Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice.

A2A adenosine receptors (A2A-AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [18F]FLUDA to non-invasively determine the A2A-AR availability for diagnosis of the A2AR status. Therefore, we compared mice with cardiomyocyte-specific overexpression of the human A2A-AR (A2A-AR TG) with the respective wild type (WT). We determined: (1) the functional impact of the selective A2AR ligand FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters (Bmax and KD) of [18F]FLUDA on mouse and human atrial tissue samples by autoradiographic studies, and (3) investigated the in vivo uptake of the radiotracer by dynamic PET imaging in A2A-AR TG and WT. After A2A-AR stimulation by the A2A-AR agonist CGS 21680 in isolated atrial preparations, antagonistic effects of FLUDA were found in A2A-AR-TG animals but not in WT. Radiolabelled [18F]FLUDA exhibited a KD of 5.9 ± 1.6 nM and a Bmax of 455 ± 78 fmol/mg protein in cardiac samples of A2A-AR TG, whereas in WT, as well as in human atrial preparations, only low specific binding was found. Dynamic PET studies revealed a significantly higher initial uptake of [18F]FLUDA into the myocardium of A2A-AR TG compared to WT. The hA2A-AR-specific binding of [18F]FLUDA in vivo was verified by pre-administration of the highly affine A2AAR-specific antagonist istradefylline. Conclusion: [18F]FLUDA is a promising PET probe for the non-invasive assessment of the A2A-AR as a marker for pathologies linked to an increased A2A-AR density in the heart, as shown in patients with heart failure.

Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia.

Measurable residual disease (MRD) status is widely adopted in clinical trials in patients with chronic lymphocytic leukemia (CLL). Findings from FILO group trials (CLL2007FMP, CLL2007SA, CLL2010FMP) enabled investigation of the prognostic value of high-sensitivity (0.7 × 10-5) MRD assessment using flow cytometry, in blood (N = 401) and bone marrow (N = 339), after fludarabine, cyclophosphamide, and rituximab (FCR)-based chemoimmunotherapy in a homogeneous population with long follow-up (median 49.5 months). Addition of low-level positive MRD < 0.01% to MRD ≥ 0.01% increased the proportion of cases with positive MRD in blood by 39% and in bone marrow by 27%. Compared to low-level positive MRD < 0.01%, undetectable MRD was associated with significantly longer progression-free survival (PFS) when using blood (72.2 versus 42.7 months; hazard ratio 0.40, p = 0.0003), but not when using bone marrow. Upon further stratification, positive blood MRD at any level, compared to undetectable blood MRD, was associated with shorter PFS irrespective of clinical complete or partial remission, and a lower 5-year PFS rate irrespective of IGHV-mutated or -unmutated status (all p < 0.05). In conclusion, high-sensitivity (0.0007%) MRD assessment in blood yielded additional prognostic information beyond the current standard sensitivity (0.01%). Our approach provides a model for future determination of the optimal MRD investigative strategy for any regimen.

Cost-effectiveness of rituximab in addition to fludarabine and cyclophosphamide (R-FC) for the first-line treatment of chronic lymphocytic leukemia.

The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was €17,979 per QALY (€15,773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone.

A network meta-analysis of progression free survival and overall survival in first-line treatment of chronic lymphocytic leukemia.

BACKGROUND: A limited evidence exists regarding comparisons of clinical effectiveness of available therapies for first-line treatment of chronic lymphocytic leukemia (CLL). METHODS: We compared available therapies for treatment-naïve, symptomatic CLL regarding progression free survival (PFS) and overall survival (OS) in all the identified random control trials and in subgroups composed of younger/fit and older/unfit patients, using a Bayesian network meta-analysis. RESULTS: In younger/fit patients we obtained median of projected mean PFS of: 19, 26, 31, 43, 51 and 75months for chlorambucil, fludarabine, alemtuzumab, fludarabine with cyclophosphamide (FC), bendamustine and fludarabine with cyclophosphamide and rituximab (FCR), respectively. We noted median OS of: 59, 66, 66, 70months for FC, chlorambucil, FCR and fludarabine, respectively. In older/unfit patients we noted PFS of: 16, 17, 24, 30, 60months for chlorambucil, fludarabine and chlorambucil with ofatumumab (OClb) or rituximab (RClb) or obinutuzumab (GClb), respectively. We obtained median OS of: 44, 58, 59 and 90months for fludarabine, RClb, chlorambucil and GClb, respectively. CONCLUSIONS: Our results suggest that: (1) FCR has higher potential of preventing CLL progression in younger/fit patients over four therapy options, which were subject of previous meta-analysis but also over bendamustine; (2) in these patients FCR does not entail prolonging of OS in comparison with chlorambucil and it is outperformed by fludarabine; (3) in older/unfit patients GClb demonstrates longer projected PFS than all assessed comparators; (4) in this group GClb has also the highest potential of increasing OS.

Treatment practice in the elderly patient with chronic lymphocytic leukemia-analysis of the combined SEER and Medicare database.

The median age at diagnosis of chronic lymphocytic leukemia (CLL) is 72, but patients enrolled in randomized trials are often a decade younger. Therapy selection and outcomes in the older, comorbid population are less understood. We evaluated treatment patterns and outcomes among 2,985 first primary CLL patients from the linked Surveillance, Epidemiology, and End Results-Medicare database. There were 151 chlorambucil (CLB), 594 rituximab monotherapy (R-mono), 696 rituximab + intravenous chemotherapy (R + IV Chemo), and 1,544 IV chemo-only patients. Patients administered CLB and R-mono were the oldest and had the highest comorbidity burden while patients receiving R + IV Chemo were the youngest and had the lowest comorbidity burden (p < 0.0001). In the multivariate survival analysis, receipt of R + IV Chemo was associated with significantly lower mortality risk vs. IV Chemo-only (hazard ratio (HR) = 0.73; 95 % confidence interval (CI) 0.62-0.87) and a non-significant mortality risk reduction with R-mono vs. CLB (HR = 0.47; 95 % CI: 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. These findings suggest that chemoimmunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity, and this extends the conclusions from clinical trials in younger, medically fit patients.

Comprehensive assessment of prognostic factors predicting outcome in Chinese patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide.

To determine whether prognostic factors remain relevant to chronic lymphocytic leukemia (CLL) patients treated with fludarabine and cyclophosphamide (FC), we prospectively evaluated 86 Chinese CLL patients who received FC in first-line therapy. Twenty-four patients (27.9%) achieved complete remission (CR), and overall response rate was 75.6%. With a median follow-up of 41 months, the median progression-free survival (PFS) was 36.0 months and median overall survival (OS) has not been reached. The strong correlations of lower CR rate with advanced Binet stage, unmutated IGHV, cytogenetic abnormalities of del(17p13) or del(11q23), and p53 mutations were observed by univariable analyses. Stepwise logistic regression identified that unmutated IGHV and p53 abnormality (p53 deletion or mutation) were associated with a decreased odds of achieving CR. The less cycles of treatment, not achieving CR, advanced Binet stage, and p53 abnormality significantly correlated with a shortened PFS. Furthermore, in a multivariate analysis, p53 abnormality and advanced Binet stage were identified as being significant risk factors for early relapse. Not achieving CR, advanced Binet stage, ZAP-70-positive, and p53 abnormality were the adverse factors in determining OS. Only p53 aberration was independently associated with significantly shorter OS by a multivariate analysis. These results suggest that patients with p53 abnormality should be considered for alternative therapies.

Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for the treatment of previously untreated chronic lymphocytic leukemia.

A recent phase III trial demonstrated improved progression-free survival (PFS) and overall survival (OS) associated with adding rituximab to fludarabine and cyclophosphamide (R-FC) compared to FC in treatment of previously untreated chronic lymphocytic leukemia (CLL). A cost-effectiveness analysis of R-FC over FC was performed from a US third-party payer perspective over a lifetime horizon in the base case. One-way, two-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. A secondary analysis was performed by also considering a societal perspective. R-FC was associated with an incremental 1.15 quality-adjusted life-years (QALYs) compared to FC and resulted in an incremental cost-effectiveness ratio of $23 530 per QALY in the base case and $31 513 per QALY considering a societal perspective. Results were most sensitive to time horizon, discount rate and unit drug cost for rituximab. Within the limitations of modeling long-term outcomes, R-FC is cost-effective for previously untreated CLL.

