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The armantarium of agents for treatment of CLL has been enriched by many new agents and combination strategies. The clinical difficulty now is to decide about the optimal therapy of the individual patient according to the aim of treatment, either cure or palliation
Department of Internal
University of Munich
Department of Internal
University of Munich
Clinical and laboratory investigations are driving the rapid change in treatments for patients with chronic lymphocytic leukaemia (CLL). The purine analog fludarabine is the backbone of combination therapy in first-line or second-line treatment but new combinations and agents have been recently explored in clinical studies. Bendamustine, a re-discovered alkylans, is easily to administer also in an ambulatory setting and as monotherapy or in combination with monoclonal antibodies highly effective. Monoclonal antibodies against the CD20 antigen underwent further development. Recently a randomised trial has demonstrated superior activity for chemoimmunotherapy with rituximab and fludarabine combined with cyclophosphamide (FCR) versus fludarabine combined with cyclophosphamide (FC) and so defined the new first-line standard in treating physically fit CLL patients. Another monoclonal antibody against CD20, ofatumumab, achieved promising results within phase I and II trials in poor-prognostic CLL patients. Alemtuzumab, a monoclonal antibody against CD52, takes an important role in the treatment of fludarabine refractory patients or patients with a 17p-deletion. Further prolongation of progression free survival is the aim which may lead to prolong survival and potentially cure patients of this disease.
Chronic lymphocytic leukaemia (CLL) is the most prevalent lymphoid malignancy in people of Western European genetic heritage with an overall incidence of 4/100,000/year. In the elderly population above 70 years the incidence increases up to 50/100,000/year, and only 11% of CLL Patients are younger than 55 years. Diagnosis is often made within routine check ups due to otherwise unexplicable lymphocytosis and detailed diagnostic procedures are standarised. The median survival at diagnosis varies between 1 and more than 10 years according to the initial stage of the disease. In Europe the Binet staging system is generally used (see Table 1). Patients are only treated in advanced stage, Binet C or Binet A and B with significant B-symptoms or cytopenias due to leukaemic bone marrow infiltration. The standard treatment of patients with early disease is a watch-and-wait strategy with regular controls of blood cell counts and clinical examination every 3-6 months.
In the case of symptomatic patients or advanced stage disease, personalised therapy has to take into account physical fitness and comorbidities of patients as well as prognostic markers like genetics. Thus, the range of treatment options varies from the oldfashioned chlorambucil to the newest state-of-the-art chemoimmunotherapy with FCR.
The introduction of purine analogues has changed treatment options for patients with CLL. Fludarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono- D-arabino-furanosyl) (2-fluoro-ara-AP).
Fludarabine monotherapy in untreated CLL
In a prospective randomised study, fludarabine monotherapy (25 mg/m² IV daily for 5 days every 28 days) achieved higher overall response rates (OR) rates compared with chlorambucil (40 mg/m² PO every 28 days), including more complete responses (CR) (20% versus 4%), but no survival benefit was observed.3,4 Fludarabine also induced higher remission and CR rates (7%-40%) than alkylator-based combination chemotherapies, like CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CAP (cyclophosphamide, doxorubicin, prednisone), but did not improve overall survival.
A multicentre randomised phase III trial for CLL patients older than 65 years compared first-line therapy with fludarabine (25 mg/m² IV daily for 5 days every 28 days, for 6 cycles) to chlorambucil (0.4 mg/kg body weight with increase to 0.8 mg/kg, every 15 days, for 12 months) in 193 patients with a median age of 70 years. Fludarabine resulted in a significantly higher OR and CR (72% versus 51%; 7% versus 0%). Time to treatment failure was significantly shorter in the chlorambucil arm (11 versus 18 months), but no difference in progression-free survival (PFS) time was observed (fludarabine: 19 months vs chlorambucil: 18 months). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit when compared to chlorambucil.
