Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia

Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34

Rituximab maintenance therapy: a step forward in follicular lymphoma

Whilst recent advances in the treatment of follicular lymphoma (FL) have improved the outlook for many patients, relapses still occur and the search continues for strategies to extend the duration of remission without significantly increasing toxicity. One such strategy is the use of rituximab maintenance therapy for patients responding to initial induction. There is now a large body of evidence demonstrating clear benefits of rituximab maintenance versus observation following induction with either rituximab plus chemotherapy (R chemo), chemotherapy alone, or rituximab monotherapy, in both first-line and relapsed/refractory settings. A very important finding is that rituximab maintenance can significantly improve overall survival in FL patients responding to induction with either R-chemo or chemotherapy alone. Also, compared with rituximab retreatment at disease progression, the maintenance approach produces much better complete remission rates and significantly longer continuous remissions and progression-free survival. Various maintenance schedules have been explored, all of which demonstrate clear benefits. However, the optimal dose, schedule, and duration of maintenance therapy still need to be established. Current data indicate that rituximab maintenance can be safely administered for up to 2 years, although assessment of long-term safety requires longer follow-up. From the patient's perspective, rituximab maintenance also prolongs the period in which patients are symptom-free and able to lead a relatively normal daily life. Also, rituximab maintenance may help patients feel they can control their disease, rather than passively waiting for relaps

Rituximab maintenance in indolent lymphoma: indications and controversies

Over the past few years it has been shown in previously untreated and relapsed/refractory follicular lymphoma that rituximab maintenance has a clear clinical benefit after induction with rituximab plus chemotherapy, chemotherapy alone, or rituximab monotherapy. However, the optimal dose, schedule, and duration of rituximab maintenance therapy still need to be established. The important issue of maintenance treatment versus retreatment upon relapse is the topic of the ongoing large randomized phase III Rituximab Extended Schedule or Retreatment Trial (RESORT). Current data indicate that rituximab maintenance can be safely administered for up to 2 years, although assessment of long-term safety requires longer follow-u

Treatment strategies in advanced stage follicular lymphoma

Although the introduction of anti-CD20 monoclonal antibodies has improved the outcome of patients with follicular lymphoma, a curative treatment is still not available. Many questions still remain to be answered: when should treatment be initiated? Is there an optimal first line treatment and can this treatment be individualized on the basis of prognostic markers? What is the best treatment strategy for relapsed follicular lymphoma and what is the place of the many novel agents? Should maintenance treatment be given to all patients and how? In the present review we will address these question

Cellular immune therapy for chronic lymphocytic leukemia

Although chemotherapy can induce complete responses in patients with chronic lymphocytic leukemia (CLL), it is not considered curative. Treated patients generally develop recurrent disease requiring additional therapy, which can cause worsening immune dysfunction, myelosuppression, and selection for chemotherapy-resistant leukemia-cell subclones. Cellular immune therapy promises to mitigate these complications and potentially provide for curative treatment. Most experience with this is in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT), in which graft-versus-leukemia (GVL) effects can be observed and shown responsible for. long-term disease-free survival. However, use of allo-HSCT for CLL is limited because of the lack of suitable donors and the treatment-related morbidity/mortality for elderly patients, who constitute the majority at risk for developing this disease. The GVL effect, however, suggests there are specific CLL-associated antigens that could be targeted in autologous cellular immune therapy. Effective strategies for this will have to overcome the disease-related acquired immune deficiency and the capacity of the leukemia-cell to induce T-cell tolerance, thereby compromising the activity of even conventional vaccines in patients with this disease. We will discuss the different strategies being developed to overcome these limitations that might provide for effective cellular immune therapy of CL