The identification of TCF1+ progenitor exhausted T cells in THRLBCL may predict a better response to PD-1/PD-L1 blockade

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL due to its peculiar cellular composition (< 10% neoplastic B cells interspersed in a cytotoxic T-cell/histiocyte-rich background). A significant percentage of THRLBCL is refractory to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-based regimens and to chimeric antigen receptor T-cell therapy; thus, the development of a specific therapeutic approach for these patients represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, and further corroborated our findings in an extended in silico set. Gene coexpression network analysis identified the predominant role of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of 48 genes related to the functional exhaustion of T cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly suggest that THRLBCL may be responsive to anti-PD-1 therapy but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we validated our results by immunohistochemistry, identifying a subset of TCF1(+) (T cell-specific transcription factor 1, encoded by the TCF7 gene) progenitor exhausted T cells enriched in patients with THRLBCL. This subset of TCF1(+) exhausted T cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti-PD-1 response in patients with THRLBCL

Italian real life experience with ibrutinib: Results of a large observational study on 77 relapsed/refractory mantle cell lymphoma

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventyseven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world

Hematologic toxicity and double autografting of stem cells after myeloablative activities of Yttrium-90-Ibritumomab tiuxetan

No abstract availabl

The role of dosimetry in the high activity 90Y-ibritumomab tiuxetan regimens: Two cases of abnormal biodistribution

Radioimmunotherapy (RIT) with a commercially available brand of yttrium-90 (90Y)-ibritumomab-tiuxetan at the prescribed activity of 14.8 MBq/kg (0.4 mCi/kg) represents a complementary approach in the treatment of resistant/refractory B-cell non-Hodgkin's lymphoma. A trial based on higher activities is ongoing in our institute. In this paper, we report atypical pharmacokinetics and liver uptake in 2 patients. Before RIT, all patients underwent dosimetry with 111In-ibritumomab-tiuxetan. Imaging data were analyzed to obtain predicted absorbed doses to nontarget organs. Therapy was administered only if a 20-Gy-limit dose to normal organs (except red marrow) was guaranteed. Both patients we describe showed abnormal liver uptake, increasing for 6 days post injection. In patient 1, there was atypical biodistribution in whole-blood images at 16 hours, with a prevalent high liver uptake (45% at 20 hours). Injected activity (IA%) was above 40% at 26 hours in the liver and lower than 60% in the total body. In patient 2, early images showed regular biodistribution. Subsequent images showed progressive increase of liver uptake (above 25% of percent injected activity at 25 hours). Liver-absorbed doses of 51 and 53 Gy, respectively, would have resulted with the administration of the prescribed 56 MBq/kg. Following these dosimetric results, both patients did not receive the planned therapy. These findings support the recommendation to include dosimetry in high-dose RIT. © 2009 Copyright 2009, Mary Ann Liebert, Inc

Efficacy of 90Yttrium-ibritumomab tiuxetan in relapsed/refractory extranodal marginal-zone lymphoma

We evaluated clinical activity of 90Yttrium-ibritumomab (90Y-ibritumomab) tiuxetan in extranodal marginal-zone lymphoma. From May 2004 to April 2011, 30 patients affected by relapsed/refractory marginal-zone lymphoma-arisen at any extranodal site-received 90Y-ibritumomab tiuxetan at the activity of 0.4mCi/kg. Median age was 57years. At time of treatment, 13 out of 30 patients had disseminated disease (stage III/IV). All patients had received a previous treatment with a maximum of 7. Overall response rate was 90%: 23 patients achieved a complete response (77%); partial response occurred in 4 patients (13%), stable disease in 2 patients (7%) and 1 progression (3%). With a median follow-up of 5.3years, median time to relapse was not reached; 2 patients relapsed after complete response; 18 out of 23 complete responses are still responders after >3years, 12 of them after >5years. 90Y-ibritumomab tiuxetan seems to be active in patients with extranodal marginal-zone lymphoma relapsed/refractory to conventional treatment including radiotherapy. These results suggest that radioimmunotherapy could represent a possible option for the treatment in this subset of patients. © 2013 John Wiley & Sons, Ltd

Rituximab in Hodgkin lymphoma: Is the target always a hit?

In 1997, the anti-CD20 monoclonal antibody (MAb) rituximab became the first MAb approved for clinical use in oncology, and ushered in a new era of rationally designed targeted agents in cancer therapeutics. It is currently approved for use in non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and rheumatoid arthritis (RA). Rituximab is non-mutagenic, associated with low treatment-related toxicity, and few, if any, long term adverse events, making it an attractive agent to be tried in off-label settings like Hodgkin lymphoma (HL). HL consists of two distinct subtypes - classic HL (cHL) and lymphocyte predominant HL (LPHL). CD20 is present in virtually all patients with LPHL, and in a significant minority of patients with cHL. In this CD20 positive sub-population, the use of rituximab is a rational intervention strategy. Rituximab has been used in patients with cHL as well as LPHL with good efficacy. In this article, we provide a clinically-oriented overview of the use of rituximab in the different sub-types of HL, and report updated results of our series of 8 LPHL patients treated with rituximab. A systematic review of the literature is also presented. © 2010 Elsevier Ltd

High activity 90Y-ibritumomab tiuxetan (Zevalin®) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell non-Hodgkin lymphomas

Radioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B-cell non-Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y-ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed - 30 MBq/kg (0.8 mCi/kg), 45 MBq/kg (1.2 mCi/kg) and 56 MBq/kg (1.5 mCi/kg) - and 13 patients enrolled. One week before treatment all patients underwent dosimetry. ASCT was performed 13 d after Zevalin® administration. Treatment was well tolerated and all patients engrafted promptly. No differences in terms of haematological toxicities were observed among the three levels, apart from a delayed platelet recovery in heavily pretreated patients receiving 56 MBq/kg. Non-haematologic toxicity was mainly related to infections and liver toxicity. One patient died 4 months after treatment because of hepatitis C virus reactivation. One patient developed a myelodysplastic syndrome 2 years after treatment. In conclusion, high-activity Zevalin® with ASCT is feasible and could be safely delivered in elderly and heavily pretreated NHL patients, including those who previously received high-dose chemotherapy and ASCT. Maximum tolerated dose was not clearly defined according to dosimetry and clinical toxicities, and further studies are needed to confirm the toxicity profile and evaluate efficacy. © 2007 The Authors

Erratum: Lung toxicity in radioiodine therapy of thyroid carcinoma: Development of a dose-rate method and dosimetric implications of the 80-mCi rule (Journal of Nuclear Medicine (2006) 47, (1977-1984))

Not available - Erratu