Low‐dose alemtuzumab in refractory/relapsed chronic lymphocytic leukemia: Genetic profile and long‐term outcome from a single center experience

Relapsed/refractory chronic lymphocytic leukemia (CLL) represents a clinical challenge, in particular when high risk gene mutations occur. In this setting, alemtuzumab was recognized to be effective. This retrospective study evaluates long‐term efficacy and tolerability of low‐dose alemtuzumab in relapsed/refractory CLL and correlates clinical outcome with biological feature. Sixty‐two consecutive patients (median age 68 years) were evaluated; alemtuzumab was administered 30 mg weekly for up to 18 weeks. Among the patients included in the analysis, 37% were fludarabine‐refractory, 33.3% carried a TP53 disruption, 14.8% a NOTCH1 mutation and 9% a SF3B1 mutation. Overall response rate (ORR) was 61.3% (complete remission 25.8%). After a median follow‐up of 43 months, overall survival (OS) and progression free survival (PFS) were 43.1 and 15 months, respectively; while ORR was 77.8% for patients carrying TP53 disruptions (OS 33.8 months) and 43.5% for fludarabine‐refractory patients (OS 30 months). Noteworthy, long‐term survivors (OS ≥ 36 months) were 54.8%. None of the biological poor risk factors negatively impacted on ORR, PFS and OS. Grade ≥3 cytopenia occurred in 24.2% patients, 6.5% experienced a grade ≥3 non‐CMV infection and no grade ≥3 CMV‐event occurred. In conclusion, low dose‐alemtuzumab is safe and effective in relapsed/refractory CLL, also in a long‐term follow‐up and high‐risk genetic subgroups. Am. J. Hematol. 90:970–974, 2015. © 2015 Wiley Periodicals, Inc.     

Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.     

Alemtuzumab (anti-CD52 monoclonal antibody) as single-agent therapy in patients with relapsed/refractory chronic lymphocytic leukaemia (CLL)—a single region experience on consecutive patients

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is used in patients with refractory chronic lymphocytic leukaemia (CLL). We report results in health care with alemtuzumab on consecutive, advanced-stage patients from a well-defined geographical region. Records from 1,301 patients (Stockholm-Cancer-Registry 1991–2010) identified 56 relapsed/refractory patients treated with alemtuzumab. Median age was 69 years, 88 % had advanced Rai-stage with median 3 prior therapies. One fourth had bulky lymphadenopathy and 73 % were refractory to purine analogues. Median treatment length was 11.6 weeks. Median cumulative dose was 930 mg, significantly higher (p?=?0.0277) for responders. Overall response-rate (ORR) was 43 %; 32.5 %, 50 % and 87.5 % in the Refractory, Purine analogue relapsed and Relapsed/Other subgroup, respectively. Response rate was significantly associated with subgroup (p?=?0.0104). Good performance status (PS) was associated with better response rate (p?=?0.0227). Median time-to-treatment-failure (TTF) (months) was 7.8 months, significantly (p?p?p?=?0.0038). Twenty percent were retreated with alemtuzumab with an ORR of 54.5 %, and a TTF of 7.1 months. A high cumulative dose/longer duration of therapy and a relatively high response rate was observed compared to previous reports. Optimal patient identification and management may result in avoidance of early discontinuation and possibly better outcomes.     

An Italian retrospective study on the routine clinical use of low-dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients

Low‐dose alemtuzumab has shown a favourable toxicity profile coupled with good results in terms of efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). We conducted a multicentre retrospective study on the routine clinical use of low‐dose alemtuzumab in this patient setting. One hundred and eight relapsed/refractory CLL patients from 11 Italian centres were included in the analysis. All patients had an Eastern Cooperative Oncology Group performance status ≤2 and the majority (84%) had adenopathies <5cm. Low‐dose alemtuzumab was defined as a total weekly dose ≤45 mg and a cumulative dose ≤600 mg given for up to 18 weeks. The overall response rate was 56% (22% complete remissions). After a median follow‐up of 42·2 months, the median overall survival and progression‐free survival were 39·0 and 19·4 months, respectively. In univariate analysis, response was inversely associated with lymph node (P = 0·01) and spleen (P = 0·02) size, fludarabine‐refractoriness (P = 0·01) and del(11q) (P = 0·009). Advanced age and del(17p) were not associated with a worse outcome. Cumulative dose of alemtuzumab was not associated to response. Toxicities were usually mild and manageable; severe infections occurred in seven patients (7%) during therapy. This retrospective analysis confirms that low‐dose alemtuzumab is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL.     

