Lorenzo Falchi

Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study

Patients with diffuse large B-cell lymphoma with an intermediate/high or high-risk according to the age-adjusted International Prognostic Index have a dismal prognosis. This clinical trial suggests that the addition of rituximab to high-dose chemotherapy is effective and safe in diffuse large B-cell lymphoma with a poor prognosis. See related perspective article on page 1194. Background We investigated the addition of rituximab to dose-dense and high-dose chemotherapy with autologous stem cell transplantation in patients with untreated poor-prognosis diffuse large B-cell lymphoma. Design and Methods Ninety-four young patients (age, 18–60) with stage III–IV diffuse large B-cell lymphoma at intermediate/high or high risk according to the age-adjusted International Prognostic Index were enrolled into a phase II trial. The treatment was as follows: four courses of bi-weekly rituximab-cyclophosphamide-epirubicin-vincristine-prednisone (R-MegaCEOP14), two courses of rituximab-mitoxantrone-cytarabine-dexamethasone (R-MAD) and carmustine-etoposide-cytarabine-melphalan (BEAM) with autologous stem cell transplantation. Results The complete response and toxic death rates were 82% and 5%, respectively. Failure-free survival and overall survival rates at 4 years were 73% and 80%, respectively. The outcomes of these patients were retrospectively compared to those of 41 patients with similar characteristics enrolled into a previous phase II trial of high-dose chemotherapy without rituximab. This historical group was treated with eight weekly infusions of methotrexate-doxorubicin-cyclophosphamide-vincristine-prednisone-bleomycin (MACOP-B), two courses of MAD and BEAM with autologous stem cell transplantation. The 4-year failure-free survival rates for the rituximab and historical groups were 73% versus 44%, respectively (p=0.001); the 4-year overall survival rates were 80% and 54%, respectively (p=0.002). A Cox’s multivariable model was applied to adjust the effect of treatment for unbalanced or important prognostic factors: failure and death risks were significantly reduced in the rituximab group compared to the historical group, with an adjusted hazard ratio of 0.44 (p=0.01) for failure-free survival and 0.46 (p=0.02) for overall survival. Conclusions These results suggest that the addition of rituximab to high-dose chemotherapy is effective and safe in diffuse large B-cell lymphoma with a poor-prognosis and such regimens need to be compared to dose-dense chemoimmunotherapy without autologous stem cell transplantation in randomized trials.

The coexistence of chronic lymphocytic leukemia and myeloproliperative neoplasms: a retrospective multicentric GIMEMA experience

Although the coexistence of chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) has been sporadically reported in the literature, no systematic studies on this disease association are available. We retrospectively analyzed 46 patients affected by CLL/MPN referred by 15 Italian GIMEMA centers. The aim of this retrospective multicenter study was to define the following: clinico‐biological characteristics, possible familiarity, clinical course of both diseases, and influence of MPN chemotherapy on the course of CLL. Among 46 patients, 30 patients were males, 16 patients were females; median age was 71 years. Only one case had familiar CLL. Myeloproliferative disorders consisted of essential thrombocytemia in 18 cases, polycythemia vera in 10 cases, chronic myeloid leukemia in 9 cases, primary myelofibrosis in 6 cases, and MPN/myelodysplastic syndrome in 3 cases. The lymphoproliferative disorder was diagnosed as monoclonal B‐cell lymphocytosis in 8 patients and as Binet Stage A CLL in 38 patients. After a median follow‐up of 49 months, 9 patients experienced progressive CLL and only 6 patients required treatment after a median of 57.5 months. The biological profile confirmed a subset of low‐risk CLL. Twenty patients received chemotherapy for MPN without influence on the course of CLL: lymphocyte counts remained unchanged after 3, 6, and 12 months of treatment. This series is the largest so far reported in literature. The diagnosis of concomitant CLL/MPN is a rare event and lymphoproliferative disorders present a clinical indolent course with a low‐risk biological profile. MPN therapy does not interfere with the prognosis of patients with CLL. Am. J. Hematol. 2011.

