehl (NEJM 1998). As shown, R-ABVD improved EFS in all IPS groups with the biggest impact seen in patients with IPS 〉 2. In two patients, fine needle aspiration of a peripheral lymph node was performed before the first and after the third dose of rituximab (schedule B-before starting ABVD). Rituximab induced complete depletion of CD20 and CD19 positive B cells from HL node. We conclude that in patients with classical HL, the addition of 6 weekly doses of rituximab to standard dose and schedule of ABVD chemotherapy is effective in terms of remission rate and remission duration irrespective of CD20 expression on HRS cells or IPS category. A randomized phase-II study is planned to evaluate this strategy in patients with high IPS score. IPS Score Group ABVD EFS (Hasenclever and Diehl) R-ABVD EFS (Current Study) 0–1 79% 95% 0–2 74% 87% 2 67% 76% 〉1 60% 76.5% 〉2 55% 77% 〉3 47% 71%

Description: Abstract 2656 Introduction: The International Prognostic Index (IPI) was first developed in 1993 to risk stratify patients with aggressive Non-Hodgkin's lymphoma (NHL) for outcome prediction (Shipp, NEJM, 1993). Since the addition of rituximab to conventional CHOP chemotherapy for the treatment of DLBCL, there have been many efforts to validate the IPI as well as to improve upon the model's capacity to distinguish subgroups with discrete clinical outcomes, especially high-risk patients. Previous studies have focused on adding clinical or biologic prognostic factor(s) to the original model or regrouping the original IPI score (R-IPI; Sehn, Blood, 2007). We, therefore, built anew a modern IPI based solely on clinical factors available in the real world NCCN clinical database. Methods: Using the nationwide population-based NHL lymphoma database from NCCN, patients with newly diagnosed DLBCL enrolled between June 2000 and Dec. 2010 at 7 NCCN cancer centers were included with at least 1 year and up to 5 years of follow-up. Clinical characteristics including age, Ann Arbor stage, ECOG performance status, disease in extranodal sites (including positivity in bone marrow, CNS, liver/GI tract, lung, other sites and spleen), LDH, presence of bulky disease (〉10 cm) as well as B symptoms were studied as potential predictors for model development using COX proportional hazards regression. IPI scores were assigned proportionally based on parameter estimates of the statistically significant predictors in the final COX model. Model selection and its comparison to the original IPI model were made based on Akaike Criteria (AIC) and the likelihood ratio test. Categorization of age and LDH was decided by testing the linearity assumption and Martingale residuals. Kaplan-Meier curves were plotted for stratified risk groups per the new and original IPI. Finally, both IPI models were compared using the initial randomly selected 15% validation sample. Results: There were 1,650 DLBCL patients with complete clinical information included for model development. The new IPI model consisted of similar component predictors but used a maximum of 8 scoring points by further categorizing age group into 〉40–60 (score of 1), 〉60–75 (score of 2) and 〉75 yrs (score of 3), and normalized LDH between 〉1–3 times (score of 1) and 33 times (score of 2) upper limit of normal. These categorizations minimized the Martingale residuals. Age effect was linear and 20-year increments fit the model best, whereas the effect of normalized LDH was not linear and reached plateau at a ratio of 3. Lymphomatous involvement either of bone marrow, CNS, Liver/GI tract or lung appeared as a stronger predictor (p

Description: Abstract 1387 Poster Board I-409 BACKGROUND: Utility and optimal timing of surveillance imaging for patients with treated diffuse large B-cell lymphoma (DLBCL) remains uncertain, especially in the era of positron emission tomography. METHODS: Data were obtained from the NCCN Non-Hodgkin's Lymphoma Outcomes Database, a prospective cohort study collecting comprehensive clinical, treatment, and outcome data for patients seen at 7 participating NCCN centers. Patients who presented between January 1, 2001 and June 30, 2007 with a new diagnosis of DLBCL in remission for at least three months after the completion of initial therapy were eligible for this study. For those patients with at least two years of follow-up, we assessed overall number and modality of imaging studies performed starting 90 days after the end date of their first-line therapy until documented relapse or end of two-year follow-up window. We then created three subcategories depending upon surveillance strategy: “PET” = positron emission tomography scans or combined positron emission tomography/limited computed tomography scans only; “CT”= computed tomography scans only; or “BOTH PET AND CT” = combination of both “PET” and “CT” at different times. For those who relapsed after being in primary remission for at least 90 days, we assessed the nature of the visit where relapse was first documented, recent accompanying imaging, and the presence of a confirmatory biopsy within one month before or after that relapse. RESULTS: As of July 1, 2009, 433 newly-diagnosed DLBCL patients had at least two years of follow-up from 6 of the 7 participating NCCN centers; median age was 56 and 57% were male. Initial stage and International Prognostic Index (IPI) were as follows: I = 24%; II= 24%; III= 16%; IV=36%; and low= 47%; low-intermediate= 26%; high-intermediate= 19% and high= 8%. For surveillance imaging as defined above, 14% received PET, 48% received CT, and 38% received BOTH PET AND CT. Range of median frequencies across NCCN centers are reported below, both overall and by test type. Overall median number of tests received per year differed significantly across NCCN centers (p for Kruskal-Wallis 〈 0.0001). Of 990 patients in primary remission for at least 90 days, there were 108 (11%) documented relapses. Of those, 20% were found at non-routine visits with symptoms, 41% at routine visits with symptoms, 37% at routine visits without symptoms and 2% were unclear. Of those found at routine visits without symptoms, 73% had undergone imaging within one month before and up to the date of relapse. Finally, 77% of those with relapse underwent confirmatory biopsy within one month before or after relapse. CONCLUSIONS: The frequency of surveillance imaging for patients with treated DLBCL is highly variable, even within the context of tertiary care academic centers. Despite controversy surrounding its use, a high proportion of DLBCL patients in remission are followed with PET modalities. Those being followed exclusively with PET modalities tend to have less frequent imaging, which may have implications for comparative effectiveness. Routine imaging likely identifies relapse in about a quarter of patients with DLBCL; the impact on ultimate outcome remains to be further evaluated. Disclosures: Friedberg: Genentech: Membership on an entity's Board of Directors or advisory committees. Blayney: American Society of Clinical Oncology: Membership on an entity's Board of Directors or advisory committees; BlueCross Blue Shield of Michigan: Research Funding; NCCN: Honoraria; University of Michigan Health System: Employment.