[Economic evaluation of rituximab added to fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide for the treatment of chronic lymphocytic leukemia]. / Evaluación económica de rituximab en combinación con fludarabina y ciclofosfamida en comparación con fludarabina y ciclofosfamida en el tratamiento de la leucemia linfática crónica.

OBJECTIVES: We evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabine plus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). METHODS: Two Markov models were built, using published results on progression-free survival (PFS) in patients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortality rates in Spain. Patient-elicited utilities were applied to PFS and progressed health states. The cost of drugs, supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariate and probabilistic (Monte Carlo) sensitivity analyses were performed. RESULTS: The addition of rituximab to chemotherapy in first- and second-line therapy increased life-years gained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALY gained was €20,703 and €19,343 for first-line treatment and was €23,183 and €24,781 for second-line treatment. CONCLUSION: In patients with previously untreated or relapsed/refractory CLL, the addition of rituximab to the FC regimen increased life expectancy and quality-adjusted life expectancy. In both types of patient, the treatment was cost-effective.

Assessment of ovarian function after preparative chemotherapy and total body radiation for adoptive cell therapy.

The aim of the study is to analyze treatment-induced gonadal damage and premature ovarian failure after adoptive cell therapy (ACT) after a cytotoxic lymphodepleting preparative regimen. Records of 66 consecutive females who received ACT at the Surgery Branch, National Cancer Institute, NIH (Bethesda, MD) were reviewed. Patients received a conditioning regimen of high-dose cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m² x 5 doses). Some patients also received total body radiation at 200 or 600 cGy. Assessment of ovarian function was determined by analysis of monthly follicle stimulating hormone (FSH) levels, menstrual history, and symptoms. Among patients with serum available and normal pretreatment ovarian function, 21 had a preparative regimen with chemotherapy alone and 5 patients had received chemotherapy with total body radiation. Nine (43%) patients in the chemotherapy cohort and all 5 patients in the chemotherapy plus total body radiation cohort had persistently elevated FSH levels and were given the diagnosis of premature ovarian failure. Twelve (57%) patients had normal FSH levels at 6 months posttreatment. Median age of all patients at treatment was 34 years. Median age of women retaining normal ovarian function was 30 (range, 19-45) vs. 41 years (range, 30-49) for those who did not regain function. The conditioning regimen of 2 doses of cyclophosphamide (60 mg/kg) and 5 doses of fludarabine (25 mg/m²) may induce gonadal damage and premature ovarian failure. Younger age at treatment was associated with a higher frequency of normal ovarian function posttreatment, whereas adding total body radiation was associated with a high risk of ovarian failure.

Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors.

PURPOSE: To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation. METHODS AND MATERIALS: A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity. RESULTS: The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen). CONCLUSIONS: Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.

The European Medicines Agency review of ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukemia in patients refractory to fludarabine and alemtuzumab: summary of the scientific assessment of the European medicines agency committee for medicinal products for human use.

On April 19, 2010, the European Commission issued a conditional marketing authorization valid throughout the European Union (EU) for ofatumumab (Arzerra®; Glaxo Group Ltd, Greenford, Middlesex, U.K.). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a conditional marketing authorization for ofatumumab for the treatment of chronic lymphocytic leukemia (CLL) in patients refractory to fludarabine and alemtuzumab. A conditional marketing authorization means that additional data to confirm the benefit-risk balance of ofatumumab are awaited. The active substance of Arzerra® is ofatumumab, a monoclonal antibody medicinal product (ATC code L01XC10). The recommended dose is 300 mg of atumumab for the first infusion and 2,000 mg of atumumab for all subsequent infusions. The infusion schedule is eight consecutive weekly infusions, followed 4-5 weeks later by four consecutive monthly (i.e., every 4 weeks) infusions. Ofatumumab targets CD20, a cell surface marker of B lymphocytes, which is followed by cell lysis via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The benefit of ofatumumab is the control of CLL in patients who are refractory to both fludarabine and alemtuzumab, which was indicated by a high response rate. The most common side effects are infections and infusion reactions. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission's evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to modelling was reasonable and the sources and justification of estimates were generally sound. The base-case analysis produced an incremental cost-effectiveness ratio (ICER) of 13,189 pounds per quality-adjusted life-year (QALY) for R-FC versus FC, and 6422 pounds per QALY for the comparison of R-FC versus chlorambucil, suggesting that R-FC is cost-effective at normal willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from 10,249 pounds to 22,661 pounds per QALY for R-FC versus FC, and 5612 pounds and 6921 pounds per QALY for R-FC versus chlorambucil. Probabilistic sensitivity analysis results matched the deterministic results very closely. However, the sensitivity analysis did not fully investigate the uncertainty associated with differential values across arms or with the structural assumptions of the model, and utility values were not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.

