Mara Negri

Plerixafor and Filgrastim XM02 (Tevagastrim®) as a first line peripheral blood stem cell mobilisation strategy in patients with multiple myeloma and lymphoma candidated to autologous bone marrow transplantation

Plerixafor, a CXCR4 antagonist, has shown to be effective in increasing the number of circulating stem cells, even in patients failing a previous mobilisation attempt. Recently a number of non‐glycosylated recombinant human granulocyte‐colony stimulating factor (G‐CSF) has been clinically approved for the same indications as the originator G‐CSF for comparable safety and efficacy and their reduced cost. In an attempt to provide a less toxic strategy, 14 patients affected by haematological malignancies (non‐Hodgkin’s lymphoma = 4, Hodgkin’s disease = 2 and multiple myeloma = 8), received the combination of biosimilar filgrastim and plerixafor as a first line mobilising strategy. The median number of circulating CD34+ cells on day 4 was 16 (3–42); Plerixafor was administered to all, but one patient who had already 42 CD34+ cells per μL on day 4. On day 5, after plerixafor administration, the median number of circulating CD34+ cells had raised to 60 per μL (14–138). All the patients underwent leukapheresis and were able to collect a number of CD34+ cells ≥2.0 × 106/kg in a median number of procedures of one. Although preliminary, these data show the combination of biosimilar filgrastim and plerixafor is effective and provides a non‐toxic approach to mobilise stem cells.

Rituximab and Subcutaneous 2-Chloro-2′-Deoxyadenosine as Therapy in Untreated and Relapsed Waldenström's Macroglobulinemia

With the aim to assess the efficacy of subcutaneous cladribine in combination with rituximab, 29 newly diagnosed/pretreated WM patients were enrolled in a multicenter phase II trial. Intended therapy consisted of rituximab on day 1 followed by s.c. cladribine 0.1 mg/kg for 5 consecutive days, administered monthly for 4 cycles. The expression of genes involved in cladribine metabolism was evaluated. With a median follow-up of 50 months the ORR rate observed was 89.6% without any difference between newly or pretreated patients (P=.522). The therapy was well tolerated; no major infections were observed, no patients developed transformation to high-grade NHL nor myelodysplasia. Low expression levels of hCNT1 correlated with the failure to achieve a CR (P=.024). The combination of rituximab/cladribine is safe and effective in WM patients requiring treatment. The pharmacogenomic analysis suggests that hCNT1 might be beneficial in predicting clinical response to such a combination treatment.

Rituximab and subcutaneous cladribine in chronic lymphocytic leukemia for newly diagnosed and relapsed patients.

The aim of this study was to investigate the efficacy of combined treatment with rituximab and subcutaneous cladribine in patients with newly diagnosed and relapsed chronic lymphocytic leukemia (CLL). Forty-three patients with active CLL or small lymphocytic lymphoma received rituximab 375 mg/m2 on day 1 and cladribine 0.1 mg/kg subcutaneously on days 2–6. The treatment was repeated every 4 weeks for a total of four cycles. Sixteen patients were pretreated. The overall response rate was 88% (50% complete remission and 38% partial remission). The median time to treatment failure was 37.9 months. Grade 4 neutropenia developed in 5% of patients. The data indicate that combination therapy with rituximab and cladribine is a valuable and safe treatment for patients with CLL.

A retrospective international study on primary extranodal marginal zone lymphoma of the lung (BALT lymphoma) on behalf of International Extranodal Lymphoma Study Group (IELSG)

Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow‐up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa‐associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty‐five per cent of the patients were female. The median age at diagnosis was 62 (range 28–88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression‐free survival (p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long‐term disease‐free survival for patients with localized disease. Systemic treatment, including alkylating‐containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright

Chlorambucil-rituximab as first-line therapy in patients affected by follicular non-Hodgkin's lymphoma: a retrospective single-centre study.

Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been shown to be active in newly diagnosed and relapsed patients with follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. Many studies suggest that the prognosis of patients with FL may improve when it is used in combination with chemotherapy. Despite these advances, the disease remains essentially incurable with standard therapy, and novel approaches to treatment are needed because optimal therapy is not defined. The combination of chlorambucil–rituximab is one of several standard treatment options for FL. Here, we considered data arising from 75 patients with newly diagnosed FL at the European Institute of Oncology treated with the combination of rituximab plus chlorambucil. The aim of this study was to evaluate the efficacy and safety of chlorambucil and rituximab, delivered 6 mg/m2/day orally for 6 weeks and 375 mg/m2 in a standard 4‐weekly schedule, respectively. Patients responding to the induction therapy received a prolonged therapy with four additional cycles of chlorambucil plus rituximab. Seventy‐one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 3–4 hematological toxicity. The overall response rate was 97.3% including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow‐up of 57 months, 72 patients (96%) are alive. Median event‐free survival (EFS) and median overall survival (OS) were not reached; 5‐year OS rate was 98.4%. The 5‐year EFS was 71.3%. By univariate and multivariate analyses, elevated beta‐2 microglobulin levels and partial responses to therapy were correlated with worse EFS. These results suggest that the combination of chlorambucil and rituximab is an active and safe regimen in patients with newly diagnosed FL, principally in those with low tumour burden and favourable prognostic factors. Copyright

R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma.

Stem cell (SC) mobilization is significantly influenced by the mobilization schedule in patients with lymphoma. We evaluated data from 30 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) undergoing SC mobilization. All received R-ESHAP plus a single dose of pegfilgrastim. All patients collected ⩾ 2 × 10(6) CD34+cells/kg, 80% of them at least 5 × 10(6) CD34+cells/kg. Adverse effects of the regimen included myelosuppression and neutropenic fever. Herein, our results suggest that R-ESHAP plus pegfilgrastim is a highly effective mobilization strategy in patients affected by DLBCL associated with a low incidence of adverse events.

O-26 G-CSF AND PLERIXAFOR AS NON-TOXIC AND EFFECTIVE FIRST-LINE MOBILIZING APPROACH IN PATIENTS WITH MULTIPLE MYELOMA CANDIDATE TO ASCT

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) can be a successful treatment in patients with multiple myeloma. Administration of cytokines such as granulocyte-colony stimulating factor (G-CSF) alone or with chemotherapy have been used thus far as standard strategies to collect sufficient peripheral CD34+ cells for either single or tandem transplantation. Despite these approaches, 5% to 20% of myeloma patients are still unable to mobilize adequate hematopoietic stem cells and can require multiple mobilization attempts or, even, cannot be able to perform ASCT, with both conditions possibly reducing patients’ quality of life and treatment outcome. Plerixafor (AMD3100) an inhibitor of SDF-1 alpha/CXCR4 binding, can improve PBSC collection rate in patients with lymphoma and myeloma. We retrospectively analyzed safety and efficacy of PBSC mobilization with G-CSF and plerixafor as first line treatment in patients with multiple myeloma. From November 2010 to April 2012, a total of 16 pts with multiple myeloma, who were candidates to autologous stem cell transplant, received plerixafor at a standard dose after G-CSF treatment for 4 days in order to mobilize PBSC. Pts characteristics were the following: 13 were female, 3 were male, median age was 60 years (47–73); DS staging was IIIA in 12 patients, stage IIIB in 1 patient, stage IIA in 1 patient, stage IA in 1 patient and unknown in one patient. Median number of previous lines of therapy was 1 (1->7), 9 patients had previously received Thalidomide and three pts had also received radiotherapy or previous ASCT. Overall plerixafor administration was safe and no serious adverse events were reported. The median number of circulating CD34+ cells/ml following plerixafor administration was 61 (14–138; with 4.05-fold increase over pre-plerixafor counts); 15 patients were able to collect the targeted required dose for ASCT in a median number of one apheresis (1–2) and one patient failed to mobilize PBSC even after plerixafor administration (CD34+ cells/ml 14); median numbers of CD34+ cells collected was 6.0×106kg (1.8–10.60); notably among 12 patients who have a tandem autologous transplant program, 8 patients collected the target CD34+ cell dose in a single procedure and 4 patient required two procedure. At the time of the analysis, all 15 patients who collected PBSC had already undergone ASCT: successful engraftment occurred at median time of 11 (10–15) to ANC ≥500/ml and 12 (11–17) days to a PLT ≥20000/ml. We conclude that mobilization with plerixafor is a safe and effective strategy for pts with MM, can improve PBSC mobilization especially in patients who need to collect a greater number of CD34+ cells/kg for a tandem transplant. A comparative cost analysis of plerixafor administration in association to G-CSF versus chemotherapy in association to G-CSF is ongoing.

Intensified ChlVPP/ABVVP chemotherapy regimen and pegfilgrastim support in advanced Hodgkin lymphoma.

We present feasibility, toxicity and efficacy results of an intensified six-cycle ChlVPP/ABVVP regimen in advanced Hodgkin lymphoma (HL). From February 2004 to August 2007, 82 consecutive eligible patients were enrolled. According to the Hasenclever index, 64 patients (78%) were considered at low risk, 15 (18%) at intermediate and 3 (4%) at high risk. The most relevant toxicity was haematological: grade 3–4 neutropenia occurred in 32% of patients, grade 3–4 anaemia in 26% of patients. Severe infections and febrile neutropenia were observed in 8% of patients. With a median follow-up of 35 months (range 12–55), the three-year freedom from treatment failure (FFTF) and overall survival (OS) were 75% (95% CI 65%–86%) and 94% (95% CI 87%–99%), respectively. The intensified ChlVPP/ABVVP regimen in advanced HL is effective, does not seem to differ from standard regimens in terms of FFTF and OS and showed a favourable toxicity profile.