Armitage, Jamés O.

Abstract Background: Castleman Disease (angiofollicular hyperplasia) is a rare, lymphoproliferative disease. There has been no large study describing the natural history of this disease. Hypothesis: A retrospective analysis of clinical, pathologic, and laboratory factors predictive of outcome should be identifiable. Methods: During the period from 3/30/48 to 6/18/2002, 114 patients with Castleman Disease were seen at the Mayo Clinic (Rochester, 56; Jacksonville, 19; Arizona, 13) and at the University of Nebraska (26). Pathology, laboratory and clinical characteristics analyzed included: the presence of unicentric or multicentric disease, the pathologic variant (hyaline vascular versus plasma cell variant), co-existing POEMS syndrome, age, serum albumin, alkaline phosphatase, AST, sedimentation rate, the presence of cytopenias, organomegaly (hepatomegaly or splenomegaly), papilledema, peripheral neuropathy, sclerotic bone lesions, renal disease, B-symptoms or respiratory symptoms. The impact of these variables on overall survival from time of diagnosis was evaluated using univariate analyses, where their significance was determined based on the logrank statistic. To derive the multivariable model, the score-based model-building method was used. Based on this approach, a 3-variable model was designed, adjusting for age at diagnosis. Patients were then assigned a risk score corresponding to how many of these risk factors they possessed. A final proportional hazards model was constructed based on this risk score. Results: The median age at diagnosis was 43 (range: 5 – 78), and 48% of patients were male. Fifty-five patients had multicentric disease. Median follow-up of living patients was 5.8 years (range: 0.02 – 27). On univariate analysis, factors that predicted for overall survival included: age at diagnosis, presence of multicentric disease, presence of a monoclonal protein in the urine, co-existing POEMS syndrome, serum albumin, presence of cytopenias, organomegaly, neuropathy, thrombocytosis, and respiratory symptoms. The final multivariable model included 98 patients. Adjusting for age, the model included organomegaly, respiratory symptoms, and thrombocytosis. Patients were assigned 1 point for each risk factor they possessed based on clinical relevance and similarity of the hazard ratios for each of these 3 variables (ranging from 3.1 to 4). A final prognostic survival model was constructed using this assigned risk score. These scores were collapsed further based on observed similarities (0 factors vs. 1 or more factors). This final model yielded a hazards ratio of 5.5 (95% CI 2.3–13.4). The 10 year survival rates were 80% (95% CI: 65–98%) and 41% (95% CI: 28–59%) for the 0 factor and 1+ factor groups, respectively. The 20 year survival rates were 71% (95% CI: 52–87%) and 31% (95% CI: 19–51%), respectively. Conclusion: The most distinguishing prognostic clinical, laboratory, and pathological characteristics of Castleman’s Disease are orgnaomegaly, respiratory symptoms, and thrombocytosis. This prognostic scoring system should aid in individual cases and in assessing results of therapeutic interventions.

Abstract PURPOSE: Rheumatoid arthritis (RA) has been associated with an increased risk of non-Hodgkin’s lymphoma (NHL). We describe the characteristics of NHL patients with antecedent RA. METHODS: Records of the Nebraska Lymphoma Study Group (NLSG) registry between 1982–2004 and the Mayo Clinic lymphoma registry between 1988–1998 were systematically reviewed for RA diagnosis and classified by the quality of supporting evidence. We abstracted available follow-up data through July 1, 2004. Definite cases had either a documented RA diagnosis from a trained rheumatologist or met 4 of 7 American College of Rheumatology criteria. Probable RA cases had a non-rheumatologist diagnosis of RA in addition to one of the following: 1) radiographic joint erosions; 2) disease-modifying anti-rheumatic drug (DMARD) use or; 3) RA-associated deformities (i.e., ulnar drift, swan-neck deformities). Five-year overall survival (OAS), event-free survival (EFS), and rates of treatment response were determined. RESULTS: We identified 74 RA cases (54 definite and 20 probable) with concomitant NHL. These patients had a mean age of 67 + 8 years and were predominantly Caucasian (82%) and female (64%). Of the probable RA cases, a majority had documented DMARD use (n=17). Approximately half of the cases used methotrexate (55%) and were deceased (52%) by the common closing date. The most common NHL subtypes included B-DLCL (n=31), B-FL-1/B-FL-2 (n=12), B-FL-3 (n=6), and B-BL/B-BLL (n=4). Of the remaining 21 cases, most were of B-cell origin (n=13) and included B-EMZL (n=3), B-LPL (n=3), B-UCL (n=2), B-UCL-LG (n=2), B-DFL-2 (n=1), B-MCL (n=1), and B-SLL (n=1). The remaining NHL subtypes included NHL-NOS (n=7) or T-PTCL-LC (n=1). B-symptoms were present for 6 (19%) patients with B-DLCL and none of the patients with B-FL-1/B-FL-2. Complete response rates to NHL treatment were 48% in B-DLCL and 33% in B-FL-1/B-FL-2. For B-DLCL and B-FL-1/B-FL-2, respectively, the five-year OAS was 54% (95% CI 36%–69%) and 65% (95% CI 31%–85%) while the five-year EFS was 48% (95% CI 36%–69%) and 56% (95% CI 24%–79%). For all NHL cases the 5-year OAS was 58% (95% CI 47%–69%) and the 5-year EFS was 49% (95% CI 37%–59%). CONCLUSIONS: Lymphomas developing in the context of RA most often include diffuse large B-cell and follicular subtypes. Complete response rates to standard treatment for these major subtypes ranged from 33 to 48%. For RA patients developing NHL, five-year overall- and event-free survival rates are approximately 50%.

