Epidemiology and environmental aspects of marginal zone lymphomas.

Marginal zone lymphomas (MZLs) account for between 5% and 17% of all non-Hodgkin's lymphomas. MZLs consist of 3 different subtypes with extranodal being the most commonly reported, representing 50-70% of MZL, followed by splenic (20%) and nodal (10%). Median age at presentation varies between these lymphoma sub-types, ranging between 50 and 69 years, with an overall greater incidence noted in males compared to females. Given the rarity of these lymphomas, epidemiologic data has been sparse, although it has been suggested the aetiology is multi-factorial including ethnicity and geographical factors. Other reported associations include autoimmune disease and infection, with Helicobacter pylori and Campylobacter psittaci, being the most commonly reported pathogens. Larger population studies are required to investigate the role of these environmental factors further as these can direct the future management of these lymphomas, through the use of more effective targeted treatments.

Long-term follow-up after purine analogue therapy in hairy cell leukaemia.

Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.

An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy.

We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized. The spleen histology showed no evidence of HCL, but a five-fold thickening of the splenic capsule and areas of fibrosis in the red pulp. This process may have contributed to the lack of elasticity and caused the persistent splenomegaly. We discuss the clinical implications for future patient management. The three patients remain in remission at 1 + , 5 + and 9 + years.

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.

Improved relapse-free survival after autologous stem cell transplantation does not translate into better quality of life in chronic lymphocytic leukemia: lessons from the randomized European Society for Blood and Marrow Transplantation-Intergroup study.

In chronic lymphocytic leukemia (CLL) medical progress is driven by clinical studies with relapse-free survival (RFS) as the primary endpoint. The randomized EBMT-Intergroup trial compared high-dose therapy and autologous stem cell transplantation (ASCT) to observation and demonstrated a substantial improvement of RFS without showing improved overall survival for the transplant arm. Here we report quality of life (QoL) information of the first 3 years following randomization from that study. The main objective was to assess the impact of treatment on QoL over time. Two secondary analyses were performed to further investigate the impact of ASCT and relapse on QoL. In the primary analysis, we demonstrate an adverse impact of ASCT on QoL which was largest at 4 months and continued throughout the first year after randomization. Further, we demonstrated a sustained adverse impact of relapse on QoL which worsened over time. Despite better disease control by ASCT the side effects thus turned the net effect towards inferior QoL in the first year and comparable QoL in the following 2 years after randomization. This study emphasizes the importance of information concerning QoL impacts when patients are counseled about treatments aimed at improving RFS in the absence of a survival benefit.

High readmission rates are associated with a significant economic burden and poor outcome in patients with grade III/IV acute GvHD.

Graft-versus-host disease (GvHD) is a common complication following haematopoietic stem cell transplant but little is published about the impact of this condition on hospital readmission rates. We report a retrospective analysis of readmission rates and associated costs in 187 consecutive allogeneic transplant patients to assess the impact of GvHD. The overall readmission rate was higher in patients with GvHD (86% (101/118) vs. 59% (41/69), p < 0.001). The readmission rate was higher both in the first 100 d from transplant (p = 0.02) and in the first year following transplant (p < 0.001). 151/455 (33%) of all readmission episodes occurred within 100 d of transplant. The mean number of inpatient days was significantly higher in patients with grade III/IV acute GvHD (101 d) compared with those with grade I/II GvHD (70 d; p = 0.003). The mean cost of readmission was higher in patients with GvHD (£28 860) than in non-GvHD patients (£13 405; p = 0.002) and in patients with grade III/IV GvHD (£40 012) compared with those patients with grade I/II GvHD (£24 560; p = 0.038). Survival was higher in those with grade I/II GvHD (55%) compared to grade III/IV GvHD (14%; p < 0.001). This study shows the high economic burden and poor overall survival associated with grade III/IV GvHD.

Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy, with no standard treatment other than splenectomy. Rituximab has shown encouraging results. We therefore retrospectively assessed 43 patients from two centres, who received rituximab, either alone or with chemotherapy. All patients responded, 34/43 (79%) achieving a complete response (CR), compared with 3/10 (30%) after chemotherapy without rituximab (P = 0·005). Of these 10 patients, 9 (90%) subsequently achieved a CR after rituximab (P = 0·02). Rituximab monotherapy appeared equally as effective as rituximab combination therapy (90% vs. 79% CR, P = 0·7) with significantly less toxicity (12·5% vs. 83%, P = 0·002). Splenectomized patients were more likely to obtain a CR with rituximab (16/16, 100%) than unsplenectomized patients (18/27, 67%, P = 0·008). Disease-free survival (DFS) at 3 years was better after rituximab than after splenectomy alone [79% (95% confidence interval 60-89) vs. 29% (8-54), Hazard ratio (HR) 0·28 (0·12-0·68), P = 0·003] and better than after chemotherapy without rituximab [25% (4-55), HR 0·21 (0·08-0·51), P = 0·0004]. Survival at 3 years after rituximab was 98%. In summary, the CR and DFS rates after rituximab, given alone or with chemotherapy, were significantly better than after chemotherapy without rituximab in the same patients, with manageable toxicity. Rituximab, with or without splenectomy, should be considered for the treatment of SMZL.

Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial.

PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. PATIENTS AND METHODS: Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. CONCLUSION: Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.

Alemtuzumab therapy in T-cell prolymphocytic leukemia: comparing efficacy in a series treated intravenously and a study piloting the subcutaneous route.

Intravenous alemtuzumab is an effective and well-tolerated treatment for T-cell prolymphocytic leukemia (T-PLL). Alemtuzumab given intravenously as first-line treatment in 32 patients resulted in an overall response rate of 91% with 81% complete responses. Studies in B-cell chronic lymphocytic leukemia have shown subcutaneous alemtuzumab to be equally as effective as intravenous alemtuzumab. The UKCLL05 pilot study examined the efficacy and toxicity of this more convenient method of administration in 9 previously untreated patients with T-PLL. Only 3 of 9 patients (33%) responded to treatment. Furthermore, 2 of 9 patients (22%) died while on treatment. Recruitment was terminated because of these poor results. After rescue therapy with intravenous alemtuzumab and/or pentostatin, median progression-free survival and overall survival were similar to the intravenous group. Alemtuzumab delivered intravenously, but not subcutaneously, remains the treatment of choice for previously untreated T-PLL.

Long-term results for pentostatin and cladribine treatment of hairy cell leukemia.

Over the past 25 years we have collected data at our institution from 242 patients with hairy cell leukemia (HCL), treated with pentostatin (n = 188) or cladribine (n = 54), with a median follow-up of 16 years. From this we have been able to conclude that there is no significant difference in outcome between the two agents either at first or subsequent lines of therapy. Overall, the complete response (CR) rate is 81% and the median disease-free survival (DFS) is 16 years. After relapse or non-response patients can be successfully retreated with pentostatin or cladribine achieving a lower rate of CRs with each line of therapy, although these remain equally durable. Complete response and pretreatment counts of hemoglobin >10 g/dL together with platelets >100 × 10(9)/L are associated with the longest DFS. Importantly, for patients achieving a CR the DFS is five times as long as for those achieving a partial response (PR). Patients still in CR at 5 years have only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease have improved with the addition of rituximab to either purine analog. Overall, only eight patients have died of HCL-related causes. Patients with HCL who achieve a CR can expect a normal lifespan.

Rituximab with pentostatin or cladribine: an effective combination treatment for hairy cell leukemia after disease recurrence.

The purine analogs pentostatin and cladribine are effective treatments for hairy cell leukemia (HCL). However, alternative treatments are needed for patients with recurrent disease. We reviewed retrospectively data from 18 patients who were retreated with either pentostatin (n = 12) or cladribine (n = 6) in combination with rituximab, after 1-6 (median 2) previous treatments with either purine analog as a single agent. All 18 patients responded to therapy, with a complete response (CR) rate of 89%. This compared favorably with CR rates of 68% after second-line therapy and 47% after third-line therapy in 88 patients retreated one or more times with a purine analog alone. Toxicity with the combination treatment was minimal. At a median follow-up of 36 months (range 5-83 months) all 16 complete responders remained in CR, while one partial responder developed recurrent disease at 10 months. The estimated recurrence rate at 3 years was 7%. This compares with 21% after second-line therapy and 42% after third-line therapy in the 88 patients retreated with a purine analog alone. Furthermore, it was a marked improvement on the 55% recurrence at 3 years previously seen in these same 18 patients after their own first-line treatment with single-agent pentostatin or cladribine (p = 0.006). The combination of a purine analog with rituximab was safe and effective for patients with recurrent HCL. The results suggest an added benefit compared with single-agent purine analog therapy.

Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial.

PURPOSE: TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. PATIENTS AND METHODS: We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. RESULTS: Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. CONCLUSION: TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma).

The peripheral T-cell neoplasms are a biologically and clinically heterogeneous group of rare disorders that result from clonal proliferation of mature post-thymic lymphocytes. Natural killer (NK) cell neoplasms are included in this group. The World Health Organization classification of haemopoietic malignancies has divided this group of disorders into those with predominantly leukaemic (disseminated), nodal, extra-nodal or cutaneous presentation. They usually affect adults and are more commonly reported in males than in females. The median age at diagnosis is 61 years with a range of 17-90 years. Although some subtypes may follow a relatively benign protracted course most have an aggressive clinical behaviour and poor prognosis. Excluding anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), which has a good outcome, 5-year survival for other nodal and extranodal T-cell lymphomas is about 30%. Most patients present with unfavourable international prognostic index scores (>3) and poor performance status. The rarity of these diseases and the lack of randomized trials mean that there is no consensus about optimal therapy for T- and NK-cell neoplasms and recommendations in this guideline are therefore based on small case series, phase II trials and expert opinion.

A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial.

BACKGROUND: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001 following studies demonstrating the bioequivalence of a 40 mg/m(2) oral dose with a 25 mg/m(2) intravenous dose. We assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS: A total of 777 patients were randomized from 1999-2004 to receive fludarabine, alone or with cyclophosphamide, or chlorambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as a control group. RESULTS: Patients given oral fludarabine were less likely to receive the full dose (P = .0004) and experienced more, predominantly gastrointestinal, toxicity. Progression-free survival (PFS) and overall survival were not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87-1.40), but the overall rate of response to treatment appeared to be lower with the oral formulation (P = .003). However, patients recruited since 2001 were older (P = .03) and were more likely to have TP53 deletion, and response rates after 2001 were also lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome was attributable to the route of administration. CONCLUSIONS: Although the LRF CLL4 data suggest no important difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compliance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is being received.

T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia is a rare postthymic malignancy with distinctive clinical, morphologic, immunophenotypic, and cytogenetic features. The clinical course is typically aggressive with poor response to conventional chemotherapy and short survival. Treatment with purine analogues and alemtuzumab has resulted in significantly higher response rates and improved survival. Nevertheless, responses are relatively short, and the only potential curative treatment is allogeneic stem cell transplantation. The age and comorbidities of many of the patients has limited this option, but the growing use of nonmyeloablative transplantation has now widened the patient eligibility for this approach.