Fludarabine combination therapy in untreated CLL
The most promising combination option with the purine analog fludarabine is the alkylating agent cyclophosphamide. Although the combination is synergistic in action it has also potent immunosuppressive and myelosuppressive effects which may lead to an increased risk of infections.
More recently, three randomised trials have shown that FC combination chemotherapy improves the CR and OR rate and PFS as compared to fludarabine monotherapy. An important result of these trials was that the rate of severe infections was not significantly increased by the FC combination despite a higher frequency of neutropenias.[5-7]
The highest OR in untreated CLL patients so far had been reached with rituximab plus fludarabine/ cyclophosphamide (FCR). A large phase II trial conducted at the MD Anderson Cancer Center on 300 patients achieved an OR of 95% with 72% CR. Sixyear overall and failure-free survival were 77% and 51%, respectively.
Rituximab, a murine/human anti-CD20 monoclonal antibody is approved in Europe for the first-line treatment of CLL in combination with chemotherapy. The efficacy of rituximab as single agent in CLL is poor since the CD20 expression on the surface of CLL cells is weak. However, recently a randomised trial in 817 patients (median age 61 years) with good physical fitness and advanced stage was conducted. Patients received 6 courses of FC or FCR. FCR induced a significantly higher OR rate than FC (92.8 versus 85.4%) and significantly more CR. PFS at 2 years was 76.6% in the FCR arm and 62.3% in the FC arm (p<0.01). FCR treatment was more frequently associated with grade 3 and 4 neutropenia (FCR 34%; FC 21%), while other side effects were not increased. Treatment related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. Similar results were obtained in second-line treatment of CLL. 272 patients were treated with FC and 274 with FCR. OR was 58% and 70% for FC and FCR, respectively, with 13% and 24% CR. Taken together, these results suggest that rituximab plus fludarabinebased therapies represent a significant advance in therapy for CLL (see Table 2).
Bendamustine,4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol- 2-yl]butanoic acid, was developed in Eastern Germany in the 1960s as a unique cytotoxic bifunctional agent with structural similarities to alkylating agents and potential antimetabolite properties associated with the benzimidazole ring. This agent is noncross- resistant with alkylating agents and other drugs in vitro and in the clinic. Bendamustine has been evaluated as monotherapy and as part of combination therapy protocols for first-line or subsequent treatment of lymphomas.[11-13] In Germany, Bendamustine is approved for the treatment of patients with indolent NHL, CLL, and multiple myeloma.
Bendamustine monotherapy in untreated CLL:
Bendamustine was recently approved by the FDA for treatment of CLL based on a randomised trial which demonstrated its superiority over chlorambucil (an agent widely used in the current treatment of CLL) in previously untreated patients. Bendamustine was administered in a dose of 100 mg/m² IV for 2 days every four weeks, chlorambucil in a dose of 0.8 mg/kg orally day 1 and 15 of each 28-day cycle. Bendamustine produced improved responses with more toxicities but no survival benefit.
The ORR and median PFS were 67% and 22 months respectively for bendamustine versus 30% and 8 months for chlorambucil. The toxicities associated with bendamustine were hematological, mainly leukopenia, the incidences of infections were comparable in both study arms (see Table 3).
Bendamustine monotherapy in relapsed or refractory CLL:
Phase I/II trials with single-agent bendamustine in relapsed CLL have shown overall response rates of 56- 93% and complete response rates of 7-29%.15 Even in fludarabine or rituximab refractory CLL patients response rates up to 60% were reported.,
Bendamustine combination therapy in untreated CLL:
In vitro studies have demonstrated synergistic proapoptotic effects of bendamustine and rituximab (BR) in primary CLL cells.
In an ongoing phase III trial the German CLL Study group (GCLLSG) investigates the efficacy of BR in comparison to fludarabine-based chemoimmunotherapy (FCR) for first-line treatment of CLL.