e19063 Background: Constitutive activation of the JAK-STAT pathway has been reported in lymphomas, suggesting that targeting this pathway could show clinical benefit. Ruxolitinib phosphate, an oral JAK inhibitor represents a potential therapeutic agent for high grade lymphomas. This study is designed to investigate benefits of ruxolitinib in patients with relapsed or refractory PTCL and DLBCL Methods: Patients with relapsed/refractory DLBCL and aggressive T cell lymphomas who were ineligible for, or relapsed after, stem cell transplantation were eligible. Patients received ruxolitinib, at a dose of 10mg or 5mg BID, with gradual escalation to 25mg BID. Weekly hematological assessments were done during the first cycle, CT scans were done after every two cycles. Descriptive statistics for response to therapy were collected. Progression free survival (PFS), Overall survival (OS) curves were plotted using Kaplan-Meier method, comparisons between groups were made using the log rank test. Primary outcome of the study was to assess the overall response rate (ORR). Secondary objectives were to determine PFS, OS, duration of response and safety. Relationship between responses to oral ruxolitnib and gene expression profiling was explored. Results: Of the 60 patients enrolled, 25 patients had PTCL, 32 DLBCL, 3 pending path review. Median age was 62 yrs., 56.6% had stage IV disease. Median number of cycles received was 2 (min 1, max 60). At the time of evaluation, 76% patients had progressed on therapy. The median follow-up of patients was 3.7 months (min 0.9; max 61.4). Data for 41 patients was available for evaluation of response. Complete response (CR) was noted in 1 patient with PTCL. Partial response (PR) was noted in 1, stable disease (SD) in 4 patients. Among the responders, a PTCL patient with SD had a sustained response for 60 months, a patient with PR had a response duration of 31 months. The median OS and PFS were 5.9 and 1.8 months. PFS was 2.2 months in patients with PTCL and 1.8 months in DLBCL. Median OS was 5 months in patients with DLBCL, 6.9 months in PTCL. The estimated 6 month PFS and OS were 17% (95%CI: 9%, 28%) , 49% (95%CI: 35%, 62%). There was no difference in PFS or OS between PTCL and DLBCL (p = 0.42, p = 0.94). Grade 3 or higher adverse events were seen in 62%. Anemia was seen in 20%, thrombocytopenia in 8%, infections in 6%. Conclusions: Ruxolitinib can produce responses in some patients with relapsed/refractory NHL, particularly in patients with PTCL. It may play a role in combination therapies in future. Clinical trial information: NCT01431209.

Abstract Abstract 880 Pulmonary marginal zone lymphoma is a distinct subgroup of B-cell non-Hodgkin's lymphomas originating from the bronchial-associated lymphoid tissue (BALT) and characterized by an indolent clinical course. Here we present the data of the IELSG-28 study of the International Extranodal Lymphoma Study Group (IELSG) on primary pulmonary lymphoma patients. Clinical records and histological material of 186 patients diagnosed with pulmonary marginal zone lymphoma from December 1986 to June 2009 were collected. The pathology was reviewed centrally and the diagnosis was confirmed in 180 (96%) patients. The median age at diagnosis was 62 (30 – 88). The majority of the patients (149/180) had localized disease at diagnosis with a good performance status (0–1) and low prognostic index (IPI 0–2). Eighty-one patients (45%) received local treatment, including surgery (74%) or radiotherapy (4%). Ninety-nine patients with advanced stage disease or incomplete surgical resection received an additional systemic treatment. Most of these patients (66; 66%) received an alkylating containing regimen, 22 (22%) patients were treated with an anthracycline containing regimen and 29 (29%) received the anti-CD20 monoclonal antibody in combination with chemotherapy. With a median follow up of 67 (range 1–256) months, 47/180 patients (26%) experienced disease progression. (median time to progression 30 months, range 0–109). Progression free survival analysis showed a trend in favour of patients treated with immuno-chemotherapy versus those receiving chemotherapy alone (HR 0.53–95%CI: 0.21, 1.33), while no difference in terms of OS and PFS was observed between patients receiving systemic anthracycline or alkylating containing regimens. In twenty five cases a specific PCR-assay was carried out for detecting the presence of Achromobacter (Alcaligenes) xylosoxidans. The presence of Achromobacter was detected in 50% of patients. Our results confirm that local therapy (surgery or radiotherapy) is the treatment of choice for patients with localized disease. Chemotherapy has to be considered in case of relapse, incomplete surgical excision or advanced disease. In this setting, alkylating containing regimens plus rituximab is the most effective option. Further studies are ongoing to confirm the relevance of infection/colonization with Achromobacter (Alcaligenes) xylosoxidans for pathogenesis of BALT lymphoma. Disclosures: No relevant conflicts of interest to declare.

