Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T3 phase IB trial of the LYSA.

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.

International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI.

Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly <50%. Integrating molecular features of the tumor and microenvironment into the NCCN-IPI or IPI might better characterize a high-risk group for which novel treatment approaches are most needed.

Whole-Body Diffusion-weighted MR Imaging of Iron Deposits in Hodgkin, Follicular, and Diffuse Large B-Cell Lymphoma.

Purpose To analyze the frequency and distribution of low-signal-intensity regions (LSIRs) in lymphoma lesions and to compare these to fluorodeoxyglucose (FDG) uptake and biologic markers of inflammation. Materials and Methods The authors analyzed 61 untreated patients with a bulky lymphoma (at least one tumor mass ≥7 cm in diameter). When a LSIR within tumor lesions was detected on diffusion-weighted images obtained with a b value of 50 sec/mm2, a T2-weighted gradient-echo (GRE) sequence was performed and calcifications were searched for with computed tomography (CT). In two patients, Perls staining was performed on tissue samples from the LSIR. LSIRs were compared with biologic inflammatory parameters and baseline FDG positon emission tomography (PET)/CT parameters (maximum standardized uptake value [SUVmax], total metabolic tumor volume [TMTV]). Results LSIRs were detected in 22 patients and corresponded to signal void on GRE images; one LSIR was due to calcifications, and three LSIRS were due to a recent biopsy. In 18 patients, LSIRs appeared to be related to focal iron deposits; this was proven with Perls staining in two patients. The LSIRs presumed to be due to iron deposits were found mostly in patients with aggressive lymphoma (nine of 26 patients with Hodgkin lymphoma and eight of 20 patients with diffuse large B-cell lymphoma vs one of 15 patients with follicular lymphoma; P = .047) and with advanced stage disease (15 of 18 patients). LSIRS were observed in spleen (n = 14), liver (n = 3), and nodal (n = 8) lesions and corresponded to foci FDG uptake, with mean SUVmax of 9.8, 6.7, and 16.2, respectively. These patients had significantly higher serum levels of C-reactive protein, α1-globulin, and α2-globulin and more frequently had microcytic anemia than those without such deposits (P = .0072, P = .003, P = .0068, and P < .0001, respectively). They also had a significantly higher TMTV (P = .0055) and higher levels of spleen involvement (P < .0001). Conclusion LSIRs due to focal iron deposits are detected in lymphoma lesions and are associated with a more pronounced biologic inflammatory syndrome. © RSNA, 2017 Online supplemental material is available for this article.

Low Serum Vitamin D Levels Are Associated With Inferior Survival in Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies.

PURPOSE: Recent literature reports a potential association between high vitamin D and improved lymphoma prognosis. We evaluated the impact of pretreatment vitamin D on follicular lymphoma (FL) outcome. PATIENTS AND METHODS: SWOG participants were previously untreated patients with FL enrolled onto SWOG clinical trials (S9800, S9911, or S0016) involving CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 and 2008. Participants included in our second independent cohort were also previously untreated patients with FL enrolled onto the Lymphoma Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to rituximab maintenance v observation) between 2004 and 2007. Using the gold-standard liquid chromatography-tandem mass spectrometry method, 25-hydroxyvitamin D was measured in stored baseline serum samples. The primary end point was progression-free survival (PFS). RESULTS: After a median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 (95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin D deficient (< 10 ng/mL; 25% of cohort). CONCLUSION: Although statistical significance was not reached in the LYSA cohort, the consistent estimates of association between low vitamin D levels and FL outcomes in two independent cohorts suggests that serum vitamin D might be the first potentially modifiable factor to be associated with FL survival. Further investigation is needed to determine the effects of vitamin D supplementation in this clinical setting.