An Italian retrospective study on the routine clinical use of low‐dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients

Low‐dose alemtuzumab has shown a favourable toxicity profile coupled with good results in terms of efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). We conducted a multicentre retrospective study on the routine clinical use of low‐dose alemtuzumab in this patient setting. One hundred and eight relapsed/refractory CLL patients from 11 Italian centres were included in the analysis. All patients had an Eastern Cooperative Oncology Group performance status ≤2 and the majority (84%) had adenopathies <5cm. Low‐dose alemtuzumab was defined as a total weekly dose ≤45 mg and a cumulative dose ≤600 mg given for up to 18 weeks. The overall response rate was 56% (22% complete remissions). After a median follow‐up of 42·2 months, the median overall survival and progression‐free survival were 39·0 and 19·4 months, respectively. In univariate analysis, response was inversely associated with lymph node (P = 0·01) and spleen (P = 0·02) size, fludarabine‐refractoriness (P = 0·01) and del(11q) (P = 0·009). Advanced age and del(17p) were not associated with a worse outcome. Cumulative dose of alemtuzumab was not associated to response. Toxicities were usually mild and manageable; severe infections occurred in seven patients (7%) during therapy. This retrospective analysis confirms that low‐dose alemtuzumab is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL.

A case of nodular sclerosis Hodgkin’s lymphoma repeatedly relapsing in the context of composite plasma cell-hyaline vascular Castleman’s disease: successful response to rituximab and radiotherapy

We report the case of an Epstein‐Barr virus (EBV)‐ and human immunodeficiency virus‐serum negative patient suffering from repeatedly relapsing classical Hodgkin’s Lymphoma (cHL) associated with a histological picture of plasma cell‐hyaline vascular (PC‐HV) form of Castleman’s disease (CD). The CD30‐ and CD15‐ positive, Reed‐Sternberg/Hodgkin cells, only occasionally expressed the CD20 molecule, but not leukocyte common antigen and latent membrane protein‐1. Single‐strand polymerase chain reaction failed to detect human herpesvirus 8 or EBV in the involved tissues. At the time of second relapse in July 2005, the clinical picture was characterized by a palpable right hypogastric mass, disclosed at physical exam, in the absence of other enlarged peripheral lymph nodes, subjective symptoms or laboratory profile alterations. Combined hybrid‐(18)F‐fluorodeoxyglucose positron emission‐computerized tomography (18F‐FDG PET/CT) showed increased radionuclide uptake in multiple external iliac lymph nodes [standardized uptake value (SUV) of 7.4] and non‐palpable left supraclavicular lymph nodes (SUV of 5.8). Relapsing cHL in the context of mixed PC‐HV CD was documented in two of three surgically excised abdominal lymph nodes never previously enlarged or involved by any lymphoproliferative disease. Because of the limited disease extension and failure to induce continuous remission with previous conventional chemoradiotherapy, the patient was treated with six rituximab injections. This immunotherapy induced significant reduction in size of supraclavicular lymph nodes as evident at ultrasound (US) scan (<1 vs. 2.5 cm, post‐ vs. pretherapy), which was confirmed by the 18F‐FDG PET/CT in October 2005, despite no modification in SUV of 4.2. 18F‐FDG PET/CT also disclosed no radionuclide uptake by abdominal lymph nodes. Thus, a second course of four additional rituximab injections was given and subsequent 18F‐FDG PET/CT indicated persistent, but reduced incorporation of radionuclide compared to the pretherapy value (SUV of 2.7) in the supraclavicular area and confirmed a normal metabolic activity in the iliac external lymph nodes. Because of uncertain persistent disease in the supraclavicular nodal site, involved‐field radiotherapy (RT) was delivered in that area as consolidation treatment. After completion of rituximab and RT for 16 and 14 months respectively, US and 18F‐FDG PET/CT exams were indicative of complete remission. This case is in concordance with previously published data suggesting that rituximab immunotherapy might be a valid option in the treatment of CD and also have a role in the management of relapsing cHL.

Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin’s Lymphomas

Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.

Sustained molecular remissions are achievable with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia and additional cytogenetic clonal evolution

Little is known regarding the activity of tyrosine kinase inhibitors (TKis) on chronic myeloid leukemia (CML) clonal evolution (CE). We treated 10 CE CML patients in either hematologic chronic (8 cases) or accelerated (2 cases) phase with imatinib or second generation TKi. Additional chromosomal abnormalities appeared during the course of disease in seven cases, being present at diagnosis in three. A total of 6/10 (60%) patients achieved complete cytogenetic remission (CCyR) with imatinib in 3-14 months. Major or complete molecular remission (CMR) was obtained in four CCyR patients after 21, 25, 22, and 12 months, as well as in a fifth patient who started nilotinib because of suboptimal response after 75 months of imatinib treatment. One patient received nilotinib due to imatinib intolerance after 56 months of therapy while on CMR, and maintained such status. After a median follow-up of 82 months (range, 3-116), six patients are alive, five of which are in continuous CCyR while one patient is in his third CCyR on dasatinib after relapsing on imatinib and nilotinib. Five patients are in complete (four) or major (one) molecular remission, ongoing at 3, 48, 61, 95, and 96 months, on imatinib (three) or nilotinib (two). Although a small number of patients was studied, our results suggest that long-term cytogenetic and molecular remission can be achieved in CML CE patients with TKis treatment.

The Value of Molecular Response in Chronic Myeloid Leukemia: The Present and the Future

1.1 Historical notes The last decade has witnessed profound changes in the treatment of chronic myeloid leukemia (CML). Previously, therapeutic options were restricted to the use of conventional chemotherapeutic agents such as hydroxyurea (Goldman, & Marin, 2003) and busulfan (Brodsky, 1993). These were essentially cosmetic treatments, offering only palliative care, and not substantially altering the natural history of the disease. Later in the 90s interferon alpha (IFN┙), was introduced in the therapeutic armamentarium for CML patients (Goldman, 2003). When used at high doses, this agent proved to be superior to conventional chemotherapy in terms of hematological and cytogenetic response rates. In particular, 9or 10-year overall survival (OS) rates in the range of 27% to 53% (Bonifazi, 2001) have been reported. However, residual leukemia was still detectable at the molecular level in the vast majority of patients (Baccarani, 2003). Overall, these observations indicated that none of these treatment options were curative for CML and allogeneic bone marrow transplantation remained the only disease-eradicating therapy, albeit at the price of substantial treatmentrelated mortality, especially for the higher EBMT risk score patients (Gratwohl, 1998 ; Baccarani, 2006; Passweg , 2004).

High-dose methotrexate and temozolomide associated with intrathecal liposomal cytarabine for the treatment of primary or secondary central nervous system lymphoma: A preliminary experience

Treatment of central nervous system (CNS) lymphoma remains challenge for clinicians. Historically, whole-brain radiotherapy WBRT) has been the cornerstone of treatment for brain lymhomas. However, after initial response, virtually all patients elapsed within short periods of time. The addition of systemic ytotoxic chemotherapy has significantly improved the outcome of NS lymphoma patients, but is often burdened with severe acute nd/or delayed neurotoxicity. Particularly in the over-60 populaion. Moreover, deferring radiotherapy to the time of relapse may educe or postpone the risk of severe neurotoxicity, without apparnt detrimental effect on overall survival (OS). Finally, a recent andomized trial suggested that there may not be an OS benefit rom the addition of radiation to systemic cytotoxic therapy [1]. Chemotherapy-only approaches, have therefore been explored. ecently, high-dose methotrexate and temozolomide (HD-MTXMZ), without IT therapy or consolidating radiotherapy have een tested in previously untreated PCNSL patients older than 60 ears. This regimen showed considerable activity, while apparently ecreasing neurotoxicity [2]. Liposomal cytarabine (LC) is a sustained-release intrathecal IT) preparation approved for the treatment of lymphomatous