Lisa Argnani

Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome

BACKGROUND Peripheral T-cell lymphoma unspecified (PTCLU) and mycosis fungoides (MF) often show resistance to conventional chemotherapy. Gemcitabine should be considered a suitable option. We report the long-term update of 39 pretreated T-cell lymphoma patients treated with gemcitabine. PATIENTS AND METHODS From May 1997 to September 2007, 39 pretreated MF and PTCLU patients received gemcitabine. Inclusion criteria were as follows: histologic diagnosis of MF or PTCLU; relapsed/refractory disease; age > or =18 years; and World Health Organization performance status of two or less. Nineteen patients had MF and 20 PTCLU. All patients with MF had a T3-T4, N0, and M0 disease and patients with PTCLU had stage III-IV disease. Gemcitabine was given on days 1, 8, and 15 on a 28-day schedule (1200 mg/m(2)/day) for a total of three to six cycles. RESULTS Overall response rate was 51% (20 of 39 patients); complete response (CR) and partial response (PR) rates were 23% (9 of 39 patients) and 28% (11 of 39 patients), respectively. Patients with MF had a CR rate of 16% and a PR rate of 32% compared with a CR rate of 30% and a PR rate of 25% of PTCLU patients. Among the CR patients, 7 of 9 are in continuous complete response with a variable disease-free interval (15-120 months). CONCLUSION In our experience, gemcitabine proved to be effective in pretreated MF and PTCLU patients, even in the long term.

Combination of Lenalidomide and Rituximab in Elderly Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Phase 2 Trial

BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma and despite recent chemotherapeutic advances up to half of all patients relapse. Here we report the results from a phase 2, single-arm, single-center trial evaluating the safety and efficacy of lenalidomide plus rituximab in elderly patients with relapsed or refractory DLBCL. PATIENTS AND METHODS Between March and June 2009, elderly patients (65 years of age or older) with relapsed/refractory DLBCL who had been heavily pretreated were recruited. Oral lenalidomide (20 mg/d for 21 days of each 28-day cycle) was initiated for four cycles and rituximab (375 mg/m(2)) was administered on day 1 and day 21 of each 28-day cycle for four cycles. After this induction phase, patients achieving a complete response (CR), partial response (PR), or stable disease (SD) were given lenalidomide maintenance therapy at the same schedule for another 8 months. RESULTS A total of 23 patients with a median of three prior treatments (range, 2 to 8) were included. The overall response rate (CR + PR) at the end of the induction phase was 35% (n = 8). Ten patients (7 CR, 1 PR, and 2 SD patients) were eligible for lenalidomide maintenance and 8 of these patients achieved a CR. Adverse events were manageable and the most common included neutropenia and thrombocytopenia. CONCLUSION Oral lenalidomide in combination with rituximab is active in elderly patients with relapsed/refractory DLBCL with a high percentage of patients achieving a continuous CR after lenalidomide maintenance.

Midtreatment 18F-fluorodeoxyglucose positron-emission tomography in aggressive non-Hodgkin lymphoma.

The use of 18F‐fluorodeoxyglucose positron‐emission tomography (PET) scan has increased considerably in the clinical management of non‐Hodgkin lymphoma patients, and its role as a prognostic factor during chemotherapy has been established recently.

Brentuximab vedotin in relapsed/refractory Hodgkin’s lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials

Clinical trial results indicate that brentuximab vedotin brings considerable promise for the treatment of patients with relapsed or refractory Hodgkin’s lymphoma. A retrospective multicenter study was conducted on 65 heavily pretreated patients who underwent therapy through a Named Patient Program in Italy (non trial-setting). The primary study endpoint was the objective response rate; secondary endpoints were safety, overall survival and progression-free survival. The best overall response rate (70.7%), including 21.5% complete responses, was observed at the first restaging after the third cycle of treatment. After a median follow up of 13.2 months, the overall survival rate at 20 months was 73.8% while the progression-free survival rate at 20 months was 24.2%. Globally nine patients are in continuous complete response with a median follow up of 14 months (range, 10–19 months). Four patients proceeded to autotransplantation and nine to allotransplantation. The most frequent extra-hematologic toxicity was peripheral neuropathy, observed in 21.5% of cases (9 patients with grade 1/2 and 5 patients with grade 3/4); neurological toxicity led to discontinuation of treatment in three patients and to dose reduction in four. In general the treatment was well tolerated and toxicities, both hematologic and extra-hematologic, were manageable. This report indicates and confirms that brentuximab vedotin as a single agent is effective and safe also when used in standard, everyday clinical practice outside a clinical trial. Best overall responses were recorded after three or four cycles and showed that brentuximab vedotin provides an effective bridge to further therapeutic interventions.