Description: Abstract 1610 Background: T-cell lymphomas (TCL) are an uncommon group of diseases recently updated in the WHO classification. Accurate diagnosis requires immunophenotyping and molecular techniques. Diagnostic accuracy of TCLs utilizing the WHO classification has not previously been evaluated. Methods: The NCCN NHL database prospectively collects clinical, treatment, and outcome data for patients seen at 7 comprehensive cancer centers. Using this unique resource, we evaluated diagnostic concordance between referring and NCCN centers for TCLs, including peripheral T-cell lymphoma, NOS (PTCL NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), and ALK-negative ALCL utilizing pathology reports, immunohistochemical stains, flow cytometry, fluorescence in situ hybridization/cytogenetics, T-cell gene rearrangement, and progress notes. Results: Of 98 eligible patients enrolled from April 2007 to March 2011, 38 (39%) cases were concordant and 60 (61%) were non-concordant. Among non-concordant cases, 34 (57%) had a provisional diagnosis before referral, 6 (10%) were discordant with no additional studies performed, 17 (28%) were discordant with additional studies performed, and 3 (5%) required an additional biopsy. Concordance was highest for ALK+ ALCL at 73%, while the remaining subtypes had low concordance: PTCL NOS 28%, AITL 28%, ALK- ALCL 47%. In 13 (13%) discordant cases (referral diagnosis was benign, a B-cell NHL, or ALK status was undefined) patients may have experienced a significant change in treatment with pathologic reclassification. Conclusions: In patients with TCL, the likelihood of a concordant final diagnosis at a referring institution was low. Among non-concordant cases, the majority were referred with provisional diagnoses, and many referral diagnoses were discordant. Establishing a precise diagnosis is critical for prognosis and impacts both therapeutic decisions and clinical trial enrollment. As current and future therapies, such as brentuximab vedotin, target subsets of TCLs, our data suggest that all suspected TCLs may benefit from evaluation by an expert hematopathologist. Disclosures: Kaminski: Allos: Consultancy, Honoraria.

Description: Introduction The causal association between H. pylori and gastric MALT lymphoma has been well demonstrated and H. pylori eradication with antibiotics has emerged as the standard therapy for Stage I H. pylori positive (HPP) gastric MALT lymphoma. As per the NCCN Guidelines, radiation therapy is the preferred treatment option for early stage H. pylori negative (HPN) gastric MALT lymphoma and antibiotic therapy is not indicated. However, successful treatment of HPN early stage gastric MALT lymphoma with antibiotics was reported in small series of patients by Raderer et al, Gut, 2006 [(5/6 patients achieved complete remission (CR)] and Asano et al, Tohoku J Exp Med, 2012 (5/17 patients achieved CR). Here, we report the outcome of Stage I HPP and HPN gastric MALT lymphoma patients treated with antibiotics at MD Anderson Cancer Center, Houston, Texas, USA over a period of 20 years. Methods We reviewed medical records of all pathologically proven gastric MALT lymphoma patients (n=128) referred to MD Anderson Cancer Center at initial diagnosis between 1991 and 2011. Only patients with Stage IAE disease were considered for this analysis. Patients with large cell transformation were excluded. H. pylori status was determined by histopathology and serum antibody assay. Clinical staging was determined by upper GI endoscopy with biopsy, bone marrow biopsy, and CT scans of neck, chest, abdomen, and pelvis and/or PET-CT scan. Response was assessed by upper GI endoscopy every 3-6 months until complete resolution of lymphoma. Complete remission was defined as the absence of histopathologic evidence of lymphoma on endoscopic biopsies. Results Of the 128 patients reviewed, 81 patients had Stage IAE disease without histologic evidence of large cell transformation. The 81 Stage IAE patients were assigned to HPP (39/81, 48%) or HPN group (42/81, 52%) based on histopathologic evidence of H. pylori. The higher-than-expected proportion of HPN patients might be due to referral bias to a tertiary care cancer center. The results of H. pylori antibody serology are shown in Table 1. There was no significant difference in age, gender, and race between HPP and HPN groups. First-line antibiotic therapy was administered for all 39 (100%) HPP patients and 28/42 (67%) HPN patients. The CR rate after antibiotic therapy was significantly higher in HPP compared with HPN patients (22/39, 56% vs 7/28, 25%; p=0.019). The median time to achieve a CR was similar for the two groups (HPP: 7.8 mo, range 3-40 mo; HPN: 9.7 mo, range 3-35 mo; p=0.385). After a median follow-up of 110 mo for the HPP group and 91.5 mo for the