SummaryBone marrow damage is an important consequence of exposure to acute high‐dose whole‐body radiation. As such, haematologists can play an important role in managing this complication. However, these accident and incident scenarios are complex and often involve injuries to other organs and tissues from heat, projectiles and chemicals. In the case of a large‐scale event there will likely be severe infrastructure disruptions and injury or death to medical personnel. Accurate estimates of dose and uniformity of exposure are needed to intelligently direct appropriate interventions, which range from antibiotics, antifungals and anti‐virus drugs, molecularly‐cloned haematopoietic growth factors and, in rare instances, haematopoietic cell transplants. These therapies are ones that haematologists often use in the context of anti‐cancer therapy, especially therapy of haematological cancers like leukaemia. However, most haematologists have little knowledge of radiation biology and should consider updating this aspect of their expertise in continuing medical education. As in other areas of medicine, prevention is better than cure and haematologists should be active in decreasing risks of a nuclear war.

Purpose Although preliminary studies suggest that non-Hodgkin's lymphoma (NHL) complicating rheumatoid arthritis (RA) may be a clinically distinct entity compared with that occurring in the general population, studies examining the impact of antecedent RA on survival are limited. In this prospective study, we examined the association of RA with survival in patients with NHL. Patients and Methods Using two large lymphoma registries, we identified patients with evidence of RA preceding NHL. Survival in RA patients was compared with that of controls using proportional hazards regression, adjusting for the effects of age, sex, lymphoma diagnosis-to-treatment lag time, calendar year, International Prognostic Index score, and NHL grade. Results The frequency of NHL subtypes was similar in RA patients (n = 65) and controls (n = 1,530). Compared with controls, RA patients with NHL had similar overall survival (hazard ratio [HR] = 0.95; 95% CI, 0.70 to 1.30) but were at lower risk of lymphoma progression or relapse (HR = 0.41; 95% CI, 0.25 to 0.68) or death related to lymphoma or its treatment (HR = 0.60; 95% CI, 0.37 to 0.98), but were more than twice as likely to die from causes unrelated to lymphoma (HR = 2.16; 95% CI, 1.33 to 3.50). Conclusion RA is associated with improved NHL-related outcomes, including a 40% reduced risk of death occurring as a result of lymphoma or its treatment and approximately a 60% lower risk of lymphoma relapse or progression compared with non-RA controls. However, the survival advantage gained in RA from the acquisition of lymphomas with favorable prognoses is negated through an increased mortality from other comorbid conditions.

PURPOSE: To determine whether the source of autologous hematopoietic stem cells altered the clinical outcomes of patients undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation (HSCT) for aggressive non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Of 105 high-risk, persistent, or relapsed NHL patients slated for an autologous HSCT entered onto this trial, 93 eligible patients were randomized to receive cytokine-naive autologous bone marrow transplantation (ABMT) (n = 46) or mobilized peripheral-blood stem-cell transplantation (PBSCT) (n = 47). All patients received carmustine, etoposide, cytarabine, and cyclophosphamide as the conditioning regimen. PBSCT patients also received identical mobilization with granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/d, and both groups received G-CSF 5 μg/kg/d after the infusion of the stem-cell product until neutrophil engraftment. RESULTS: PBSCT patients had significantly faster engraftment of all cell lineages: median time to absolute neutrophil count ≥ 500/μL, 10 days versus 13 days on the ABMT arm; median time to platelet count greater than 20,000/μL untransfused, 11 days versus 15 days on the ABMT arm; and median time to RBC transfusion independence, 8 days versus 16 days on the ABMT arm. The complete response rate was 72% for PBSCT and 54% for ABMT. The death rate before posttransplant day 100 was 2% on the ABMT arm and 6% on PBSCT arm. Event-free survival was 37% for PBSCT and 37% for ABMT. However, overall survival for PBSCT was 61% compared with 43% for ABMT. CONCLUSION: Patients with aggressive NHL receiving HSCT randomized to PBSCT demonstrated improved neutrophil engraftment and platelet and RBC transfusion independence. The complete response rate and EFS were not statistically different by randomization arm. Patients whose harvests were positive for minimal residual disease by molecular analysis had poorer EFS.