Unit of Lymphoid Malignancies

San Raffaele Cimena, Italy

Unit of Lymphoid Malignancies

San Raffaele Cimena, Italy
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Ferreri A.J.M.,Unit of Lymphoid Malignancies | Sassone M.,Unit of Lymphoid Malignancies | Zaja F.,Centro Trapianti e Terapie Cellulari Carlo Melzi | Re A.,Spedali Civili | And 19 more authors.
The Lancet Haematology | Year: 2017

Background Patients with relapsed diffuse large B-cell lymphoma (DLBCL) not eligible for autologous stem cell transplantation (ASCT) or having relapse after ASCT have a low likelihood of cure. Single-drug maintenance after salvage therapy might be an attractive strategy to prolong survival in these patients. Lenalidomide is a suitable candidate for long-lasting maintenance as it is an oral drug, active against DLBCL that can be taken for years with an acceptable toxicity profile. We designed a study to investigate safety and efficacy of lenalidomide maintenance in patients with chemosensitive relapse of DLBCL not eligible for ASCT or having relapse after ASCT. Methods In this open-label, single group, multicentre phase 2 trial, we recruited HIV-negative adults with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy from 12 oncology-haematology centres in Italy. All patients were given oral lenalidomide 25 mg per day for 21 of 28 days until lymphoma progression or unacceptable toxicity (severely compromises organ function, quality of life, or both). Primary endpoint was 1-year progression-free survival. The estimated sample size was 47 patients; maintenance was deemed efficacious if at least 19 patients were progression-free survivors at 1 year. All enrolled patients were included in primary analyses, with the exception of patients who post-hoc objectively did not meet the eligibility criteria (modified intention-to-treat). This study is registered with clinicaltrials.gov registry, number NCT00799513. Findings Between March 24, 2009, and Dec 22, 2015, we recruited 48 patients. 46 of 48 enrolled patients were assessable (two patients had unconfirmed diagnoses). 36 (78%) of 46 patients had de novo DLBCL and ten (22%) of 46 patients had transformed DLBCL. At a median follow-up of 25 months (IQR 12–56), 556 lenalidomide courses had been delivered, with an average mean of 12 courses (range 3–41) per patient; 19 patients were still in treatment at a median follow-up of 25 months. Lenalidomide was well tolerated; with the exception of neutropenia, grade 3–4 toxicities were uncommon. We recorded ten severe adverse events in nine patients due to febrile neutropenia (n=4), diarrhoea (n=2), melena, stroke, vomiting, and intestinal infarction; all but one patient recovered, and six of these patients continued with lenalidomide treatment. The exception was the only death due to toxicity (intestinal infarction). At 1 year from trial registration, 28 patients were progression free, which was much higher than the predetermined efficacy threshold. During the whole observation period, 21 events occurred: progressive lymphoma in 19 patients, death due to toxicity in one, death while off therapy in one, 1-year progression-free survival was 70% (95% CI 57–83). Interpretation With the limitations of a non-randomised design, this trial supports the use of lenalidomide maintenance in patients with chemo-sensitive relapse of DLBCL who are not eligible for ASCT or who had relapse after ASCT. These results warrant further investigation of immunomodulatory drugs as maintenance in high-risk patients with DLBCL. Funding Celgene Corp. © 2017 Elsevier Ltd


Bertilaccio M.T.S.,Laboratory of Lymphoid Malignancies | Scielzo C.,Laboratory of Lymphoid Malignancies | Scielzo C.,University of Milan | Simonetti G.,Laboratory of B Cell Neoplasia | And 14 more authors.
Blood | Year: 2010

Easily reproducible animal models that allow for study of the biology of chronic lymphocytic leukemia (CLL) and to test new therapeutic agents have been very difficult to establish. We have developed a novel transplantable xenograft murine model of CLL by engrafting the CLL cell line MEC1 into Rag2 -/-γc-/- mice. These mice lack B, T, and natural killer (NK) cells, and, in contrast to nude mice that retain NK cells, appear to be optimal recipient for MEC1 cells, which were successfully transplanted through either subcutaneous or intravenous routes. The result is a novel in vivo model that has systemic involvement, develops very rapidly, allows the measurement of tumor burden, and has 100% engraftment efficiency. This model closely resembles aggressive human CLL and could be very useful for evaluating both the biologic basis of CLL growth and dissemination as well as the efficacy of new therapeutic agents. © 2010 by The American Society of Hematology.