HPN group, 3/22 (14%) and 2/7 (28%) responders relapsed, respectively (p=0.362). Patients who failed to achieve a CR with antibiotic therapy were mostly treated with radiation: 14/17 in the HPP group and 19/21 in the HPN group. All patients that received radiation achieved a CR. Of the patients in both groups who received upfront antibiotic therapy, there were no differences in time to progression (HPP, 90% vs HPN, 92% at 8 years; p=0.543) and overall survival (HPP, 93% vs HPN, 100% at 8 years; p=0.068). Conclusions Our results demonstrate that a substantial proportion of patients with Stage IAE HPN gastric MALT lymphoma achieve durable remission with antibiotic therapy alone. It is possible that such responses may be because of false-negative H. pylori test results or due to association of HPN gastric MALT lymphoma with other unidentified bacteria. We also observed that HPN gastric MALT lymphoma patients failing antibiotic therapy could be effectively salvaged with radiation therapy and their long-term outcome is not affected by delay from initial trial of antibiotic therapy. Thus, the results of this largest series-to-date of HPN patients treated with first-line antibiotic therapy, combined with results of smaller series reported previously, suggest that 1) antibiotic therapy should be considered as first-line therapy for Stage IAE HPN gastric MALT lymphoma patients, and 2) radiation therapy could be avoided in a subset of these patients. Table 1. H. pylori status in Stage IAE gastric MALT lymphoma as determined by histopathology and H. pylori antibody. H. pylori positive by histology (n=39) H. pylori negative by histology (n=28) CR (n=22) Non-CR(n=17) CR (n=7) Non-CR(n=21) H. pylori Ab Positive 4 4 0 3 H. pylori Ab Negative 8 2 1 7 Not available 10 11 6 11 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: The use of rituximab in classical Hodgkin lymphoma (HL) has been proposed to have a therapeutic value by several mechanisms; to The malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) rarely survive outside their microenvironment of reactive B-cells, and therefore we hypothesized that depleting B-cells from HL microenvironment by rituximab may deprive HRS cells from critical survival and resistance factors and therefore improving the efficacy of chemotherapy, Rituximab may have a direct killing effect on HRS cells that express CD20, and recent data from Johns Hopkins Medical Center suggested that HRS stem cells are CD20+ cells. With this background, we evaluated the safety and efficacy the combination of rituximab and ABVD (R-ABVD) chemotherapy in newly diagnosed patients with classical HL. In addition, PET after 2–3 cycles of ABVD has been shown to confer poor prognosis and therefore proposed to guide future therapy. (Hutchings et al, Blood, 2006) reported a negative PET scan after two cycles of ABVD to be a good predictor of outcome with 96% 2-year progression free survival (PFS). Those with PET positive after 2 cycles had a 0% PFS at 2 years. Thus, we examined the effect of RABVD on early PET imaging and determined whether PET status remains predictive of treatment outcome in patients receiving RABVD. To date 70 newly diagnosed pts are enrolled, of whom 65 pts had at least 12 months of follow up and are evaluable for treatment response. Median age 28 years (Range; 18–72 years). Patients had stage II (50%), stage III (31%), stage IV (19%) disease. Using the IPS prognostic score model, 36 patients (55%) had a score of 2 or higher. With a median follow up of 32 months, the estimated event-free survival (EFS) is for the entire group is 85% and overall survival 98%. EFS for patients with IPS 0–1, 2, and 〉2 are 95%, 76%, and 77%, respectively, suggesting that R-ABVD improved EFS in all IPS scores with the biggest impact seen in patients with IPS 〉 2. 55 patients had PET after 2–3 cycles and were included in the predictive analysis of PET on treatment outcome. PET became negative in 43 patients (78%) after completing 2–3 cycles of RABVD and positive in the remaining 12 patients (22%). 5-year EFS for those with negative PET was 93% and 75% for those who remained PET positive (p=0.05). We conclude that in patients with classical HL, the addition of 6 weekly doses of rituximab to standard dose and schedule of ABVD chemotherapy is effective in terms of remission rate and remission duration irrespective of IPS category. Our data confirmed prior reports that patients who remain PET positive after 2–3 cycles have worse prognosis when compared to those that achieve PET negativity. However, the outcome for those who remained PET positive after 2–3 cycles of RABVD seems to be significantly better than what has been previously reported when using ABVD alone. A randomized trial comparing ABVD with RABVD is planned to confirm these observations.