Determinants of the optimal first-line therapy for follicular lymphoma: a decision analysis.

Combination immunochemotherapy is the most common approach for initial therapy of patients with advanced-stage follicular lymphoma, but no consensus exists as to the optimal selection or sequence of available regimens. We undertook this decision analysis to systematically evaluate the parameters affecting the choice of early therapy in patients with this disease. We designed a Markov model incorporating the three most commonly utilized regimens (RCVP, RCHOP, and RFlu) in combinations of first- and second-line therapies, with the endpoint of number of quality-adjusted life years (QALYs) until disease progression. Data sources included Phase II and Phase III trials and literature estimates of long-term toxicities and health state utilities. Meta-analytic methods were used to derive the values and ranges of regimen-related parameters. Based on our model, the strategy associated with the greatest number of expected quality-adjusted life years was treatment with RCHOP in first-line therapy followed by treatment with RFlu in second-line therapy (9.00 QALYs). Strategies containing RCVP either in first- or second-line therapy resulted in the lowest number of QALYs (range 6.24-7.71). Sensitivity analysis used to determine the relative contribution of each model parameter identified PFS after first-line therapy and not short-term QOL as the most important factor in prolonging overall quality-adjusted life years. Our results suggest that regimens associated with a longer PFS provide a greater number of total QALYs, despite their short-term toxicities. For patients without contraindications to any of these regimens, use of a more active regimen may maximize overall quality of life.

A single apheresis procedure in the donor may be enough to complete an allograft using the "Mexican method" of non-ablative allografting.

BACKGROUND: Since 1999, in Mexico we have been using a regimen to conduct allografts that involves non-myeloablative conditioning and peripheral blood stem cells (PBSC) and have introduced some changes with the main goal of decreasing the cost of the procedure. MATERIALS AND METHODS: We analysed the salient apheresis features of a group of 175 allogeneic peripheral blood stem cell transplants conducted in two institutions in a 7-year period. The grafts were conducted using the "Mexican" non-myelo ablative conditioning regimen employing oral busulphan, i.v. cyclophosphamide and i.v. fludarabine. In all instances, the apheresis machine employed was the Baxter CS3000 Plus and donors were mobilised with filgrastim. The apheresis procedures were performed on days 0, +1 and +2, the end-point of collection being 5,000 mL of blood/m2 in each procedure. Three apheresis sessions were planned but the number was adjusted according to the cell yield. RESULTS: The final number of allografted CD34 cells ranged between 0.5 and 25.4 x 10(6)/Kg of the recipient's body weight (median, 5.2 x 10(6)/Kg). One to three apheresis procedures were needed to obtain a product containing more than 0.5 x 10(6) CD34 cells/Kg of the recipient, the median being two procedures; in 72 cases (41%) a single apheresis procedure was sufficient to obtain the target number of CD34 cells. The volumes of apheresis ranged between 50 and 600 mL (median, 400 mL). CONCLUSIONS: Since the median cost of each apheresis procedure is 900 USD, the fact that two apheresis procedures was spared in 72 cases and one apheresis was spared in another 65 cases, led to a total saving of approximately 188,100 USD. It can be concluded that, in many cases, allogeneic transplants can be completed with a single apheresis session and that there are considerable financial benefits from this practice.

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 Waldenström's 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.

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial.

BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.