Bendamustine combination therapy in relapsed or refractory CLL:
In a phase II trial patients with relapsed or refractory CLL received 70 mg/m² bendamustine on day 1 and 2 combined with 375 mg/m² rituximab for the first cycle and 500 mg/m² for the second and subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. The OR was 77.4% with CR in 14.5% and PR in 62.9% of patients. Main toxicities were myelosuppression and infections, with a treatment related mortality of 3.7% of pts.
CD 20 is a glycoprotein that is highly expressed on the surfaces of normal and most malignant B cells. Monoclonal antibodies directed against CD20-positive cells are thought to result in effective cytotoxicity by either antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxictiy (CDC). Ofatumumab (HuMax-CD20) is an IgG1 fully human monoclonal antibody that binds to a unique epitope of the CD20 antigen on B cells. Also at low levels of CD20 expression in-vitro CDC of cells was significantly higher with this agent than with rituximab. The increased efficacy may be due to a lower off rate and more stable CD20 binding.
Ofatumumab monotherapy in relapsed and refractory CLL:
Recently, a phase I/II open-label, multicenter, doseescalating clinical trial was published. 33 patients (three cohorts of 3 (A), 3 (B), and 27 (C)) with relapsed or refractory CLL received once-weekly, infusions of ofatumumab for four weeks at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Patients received oral acetaminophen, intravenous antihistamine and corticosteroids before infusion and were followed up for 12 weeks. The maximum tolerated dose was not reached. The most common symptoms occurred after starting the first infusion and were transient chills, fever, rash and sweating. Main toxicities were infections, grade 1-2 with one fatal interstitial pneumonia. The OR was 44%, in the high dose cohort C 50%. The median PFS was 106 days, but with a median time to next treatment of about one year.
In an international, multicentre trial 138 patients either refractory to fludarabine and alemtuzumab (double- refractory, DR) or refractory to fludarabine alone with bulky (>5cm) lymphadenopathy (bulky fludarabine-refractory, BFR) were treated with ofatumumab.
Patients with DR or BFR CLL received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2-12, 2000 mg). 54% received all 12 infusions and 90% received 8 infusions. The OR to salvage therapy for such patients is generally 20% with a median survival of 9 months. In contrast, ofatumumab achieved an OR of 51% for the DR group and 44% for the BFR group. Median time to next CLL therapy was 9 months for the DR group and 8 months for the BFR group. The median survival was about 14 months for the DR group and 15 months for the BFR group. Toxicities were similar to the above mentioned trial. No patient tested developed antibodies to ofatumumab.
Ofatumumab combination therapy in relapsed and
An ongoing phase II open-label, randomised clinical trial in patients with CLL (n=56) compares two cohorts of 300 mg infusion of ofatumumab, followed by five infusions of 500 mg (cohort A) or 1000 mg (cohort B) with fludarabine and cyclophosphamide every 4 weeks. Completion date of this trial is scheduled for 2012.
CD52 is highly expressed on both normal and malignant lymphocytes and is also found on monocytes, macrophages and eosinophils and to the male reproductive tract. Alemtuzumab, a recombinant, fully humanised monoclonal antibody, belongs to the Campath-1 family of antibodies that target the human CD52 antigen, a 12- amino acid glycosylphosphatidylinositol-anchored cell surface glycoprotein of unknown function. Both ADCC and CDC are recognised as primary mechanisms of action for the Campth-1 family. Caspase-independent apoptosis has also been demonstrated in primary CLL cells.
Alemtuzumab has demonstrated considerable activity in relapsed/refractory CLL and in previously untreated patients. Suitable patient subgroups for alemtuzumab therapy include elderly patients, patients with 17p deletion, patients with refractory autoimmune cytopenias and patients with profound pancytopenia at baseline due to heavily infiltrated bone marrow. Clinical experience with alemtuzumab has grown significantly, especially regarding its efficacy and safety, management of cytomegalovirus (CMV) reactivation, identification of patient subgroups likely to benefit from alemtuzumab therapy.
Alemtuzumab monotherapy in untreated CLL:
In a recent prospective randomised study alemtuzumab was tested against chlorambucil in 297 patients. