Hazem A. Sayala

Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study

PURPOSE Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. PATIENTS AND METHODS Patients with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. RESULTS A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. CONCLUSION These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.

A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia.

Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front‐line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two‐stage, Phase II trial of FCM and FCM‐R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as <0·01% CLL cells. Fifty‐two patients were entered, 26 in each arm. The overall response rates to FCM and FCM‐R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4–35%) for FCM and 42% (95%CI:23–63%) for FCM‐R, with eight patients achieving MRD negativity (3 FCM; 5 FCM‐R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.

Development of EBV-associated diffuse large B-cell lymphoma in Waldenström macroglobulinemia and mantle cell lymphoma

Large cell transformation is a well-recognised late event in follicular lymphoma, mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM) and chronic lymphocytic leukemia (CLL). This is traditionally considered to be due to transformation of the underlying clone as a consequence of the acquisition of new genetic events. However, there is increasing evidence in CLL at least, that apparent histological ‘‘transformation’’ can occur as a consequence of the development of a de-novo diffuse large B-cell lymphoma (DLBCL) in a clonally unrelated population which is frequently associated with Epstein-Barr virus (EBV) [1,2]. Here we report the development of EBV-associated DLBCL in 2 patients with WM and MCL. An 80-year-old male patient was found to have mild anemia and an IgMk paraprotein during preoperative screening in 2003. His bone marrow was diffusely infiltrated by small lymphocytes and plasma cells and was associated with a reactive increase in mast cells. B-cells, identified on the basis of scatter characteristics and CD19 expression were monotypic (IgMkþ) and had the following immunophenotype: CD20þ CD38þ/7 CD57 CD107 CD22þ FMC7þ CD237 CD11aþ/7 CD79bþ. A diagnosis of WM was made [3]. He was not treated initially but subsequently received chlorambucil in 2004 and fludarabine in 2005 achieving partial responses in both instances. He then presented in August 2006 with abdominal distension and was found to have a heterogeneous mass in the mesentery close to small bowel loops without any other lymph node enlargement. He had a laparoscopic biopsy of the mesenteric mass, which showed histological features typical of DLBCL. This had the following immunophenotype: CD57CD107BCL2þCD20þCD79þBCL6þ/7 CD237 MUM-17 FOX-P17. EBV-associated latent membrane protein-1 (LMP-1) expression was demonstrable in a significant proportion of tumor cells. He was commenced on CVP-R but unfortunately suffered significant complications and finally succumbed to MRSA septicemia. A 62-year-old male patient originally presented in 1998 with peripheral blood lymphocytosis, lymphadenopathy and bone marrow infiltration and a diagnosis of MCL was made on the basis of a CD5þ CD107 CD20þ CD237 CD79þ BCL2þ immunophenotype and nuclear expression of cyclin D1 protein. He was initially treated with chlorambucil and achieved a good partial response. He relapsed in 2000 and was treated with CHOP, and again in 2003 when he was treated with FCR. He presented with a small bowel mass in May 2004, which showed the typical morphological features of DLBCL with a CD57 CD20þ CD79þ CD10þ BCL67 BCL2þ CD30þ immunophenotype. Cyclin D1 immunostaining was negative while LMP1 staining was clearly demonstrable in a significant proportion of tumor cells. Interphase FISH studies failed to demonstrate the t(11;14) although retrospective analysis confirmed its presence in the biopsy material from 1998. Unfortunately the patient succumbed to the