Ferreri A.J.M.,Unit of Lymphoid Malignancies | Govi S.,Unit of Lymphoid Malignancies | Ponzoni M.,Unit of Lymphoid Malignancies | Ponzoni M.,San Raffaele Scientific Institute
Current Opinion in Oncology | Year: 2013

PURPOSE OF REVIEW: This review is focused on the effect of Helicobacter pylori eradication with antibiotics in patients with primary gastric lymphomas of indolent and aggressive nature. RECENT FINDINGS: Gastrointestinal lymphoma is the most common form of extranodal lymphoma, involving primarily the stomach in 60-75% of cases. The most common histological subtypes are diffuse large B-cell lymphoma (DLBCL) and marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type. H. pylori infection has been implicated in the pathogenesis of gastric MALT lymphoma; its role in gastric DLBCL remains controversial. Recently, international guidelines established that patients with gastric MALT lymphoma should be treated with upfront H. pylori-eradicating antibiotic therapy and that residual microscopic or molecular disease does not need for additional antiblastic treatment. The excellent prognosis of patients with gastric DLBCL managed with conservative chemo-radiotherapy led some investigators to test H. pylori eradication as exclusive treatment in prospective trials, keeping chemo-radiotherapy for unresponsive patients. This conservative strategy was well tolerated and active in patients with limited-stage DLBCL (±MALT areas) of the stomach. SUMMARY: H. pylori eradication is a suitable strategy as exclusive upfront treatment for both patients with MALT-type lymphomas or with DLBCL of the stomach. Additional trials are needed to elucidate related controversial issues. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Ferreri A.J.M.,Unit of Lymphoid Malignancies | Bruno-Ventre M.,Unit of Lymphoid Malignancies | Donadoni G.,Unit of Lymphoid Malignancies | Ponzoni M.,Unit of Lymphoid Malignancies | And 8 more authors.
British Journal of Haematology | Year: 2015

Summary: The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B-cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk-tailored CNS prophylaxis in 200 human immunodeficiency virus-negative adults with DLBCL treated with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high-dose methotrexate ± intrathecal chemotherapy (IT) was routinely used in high-risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high-risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow-up of 60 months, one low-risk and nine high-risk patients (1% vs. 8%; P = 0·01) experienced CNS relapse. In the high-risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (2·5%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with "inadequate" prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 0·03). In conclusion, high-dose methotrexate-based prophylaxis significantly reduces CNS failures in high-risk patients stratified by involvement of specific extranodal sites and International Prognostic Index. © 2014 John Wiley & Sons Ltd.


PubMed | Unit of Lymphoid Malignancies
Type: Journal Article | Journal: Leukemia & lymphoma | Year: 2010

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation in primary and secondary lymphoid tissues of CD5+ B cells that have the same B cell receptor (BCR) rearrangement. Genetic alterations and different stimuli originating from the microenvironment cooperate in the selection and expansion of the malignant clone. Molecular and functional analyses suggest that stimulation through the BCR affects the destiny of leukemic cells in terms of life or death. Microenvironmental signals are crucial for this process, inducing proliferation and leading to the survival and accumulation of leukemic cells within lymphoid organs. Nevertheless, a number of major biological issues still remain to be solved, including the relationships between cell proliferation and cell accumulation within lymphoid organs as well as the mechanisms that regulate CLL cell migration and recirculation between peripheral blood and lymphoid tissues. We focused on the role played by the cytoskeleton, given its relevance in controlling cellular shape, mobility, and homing. We hypothesize that hematopoietic cell-specific Lyn substrate 1 (HS1), a putative prognostic marker in CLL that interacts with distinct cytoskeleton adapters in leukemic B-lymphocytes, could regulate the CLL cell cytoskeleton.


PubMed | Unit of Lymphoid Malignancies
Type: Clinical Trial | Journal: British journal of haematology | Year: 2015

The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B-cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk-tailored CNS prophylaxis in 200 human immunodeficiency virus-negative adults with DLBCL treated with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high-dose methotrexate intrathecal chemotherapy (IT) was routinely used in high-risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high-risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow-up of 60 months, one low-risk and nine high-risk patients (1% vs. 8%; P = 001) experienced CNS relapse. In the high-risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (25%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with inadequate prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 003). In conclusion, high-dose methotrexate-based prophylaxis significantly reduces CNS failures in high-risk patients stratified by involvement of specific extranodal sites and International Prognostic Index.

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