ALBERT

Description: Background: Immunochemotherapy has improved the clinical outcome of patients diagnosed with diffuse large B-cell lymphoma (DLBCL), but only 60% of all DLBCL patients are potentially cured. A response-adaptive imaging strategy that accurately determines the initial response to therapy could improve clinical outcomes. Although there has been an increasing trend to perform interim PET/CT to monitor response, the optimal interpretation method for interim PET analyses remains uncertain. Studies using maximum standard uptake value (SUVmax), have not defined a uniformly applicable SUVmax reduction cutoff that accurately predicts clinical outcome. Here, we hypothesized that a method that maximized the detection of all metabolically active regions within the tumor mass, defined as the metabolic tumor volume (MTV), could serve as a better predictor of clinical outcome than SUVmax measurement. Methods: All patients with DLBCL that were treated from Dec 2006 to Dec 2014 at the University of Cincinnati were studied, retrospectively. Interim PET analysis was performed after 2-4 cycles of chemotherapy. SUVmax and MTV on the initial and interim PET CT for each patient was determined. To evaluate the contribution of metabolic activity within the tumor periphery in assessing clinical outcomes, MTV was measured by two separate methods: fixed-threshold and gradient-segmentation using MIMSoftware, OH, USA. The primary end point of the study was progression free survival (PFS). To identify an optimal threshold cutoff that could predict PFS more accurately, the receiver operating characteristic (ROC) curve analysis was used. Results: A total of 197 patients with pathology confirmed diagnosis of DLBCL were recognized. Of the 197 patients, 167 underwent interim PET analysis. All patients fasted 〉6 h before intravenous injection of 18F-glucose, had glucose levels 〉90 and 48 h before imaging. The median follow-up period for patients in the study was 37 months. R-CHOP (Rituximab, Cyclophosphamide, doxorubicin/Hydroxydaunomycin, vincristine/Oncovin and Prednisone) and R-DA-EPOCH (Dose-Adjusted Etoposide, Prednisone, Oncovin, Cyclophosphamide and Hydroxydaunorubicin) were the first line of therapy in 74% and 26% of patients, respectively. On interim PET/CT, 69% of patients achieved complete response with the remaining patients showing partial response based on visual assessment. Dichotomous visual interpretation of interim PET did not correlate with PFS (log-rank P= 0.37). Compared with the threshold-based method, the gradient-based method resulted in a statistically significant greater MTV in pretreatment, as well as interim PET images. However, no significant difference was noted between the reduction in MTV determined by the threshold-based (ΔMTVT) or gradient-based (ΔMTVG) methods (median 34% vs 36%, P =0.29). Thresholds of ΔSUVmax and ΔMTV by ROC curve were 72% and 52%, respectively. ΔMTV predicted PFS better than ΔSUVmax as the AUC for ΔMTV was significantly larger compared with that for ΔSUVmax (Figure 1). All patients who achieved a SUVmax reduction greater than the cutoff value determined by the ROC analysis (ΔSUVmax〉72%) were then stratified into two groups based on a ΔMTV cutoff value 〉 or 72% on interim PET/CT imaging, 77 (67%) had a ΔMTV 〉52%. Importantly, patients who achieved a ΔMTV 〉52% had a statistically significantly greater PFS compared with patients who achieved a ΔMTV 72% on interim PET and those who demonstrated a ΔMTV 〉52% exhibited greater PFS. Conclusion: Our study highlights the importance of MTV assessment for patients who achieved background SUVmax on the interim PET to better predict the clinical outcome of DLBCL patients. The MTV measurement with the gradient-based method renders a larger volume of tumor than the threshold-based method; however, these two methods report a similar percentage reduction and are interchangeable in terms of interim PET interpretation. Metabolic activity of the peripheral area of the tumor should be incorporated into response-adaptive strategies and prospective trials that evaluate the response to current and novel therapeutic regimens to treat DLBCL patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: INTRODUCTION CNS relapse in DLBCL carries poor prognosis. Some studies have suggested decreased incidence with rituximab, but there are several others reporting otherwise. We analyzed prospective studies in literature to understand the role of rituximab and CNS prophylaxis in DLBCL, in comparison to CHOP based therapy. METHOD Extensive searches using PUBMED, EMBASE, CENTRAL and major hematology conferences were conducted for prospective studies. The keywords CNS, diffuse large B-cell lymphoma, relapse, prophylaxis, rituximab, CHOP were used. Inclusion: (i) prospective or randomized trials (ii) Entire study population or a significant majority of patients were newly diagnosed DLBCL, (iii) no evidence of CNS involvement at baseline, (iv) use of rituximab-chemotherapy or CHOP-based chemotherapy, (v) have data relevant to our study. Exclusion: (i) retrospective studies, review article or case reports, (ii) exclusively testicular, mediastinal or double hit lymphoma, (iii) HIV positive patients. Data is presented as mean ± standard error of mean. Significant differences (at P