Phase II Trial of Short-Course R-Chop Followed by 90Y-Ibritumomab Tiuxetan in Previously Untreated High-Risk Elderly Diffuse Large B-Cell Lymphoma Patients

Purpose: This study aimed to evaluate the efficacy and safety of the treatment with 90Y-ibritumomab tiuxetan following a short-course of rituximab with cyclophosphamide-adriamycin-vincristine-prednisone (R-CHOP) in high-risk elderly patients with previously untreated diffuse large B-cell lymphoma (DLBCL). Experimental Design: From December 2006 to October 2008, 55 high-risk elderly (age ≥60 years) untreated DLBCL patients were treated in seven Italian institutions with a short-course of chemotherapy consisting of four cycles of R-CHOP21 followed by 90Y-ibritumomab tiuxetan 6 to 10 weeks later. Results: Of the 55 patients, 48 underwent radioimmunotherapy. The overall response rate to the entire treatment regimen was 80%, including 73% complete remissions and 7% partial remissions. Eight (50%) of the 16 patients who achieved less than a complete response with CHOP improved their remission status after 90Y-ibritumomab tiuxetan administration. With a median follow-up of 18 months, the 2-year progression-free survival was estimated to be 85%, with a 2-year overall survival of 86%. 90Y-ibritumomab tiuxetan toxicity consisted of grade 3 to 4 hematologic toxicity in 28 of 48 patients, mainly neutropenia (23 patients) and thrombocytopenia (15 patients). Red cells and/or platelets transfusions were given to three patients. Conclusion: This study evaluated the feasibility, efficacy, and safety of a short-course R-CHOP21 regimen followed by 90Y-ibritumomab tiuxetan in high-risk elderly DLBCL patients. Clin Cancer Res; 16(15); 3998–4004. ©2010 AACR.

Interim Positron Emission Tomography Response-Adapted Therapy in Advanced-Stage Hodgkin Lymphoma: Final Results of the Phase II Part of the HD0801 Study.

PURPOSE The clinical impact of positron emission tomography (PET) evaluation performed early during first-line therapy in patients with advanced-stage Hodgkin lymphoma, in terms of providing a rationale to shift patients who respond poorly onto a more intensive regimen (PET response-adapted therapy), remains to be confirmed. PATIENTS AND METHODS The phase II part of the multicenter HD0801 study involved 519 patients with advanced-stage de novo Hodgkin lymphoma who received an initial treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and who underwent an early ifosfamide-containing salvage treatment followed by stem-cell transplantation if they showed a positive PET evaluation after two cycles of chemotherapy (PET2). The primary end point was 2-year progression-free survival calculated for both PET2-negative patients (who completed a full six cycles of ABVD treatment) and PET2-positive patients. Overall survival was a secondary end point. RESULTS In all, 103 of the 512 evaluable patients were PET2 positive. Among them, 81 received the scheduled salvage regimen with transplantation, 15 remained on ABVD (physicians decision, mostly because of minimally positive PET2), five received an alternative treatment, and two were excluded because of diagnostic error. On intention-to-treat analysis, the 2-year progression-free survival was 76% for PET2-positive patients (regardless of the salvage treatment they received) and 81% for PET2-negative patients. CONCLUSION Patients with advanced-stage Hodgkin lymphoma for whom treatment was at high risk of failing appear to benefit from early treatment intensification with autologous transplantation, as indicated by the possibility of successful salvage treatment in more than 70% of PET2-positive patients through obtaining the same 2-year progression-free survival as the PET2-negative subgroup.

Lenalidomide monotherapy for relapsed/refractory peripheral T-cell lymphoma not otherwise specified

Current therapeutic strategies for peripheral T-cell lymphoma, not otherwise specified (PTCL-nos) remain poorly defined; they are extrapolated from treatment paradigms of B-cell lymphomas. In particular, patients with aggressive PTCL are traditionally treated with an anthracycline-containing regimen, and complete response rates of 50–70% have been reported [1–3]. However, 5-year overall survival (OS) for patients with PTCL-nos was 20–30%. Autologous stem cell transplant (ASCT) seems to offer long-term disease control in only 30–40% of cases if performed in a status of remission [4,5]. In recent years, there have been a plethora of new agents that have shown promising activity in the treatment of patients with PTCL. Pralatrexate, a new antifolate, showed an overall response rate (ORR) of 29%, with 9% of patients achieving complete remission (CR) in a prospective single-arm multicenter study [6] of relapsed/refractory PTCL. Among histone deacetylase inhibitors (HDACIs), a phase II trial of romidepsin in patients with PTCL who had failed at least one systemic therapy showed an ORR of 31% (with a CR rate of 8%) [7]. Gemcitabine, a nucleoside analogous, has been studied as a single agent in relapsed patients with PTCL, and showed an ORR of 59% with 12% CRs [8,9]. Lenalidomide is an immunomodulatory agent with potent anticancer properties. A phase II trial of lenalidomide in PTCL was reported by Dueck and co-workers [10] in which 24 patients with T-cell lymphoma were enrolled; the ORR was 30%, without CRs. On the strength of these findings we decided to investigate the efficacy and safety of lenalidomide monotherapy in pretreated patients with PTCL-nos. Patients aged 18 years or older with biopsy-proven, bidimensionally measurable, stage II, III or stage IV PTCL-nos were considered eligible for this prospective, single-arm, open-label, bi-centric non-randomized phase II trial. Patients were to be relapsed ( 1) or refractory and should have a World Health Organization (WHO) performance status 2. All diagnostic biopsies were reviewed by an expert pathologist (S.P.) in accordance with the WHO classification [11]. All the patients underwent full medical history, physical examination, complete blood cell and platelet counts, a computed tomography (CT) scan of the neck, chest, abdomen, and pelvis, whole-body F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan, and a bone marrow biopsy. Disease stage was established according to the Ann Arbor staging system. Patients were also tested for kidney and liver function (including hepatitis B and C viruses [HBV and HCV]) and were subjected to electrocardiography. All patients signed a written informed consent, approved in accordance with institutional guidelines, including the Declaration of Helsinki. The study was approved by the institutional review board.

Hairy cell leukemia: Evaluation of the long-term outcome in 121 patients

Historically, the first treatment choices for hairy cell leukemia (HCL) were splenectomy and alpha‐interferon. Recently, purine analogues (pentostatin and cladribine) changed radically the treatment modality, inducing complete and durable responses in the majority of patients.

A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 90Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma

BACKGROUND A prospective, single-arm, open-label, multicenter, nonrandomised phase II trial to evaluate efficacy and safety of short fludarabine, mitoxantrone, and rituximab (FMR) induction followed by radioimmunotherapy, in untreated, intermediate/high-risk follicular non-Hodgkins lymphoma (NHL) patients. PATIENTS AND METHODS Fifty-five patients were treated using a sequential treatment schedule of four induction cycles of FMR chemoimmunotherapy, and a subsequent consolidating single administration of (90)Y-ibritumomab tiuxetan ((90)Y-IT), 8-14 weeks later. Patients were eligible for radioimmunotherapy if at least in partial response (PR) after induction, with normal platelet and granulocyte counts and a bone marrow infiltration ≤ 25%. Primary study end points were response rate and hematologic toxic effects; secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS All the 55 patients received four induction cycles with an overall response rate of 96% (38 complete responses [CR] and 15 PR). Fifty-one patients (38 in CR and 13 in PR) received (90)Y-IT. By the end of the treatment, 49/55 patients achieved a CR. With a median follow-up of 21 months, the estimated 3-year PFS was 81% and the 3-year OS 100%. CONCLUSIONS This study has established feasibility, tolerability, and efficacy of a regimen composed by short FMR induction with (90)Y-IT consolidation in untreated intermediate/high-risk follicular NHL patients.

Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell lymphoma patients

2 To the Editor Standard first-line treatment for diffuse large B-cell lymphoma (DLBCL) patients is based since 2002 on the association of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone [1]. Even if the natural history of DLBCL has been changed with this combination, there is clearly a need of improvement of long-term results. In fact, a significant number of patients still experiences disease relapse or progression after first or second line therapy and 30-35% of patients dies within 5 years [2]. In particular, elderly patients and those ineligible for high-dose therapy require effective salvage treatment options with favorable toxicity profile. Lenalidomide is an immunomodulatory agent whose mechanism of action is not quite understood but may affect tumor microenvironment rather than tumor itself; lenalidomide may also act by decreasing proliferation and angiogenesis through the upregulation of tumor suppressor genes. Data emerging from early clinical trials demonstrated that lenalidomide has a significant activity against relapsed/refractory DLBCL either as monotherapy or in association with rituximab [3–5]. We now report updated long-term efficacy results of a single-center phase II trial on the association of lenalidomide and rituximab, demonstrating that this combination was safe and very effective in elderly pretreated DLBCL patients [5]. Twenty-three patients with relapsed/refractory DLBCL were enrolled in 2009 at our institution. Briefly, treatment schedule was the following: four 28-day cycles of oral lenalidomide (20 mg/day for 21 days) and rituximab