A pilot study of low-dose subcutaneous alemtuzumab therapy for patients with hemotherapy-refractory chronic lymphocytic leukemia

Subcutaneous low-dose alemtuzumab (10 mg t.i.w. for 18 weeks) induced a 50% response rate, including 25% complete response, in 16 patients with refractory chronic lymphocytic leukemia (CLL) patients. The responses were substantial even in patients with unfavorable cytogenetics, fludarabine/rituximab refractoriness, Rai stage IV, previous infections, and age over 65 years. Subcutaneous low-dose alemtuzumab is effective in poor prognosis B-CLL, and has a particularly favourable toxicity profile.     

Combination therapy with fludarabine and cyclophosphamide as salvage treatment in lymphoproliferative disorders

Seventeen patients (aged 50-85 years) with relapsed or refractory non-Hodgkin's lymphoma (NHL, 10 patients) or chronic lymphocytic leukaemia (CLL, seven patients) were treated with a combination of fludarabine 25 mg/m2/d and cyclophosphamide 250 mg/m2/d for 3 d repeated every 4 weeks. 12 patients had previously received purine analogue therapy of which four had progressive disease during treatment. The overall response rate of patients with CLL was 71% (28% CR, 43% PR) and for NHL was 50% (0% CR, 50% PR). Toxicity consisted of nausea and vomiting which was maximal in the 3 d after therapy, infections and haematological suppression which was prolonged in some patients. This combination, which is based on a rational prediction of synergistic activity, is highly effective but associated with significant problems with tolerance.     

Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia

Campath-1H (alemtuzumab) is the most effective monoclonal antibody in single-agent use in B-cell chronic lymphocytic leukemia (CLL) with reported response rates of 33% to 70%. Combination therapy is now the conventional treatment for most hematologic malignancies. Monoclonal antibody treatments may sensitize tumor cells to subsequent chemotherapy. We report the combination of Campath-1H with fludarabine in patients with CLL refractory to each agent used singly. Six patients who had received a median of 8 courses of fludarabine (range, 4-10 courses) and 16 weeks of Campath-1H (range, 8-32 weeks) were treated. Five patients responded, including one who had a complete response by National Cancer Institute criteria. The responses observed were better in each patient than responses after each agent used singly. Complete morphologic bone marrow responses were seen in 3 patients, including eradication of disease measured by sensitive flow cytometry in 2. Campath-1H combined with fludarabine is a highly promising novel therapy for refractory CLL.     

A randomized,open‐label,multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine,cyclophosphamide and rituximab versus fludarabine,cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia

Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B‐cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open‐label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty‐seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression‐free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.     

Fludarabine,cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia

We evaluated the efficacy and toxicity of fludarabine combined with cyclophosphamide and mitoxantrone (FCM) in patients with relapsed or resistant chronic lymphocytic leukaemia (CLL). In total, 37 patients with recurrent or resistant CLL received FCM: fludarabine 25 mg/m2 intravenously (IV), d 1-3; cyclophosphamide 200 mg/m2 IV, d 1-3; and mitoxantrone 6 mg/m2 IV, d 1, at 4-week intervals for up to six courses. Moreover, 23 patients received FCM with cyclophosphamide 600 mg/m2 i.v. and mitoxantrone 8 mg/m2 i.v. on d 1. In addition to clinical methods, response was assessed using cytofluorometric and molecular techniques. 'In vitro' sensitivity to the FCM regimen was also analysed in 20 samples. The median number of courses given was 3 (range: 1-6). Overall, 30 patients (50%) achieved complete response (CR), including 10 cases of negative minimal residual disease (MRD(-)) (17%), and 17 (28%) partial response (PR). The median duration of response was 19 months. 'In vitro' sensitivity also correlated with CR achievement (P = 0.04). Main toxicity consisted of neutropenia, infections (8% of courses), and nausea and vomiting. The treatment-related mortality was 5%. FCM did not hamper stem cell harvesting in patients who were candidates for autologous stem cell transplantation. FCM induced a high CR rate, including an important number of MRD(-), in patients with previously treated CLL.     

Platinum and high‐dose cytarabine‐based regimens are efficient in ultra high/high‐risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study

Ultra high‐risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine‐based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty‐seven patients had R/R CLL (including 36 ultra high‐risk CLL) and 28 had RS. Median age was 62 years (range, 18–79 years). Median number of previous therapies was 3 (range, 1–7), including fludarabine‐based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression‐free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high‐dose cytarabine‐based regimens provide high response rates in high‐risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non‐transformed CLL.     

Role of fludarabine as monotherapy in the treatment of chronic lymphocytic leukemia

Fludarabine is a synthetic adenine nucleoside analog that is indicated for first- and second-line treatment of chronic lymphocytic leukemia (CLL). The recommended intravenous (i.v.) dosage regimen is 25 mg/m2 daily for 5 consecutive days, with treatment cycles repeated every 28 days. In treatment-na?ve patients with Binet stage B and C CLL, i.v. fludarabine produces superior responses to established first-line chemotherapies. Fludarabine produces a higher overall remission rate (60-70%) and longer progression-free survival (median approximately 20-30 months) than standard therapy with chlorambucil+/-prednisone and CAP (cyclophosphamide/doxorubicin/prednisone), and a comparable overall remission rate to CHOP (cyclophosphamide/vincristine/prednisone/doxorubicin). Fludarabine demonstrates high efficacy in both intermediate-risk (Rai stage I or II) and high-risk (Rai stage III or IV) patients. Furthermore, fludarabine is equally effective in younger (< or =65 years) and older (>65 years) patients. Fludarabine has significant activity as monotherapy in previously treated CLL, producing objective response rates of up to 94% in typically small-scale, noncomparative studies, with the majority of studies yielding rates of 30-60%. In a phase III multicenter study, the overall remission rate was significantly higher with fludarabine than with CAP (48 versus 27%) among the subset of treatment-refractory patients (n=96). For those patients who are refractory to or have relapsed following conventional chemotherapy (chlorambucil, CAP and CHOP), fludarabine can be considered the treatment of choice for second-line therapy. Moreover, patients with relapsed CLL may benefit from retreatment with fludarabine if they have previously demonstrated sensitivity to the drug. Standard-dose i.v. fludarabine has an established safety profile and comparable tolerability to anthracycline-based regimens (CAP and CHOP) in terms of its myelosuppressive and immunosuppressive effects, and offers the advantage of a markedly lower incidence of gastrointestinal effects (nausea/vomiting) and alopecia.     

Rediscovering alemtuzumab: current and emerging therapeutic roles

The humanized anti-CD52 monoclonal antibody alemtuzumab belongs to the family of Campath-1 antibodies, which were initially developed for their ability to prevent graft- versus -host disease (GVHD) and graft rejection in stem cell transplantation. Alemtuzumab is indicated for the treatment of chronic lymphocytic leukaemia (CLL) and has demonstrated considerable activity in relapsed/refractory disease and in previously untreated disease. It has been shown to induce minimal residual disease-negative responses as a single agent or as part of consolidation therapy in a meaningful proportion of patients with CLL and has shown promising activity in patients with high-risk cytogenetic markers. Alemtuzumab may also have significant activity in T-cell malignancies, such as mycosis fungoides and T-cell prolymphocytic leukaemia. Recent studies also have evaluated alemtuzumab as part of a conditioning regimen to prevent GVHD in stem cell transplantation. This article reviews our current understanding of alemtuzumab and discusses its emerging role in the treatment of CLL and other haematological malignancies.     

Circulating CD52 and CD20 levels at end of treatment predict for progression and survival in patients with chronic lymphocytic leukaemia treated with fludarabine,cyclophosphamide and rituximab (FCR)

CD52 and CD20 antigens are important therapeutic targets for the monoclonal antibodies (mAbs) alemtuzumab and rituximab respectively. Circulating CD52 (cCD52) and CD20 (cCD20) have prognostic utility in lymphoid malignancies. The efficacy of mAb therapy in patients with chronic lymphocytic leukaemia (CLL) may be adversely affected by cCD52 or cCD20. In this report, blood and bone marrow (BM) cCD52 and cCD20 were measured at response assessment in previously treated (N = 235) patients with CLL who received fludarabine, cyclophosphamide, and rituximab (FCR). Univariate and multivariate statistical models evaluated correlations of pre‐ and response variables with progression‐free (PFS) and overall survival (OS). Response variables included 1996 National Cancer Institute‐Working Group (NCI‐WG) response, polymerase chain reaction (PCR) for immunoglobulin heavy chain (IGHV) in BM, and cCD52 and cCD20 levels (blood and BM) at response assessment. Using multivariate analysis, response blood and BM cCD52, blood cCD20, and NCI‐WG response were significant independent predictors of PFS. At the time of response assessment, BM cCD52 correlated with OS in univariate analysis. cCD52 and cCD20, therefore appear useful in predicting survival and may be important for monitoring patients following salvage FCR (fludarabine, cyclophosphamide, rituximab) therapy. These data further indicate that plasma may be a good target to evaluate for minimal residual disease using cCD52/cCD20 levels.     

Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL

Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population.     

Bendamustine plus mitoxantrone for relapsed/refractory chronic lymphocytic leukaemia (CLL): results of a multicentre phase II study of the German CLL Study Group (GCLLSG)

The efficacy of bendamustine (50 mg/m2, days 1-3) plus mitoxantrone (10 mg/m2, day 1), every 28 days for up to four courses, was evaluated in a Phase II multicentre trial enrolling 59 patients with relapsed or refractory B-cell chronic lymphocytic leukaemia (CLL). Major toxicities were grade 3/4 leucopenia, thrombocytopenia and infections in 42%, 12% and 12% of patients, respectively. Complete and partial response was achieved in 5/59 and 25/29 patients, respectively (overall response rate, 51%). Median time to progression was 22 months (range 1-49 + ) and median survival 27 months (range 0-49 + ). The combination of bendamustine and mitoxantrone is an active regime in relapsed or refractory CLL.     

Ublituximab (TG‐1101), a novel glycoengineered anti‐CD20 antibody,in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial

Ibrutinib is effective in patients with chronic lymphocytic leukaemia (CLL); however, treatment resistance remains a problem. Ublituximab is a novel, glycoengineered anti‐CD20 monoclonal antibody with single‐agent activity in relapsed CLL. We report the results of a phase 2 study evaluating combination therapy with ibrutinib and ublituximab in patients with relapsed or refractory CLL. Patients received ibrutinib 420 mg once daily. Ublituximab was administered on days 1, 8 and 15 of cycle 1 followed by day 1 of cycles 2–6. Response assessments were completed at cycles 3 and 6; patients then continued on ibrutinib monotherapy per standard of care. Forty‐one of 45 enrolled patients were evaluable for efficacy. Safety was consistent with prior experience for each drug, with infusion reactions the most prevalent adverse event. Combination therapy resulted in an overall response rate (ORR) of 88% at 6 months. In the 20 patients with high‐risk features (17p or 11q deletions or TP53 mutation) and evaluable for efficacy, the ORR was 95%, with three patients (15%) achieving negative minimal residual disease. Median time to response was 8 weeks. Ublituximab in combination with ibrutinib resulted in rapid and high response rates. The long‐term clinical benefit of ublituximab will be defined by an ongoing phase 3 trial (NCT 02301156).     

Clinical activity of a new regimen combining gemcitabine and alemtuzumab in high‐risk relapsed/refractory chronic lymphocytic leukemia patients

Optimal treatment strategies are lacking in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Gemcitabine has shown activity and acceptable safety profile in B‐cell lymphomas. We present a retrospective case review of gemcitabine and alemtuzumab, every 21 d (for up to six courses) in 27 community‐based patients with high‐risk R/R CLL. Median age was 70 yr (44–83 yr), 55% patients had Binet stage C, deletion 17p (del(17p)) and/or deletion 11q (del(11q)) were found in 65% and 27%, bulky disease in 55.5%, and fludarabine‐refractoriness in 48% of cases, respectively. Overall response rate was 63% (29.6% clinical CR and 33.4% PR). At a median follow‐up of 31 months, median PFS and OS were 15.4 and 24 months. In multivariate analysis, median OS is influenced by prior lines of treatment = 3 and bulky disease. Combination of alemtuzumab and gemcitabine appears to be an active, easy to administrate treatment in routine practice, high‐risk R/R CLL patients.     

Novel therapies for chronic lymphocytic leukemia

New therapies for chronic lymphocytic leukemia (CLL) are moving away from non-specific cytotoxic to more targeted approaches. The monoclonal antibody alemtuzumab induces responses in 33% to 43% of patients with relapsed or refractory disease, with 2-5% CR. Side effects include infusional reactions as well as immunosuppressive effects. Rituximab has limited activity in relapsed refractory patients, but response rates are comparable to follicular non-Hodgkin's lymphoma in untreated patients. Other antibodies in early phases of development include anti-CD23 [IDEC-152], anti-CD22 [epratuzumab], Hu1D10 [apolizumab], and anti-CD80 [anti-B7, IDEC-114]. Other agents that are being studied include denileukin diftitox fusion protein (Ontak), and bcl-2 antisense [G3139, Genasense]. The mechanism of action of the new drugs and their role in CLL, as well as the emergence of new prognostic markers are discussed.     

