Paul Moreton

Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival

PURPOSE To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. PATIENTS AND METHODS Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 10(5) normal cells). RESULTS Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. CONCLUSION MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.

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.

Assessment of Bone Marrow Response in Waldenström's Macroglobulinemia

In this study we used bone marrow flow cytometry and immunohistochemistry to evaluate response to fludarabine therapy in patients with Waldenströms macroglobulinemia (WM)/lymphoplasmacytic lymphoma. Responses in serum M protein were typically delayed with a median time to maximum response of 6 months following the completion of therapy (range, 0-18 months). In contrast, bone marrow responses occurred promptly in responding patients such that there were no detectable clonal B cells at the end of therapy in 55% of patients assessed. Persistent monoclonal plasma cells were, however, readily identified by CD138 immunohistochemistry, explaining the persistence of serum M protein in these patients. This simple observation has significant implications for the assessment of responses in WM as well as the design of future therapeutic strategies.

Phase II study of subcutaneous alemtuzumab without dose escalation in patients with advanced‐stage, relapsed chronic lymphocytic leukaemia

This phase II study (n = 20) aimed to evaluate type, severity and duration of side‐effects and efficacy following subcutaneous (SC) alemtuzumab, without dose‐escalation, in advanced‐stage relapsed chronic lymphocytic leukaemia (CLL) patients. Alemtuzumab 30 and 3 mg was administered SC simultaneously day 1, followed by 30 mg three times per week. Injection‐site‐reactions were recorded every 6–24 h until resolved using National Cancer Institute criteria and a new skin toxicity subscale. The first doses of 30 mg and 3 mg produced injection‐site‐reactions (all but one were grade 1/2) in 13/20 and 9/20 patients, respectively. The second dose (on day 3) resulted in skin‐reactions in 10/20 patients and the third, fourth, fifth and sixth injections produced reactions in 6/20, 1/20, 2/20 and 0/20 patients, respectively. Mild “flu‐like” symptoms occurred during week 1 in 10/20 patients. All side‐effects had subsided by the sixth dose. 15/20 patients (75%) responded (12 partial responses, three complete responses) with a median time‐to‐treatment‐failure of 20 months. Symptomatic cytomegalovirus‐reactivation occurred in 6/20 patients. Two deaths occurred: one bacterial pneumonia and one adenovirus‐infection. The present study showed how to assess cutaneous‐toxicity in detail and that 30 mg alemtuzumab SC administered upfront was well tolerated. Optimized alemtuzumab therapy in properly selected patients may result in high efficacy even in advanced CLL. Our results need to be confirmed in extended studies.

B‐cell chronic lymphocytic leukaemia cells show specific changes in membrane protein expression during different stages of cell cycle

The proliferating component in chronic lymphocytic leukaemia (CLL) is usually small (<1%) and restricted to a specific micro‐environmental niche. To characterize the proliferating component, CLL cells from bone marrow or lymph nodes of 23 patients were assessed for expression of up to 66 surface antigens in combination with nuclear Ki‐67/MCM6. Ki‐67 expression was associated with step‐wise increases in CD23/CD95/CD86/CD39/CD27 and decreases in CD24/CD69/CXCR4/CXCR5. Ki‐67+ cells showed increased CD38 expression, but with considerable inter‐patient variability: in some cases Ki‐67 expression was only detectable in CD38− CLL cells. The results suggest continuous re‐entry into the cell cycle as no distinct stem cell pool was detectable.

Independent prognostic significance of minimal residual disease status in chronic lymphocytic leukaemia

Abstract Background Eradication of minimal residual disease (MRD) is an independent predictor of survival outcome in patients with chronic lymphocytic leukaemia (CLL) receiving fludarabine and cyclophosphamide (FC) or fludarabine, cyclophosphamide, and rituximab (FCR) as first-line treatment. However, the independent prognostic relevance of MRD status in other therapeutic settings is not clear. The goal of this study was to investigate the independent importance of achieving MRD negativity in CLL on progression-free survival (PFS) and overall survival (OS) with different treatments in frontline and relapsed or refractory settings compared with known prognostic markers. Methods We included all patients at our centre in Leeds and associated hospitals in West and North Yorkshire who had completed treatment for CLL from 1996 to 2007, achieved at least a partial response, and received an MRD assessment from a bone-marrow specimen after treatment. MRD assessments were done by multiparametric flow cytometry using CD5–CD19 in combination with CD20, CD22, CD32, CD38, CD79b, and CD81 in accordance with the international harmonised approach. 133 patients (17 receiving fludarabine, 65 fludarabine-based combination therapies, 26 alemtuzumab, and 25 other treatment including chlorambucil and autologous stem-cell transplantation) were followed up for a median of 5·2 years (IQR 3·0–7·3) to assess PFS and OS. Findings MRD negativity (defined as less than one CLL cell in 10 000 leucocytes) at the end of therapy independently correlated with both PFS (hazard ratio [HR] 3·22 [95% CI 2·09–4·97], Cox proportional hazards model p vs 31) and OS (78 vs 64) than did MRD-positive individuals without such adverse cytogenetic abnormalities. Interpretation MRD status is a powerful independent predictor of survival outcome in CLL across a range of therapeutic approaches including in frontline and relapse settings. MRD negativity is the most appropriate therapeutic goal for CLL patients who are fit enough for such an approach. Funding None.

The correlation between the eradication of minimal residual disease (MRD) following alemtuzumab for CLL and overall survival

6566 Background: Alemtuzumab can produce remissions with very low or even undetectable levels of CLL. MRD flow cytometry for CLL can detect as few as one malignant cell in 100,000 blood or bone marrow cells. METHODS 91 patients with previously treated or refractory CLL received alemtuzumab between 1996 and 2003. All patients had regular bone marrow assessments by MRD flow cytometry during therapy with the aim of achieving the best possible response including to MRD negativity. RESULTS There were 74 men and 17 women with a median age of 58 (range 32 to 75). Patients received a median of 12 weeks of intravenous alemtuzumab therapy. There were 19 mild (grade 1 or 2) and 33 severe (grade 3 or 4) infectious episodes. Responses according to NCI criteria were: 33 (36%) patients achieved a complete response (CR), 17 (19%) a partial response (PR), and 41 (45%) no response. CLL was eradicated from the marrow below the level of detection by MRD Flow in 18 (20%) patients. There was no significant difference in response or survival between purine analogue refractory and purine analogue sensitive patients. Median survival was significantly longer in MRD negative patients compared to MRD positive CR, a PR, or no response (median not reached for MRD negative CR, 41 months for MRD positive CR, 30 months for PR and 15 months for NR, p=0.0004). Those patients that achieved an MRD negative CR had a significantly longer treatment free survival than patients with MRD positive CR, PR or non-responders (not reached for MRD negative CRs, 20 months for MRD positive CRs, 13 months for PRs, 6 months for NR, p<0.0001). The overall survival for the 18 patients with MRD negative remissions was 84% at 60 months. Eight (47%) of the MRD negative patients have converted to an MRD positive status at a median time of 28 months. CONCLUSIONS MRD negative remissions are an achievable goal with alemtuzumab. Attaining this response leads to an improved overall and treatment free survival. [Table: see text].