Description: Background/method: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) although uncommon, can be devastating. Conflicting reports have been published regarding the reduction in incidence of CNS relapse in post-rituximabera.We retrospectively identified all the patients with DLBCL who has received rituximab-based chemotherapy at initial presentation in our institute between 2004 and 2014. Patients were divided into two groups, ‘high risk’ group and ‘standard risk’ group, based on following definition. High risk group will have at least one of the following risk factors 1) LDH ≥ 650 U/L 2) Age adjusted International Prognostic Index (IPI) of ≥ 4 3) Involvement of 〉 1 extra nodal site 4) Involvement of testis 5) Breast 6) Bones 7) Kidneys 8) Adrenal glands 9) Retroperitoneal lymph nodes 10) Para-meninges or 11) Bone marrow. Patients without any of these risk factors were deemed standard risk. Descriptive statistics were used to analyze the incidence of CNS relapse, patient and disease characteristics. Historically reported incidence rates were used for comparison. Results:One hundred and forty two consecutive patients with DLBCL were included in our study. One hundred and twenty two patients received rituximab-based therapy at the initial diagnosis. Forty-nine patients (40%) met the criteria for ‘high risk’ based on the above definition. Seventy-three patients (60%) qualified for standard risk group. Standard risk group received no CNS directed prophylaxis and none of these patients had CNS relapses. Thirty-one of 49 ‘high risk’ patients received CNS prophylaxis, mainly intrathecal methotrexate. Total 5 patients (4.09%) developed CNS relapse. CNS relapse in high-risk group was 10.2% (5/49). Median age at diagnosis in patients with CNS relapse was 53 years. Median time to relapse was 8.76 months. Median survival after the CNS relapse was 9.16 months. Four out of 5 patients received CNS prophylaxis with intrathecal methotrexate or systemic methotrexate or systemic cytarabine or a combination of them. Average number of doses of prophylaxis received by each patient was 3.2 (range 1-7). Only one patient who developed CNS relapse did not receive any CNS directed therapy as prophylaxis. Conclusion:No significant reduction in the incidence of CNS relapse was noted with upfront use of rituximab. Our study confirms that majority of the DLBCL patients do not need CNS directed therapy. For high risk DLBCL patients, we not only need to develop better predictive markers for CNS relapse but also need better CNS directed therapies to prevent this fatal complication of highly curable disease. Disclosures No relevant conflicts of interest to declare.

Description: Hemophagocytic lymphohistiocytosis (HLH) is often an elusive diagnosis in adults. HLH can be primary or secondary, with treatment of secondary HLH based on the cause. It is important to identify malignancy if present to help best optimize outcomes long term. HLH is characterized clinically by highly activated, ineffective immune response with cytopenia. HLH patients often present with subtle and generalized symptoms such as fever, hepatosplenomegaly, pancytopenia and lymphadenopathy. In secondary HLH, several factors serve as triggers. These are divided into infectious, malignant, rheumatologic, and during immunosuppression. Infection and malignancy are the most common causes. One study reported 28 patients with secondary HLH, 13/28 (46%) had infectious cause (11 positive EBV serology and two patients had leishmaniasis); lymphoma was identified in 11/28 (39%) and autoimmune disease in 3 (10%)1. Another study included 56 patients with secondary HLH, 43 (76%) patients had malignancy, and 23 (41%) patients had infectious etiology. Underlying immune deficiency was present in 38 (67.8%) patients2. Although primary HLH is well documented in the literature, secondary or acquired HLH is only reported in the form of cases, small retrospective studies and single institutional case series reports. Secondary HLH is highly underreported due to its rarity and nonspecific presentation. Here we present a case of secondary HLH from T-cell lymphoma; discuss clinical features and importance of initial accurate diagnosis in optimizing outcomes. A 41 y/o gentleman with past medical history of Crohn’s disease for 5 years, presented to the emergency room for fevers of approximately 2-week duration. His therapy for Crohn’s disease included, steroids, azathioprine and two doses of adalimumab. He had pancytopenia and bone marrow biopsy demonstrated hemophagocytosis. The HLH diagnosis was further supported by elevated ferritin and elevated soluble IL-2 receptor. Cytogenetics of bone marrow sample demonstrated complex karyotype. The infectious work up demonstrated Epstein Barr Virus (EBV) by PCR. Genetic testing was unremarkable. Patient was managed based on 2004-HLH protocol with dose reduction for pancytopenia. He was maintained on oral cyclosporine and stopped after 6 months when he started having fevers and pancytopenia again. Repeat bone marrow biopsy demonstrated no reactivation of HLH but noted lymphocytosis, consistent with peripheral T cell lymphoma. Cytogenetic studies demonstrated the same complex clone but now with evolution. He received CHOP chemotherapy and etoposide was added after his cerebrospinal fluid was positive for lymphoma. PET-CT showed extensive changes in the bone marrow, spleen and T1 vertebral body. Patient responded poorly and care was drawn on d28 after CHOP. Secondary HLH is an uncommon disease usually triggered by an infection, hematologic malignancy or it may occur in the setting of a rheumatologic disease. Lymphoma is common in secondary HLH and peripheral T cell lymphoma is more commonly resistant at relapse. Clonal abnormalities may help to earlier identify individuals with an underlying malignancy. Patients may benefit from thorough evaluation at presentation for underlying hematologic malignancy as management differs completely. Studies such as PET scan should be considered to search for underlying occult malignancy and cytogenetic studies need to be performed on marrow samples. In our case, repeat cytogentic studies revealed the same clone that was diagnosed at presentation. Initial appropriate therapy for Peripheral T cell lymphoma may have improved this outcome. 1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Apr;18(2):463-5. Intensive Care Med. 2010 Oct;36(10):1695-702. Disclosures: No relevant conflicts of interest to declare.