Fludarabine,ara-C,novantrone and dexamethasone (FAND) in previously treated chronic lymphocytic leukemia patients

BACKGROUND AND OBJECTIVES: The objective of improving the quality of responses of chronic lymphocytic leukemia (CLL) patients has led to the design of protocols that combine fludarabine (FDR) with synergistic drugs. We evaluated the efficacy and toxicity of a schedule that includes fludarabine, ara-C, novantrone and dexamethasone (FAND) for the management of previously treated CLL patients under 60 years old. DESIGN AND METHODS: Thirty-one patients underwent FAND treatment. Twenty-three patients had active disease (relapsed patients: 9; unresponsive to prior therapy: 14). Eight patients had a partial response (PR) to prior therapy and were treated with the aim of further reducing residual disease. The FAND schedule included fludarabine (25 mg/m(2) i.v. days 1-3), ara-C (1 g/m(2) i.v. day 1: 8 patients; days 1-2: 23 patients), novantrone (10 mg/m(2) i.v. day 1) and dexamethasone (20 mg i.v. days 1-3). Infection prophylaxis consisted of fluconazole, acyclovir, trimethoprim/sulfamethoxasole and granulocyte colony-stimulating factor (G-CSF) in the presence of severe neutropenia. RESULTS: A response was observed in 7/14 refractory patients (complete response-CR: 29%), in all 9 relapsed patients (CR: 78%) and in 7/8 patients (CR: 87.5%) treated in PR. Taken together, 18 CRs were obtained and in 14 (78%) this was associated with a flow cytometric remission (CD5+/CD20(weak+) PB lymphocytes: <10%). Severe granulocytopenia occurred after 86 of the 124 administered courses (69%), but only after 10/86 courses (12%) were major infections recorded. In 10/15 mobilized patients (cyclophosphamide + G-CSF: 6 patients; FAND + G-CSF: 9 patients) after FAND > or = 2 x 10(6)/kg CD34+ cells were collected. Nine patients were autografted in CR and showed a longer response duration than the 9 patients in CR who did not receive further therapy after FAND (53 vs 30% at 41 months; p = 0.05). INTERPRETATION AND CONCLUSIONS: FAND associated with extensive infection prophylaxis and G-CSF support is a highly cytoreductive and well-tolerated treatment for CLL patients and in most cases does not hamper subsequent stem cell mobilization.     

Modern concepts in the treatment of chronic lymphocytic leukemia

Abstract

There has been considerable progress in the treatment of chronic lymphocytic leukemia (CLL) during last 10 years. Purine analogs and monoclonal antibodies have enabled the shift from purely palliative treatment to intensive regimens aiming at complete remissions and possible prolongation of survival. Many patients have now been shown to achieve molecular responses in addition to their hematological remission. Despite this success, virtually all patients with CLL will eventually relapse and will become refractory to treatment. Allogeneic stem cell transplantation offers a chance of definite cure but is feasible in a minority of patients only. Therefore, considerable effort has been devoted to the further development of more conventional CLL management that is applicable to patient population generally affected by the disease. Emerging treatment concepts include novel combination of well-know agents such as rituximab and chlorambucil, fludarabine, cyclophosphamide and alemtuzumab, FCR with mitoxantrone amongst many. Consolidation regimens using mainly alemtuzumab are also increasingly used but are associated with a major increase in severe infections. High-dose steroids in combination with rituximab or alemtuzumab represent a promising option for refractory patients. Modern chemoimmunotherapy with the FCR regimen has also been tested in early stage patients with unfavourable prognostic factors. Finally, a there are a wide variety of novel drugs including bendamustine, a unique cytostatic with combined properties of an alkylating agent and purine analog, the monoclonal antibodies anti-CD20 ofatumumab and the anti-CD23 lumiliximab, thalidomide and its analog lenalidomide, the semi-synthetic flavonoid flavopiridol and other agents which are currently undergoing clinical trials with promising results. This article reviews the recent advances and future possibilities in the treatment of CLL.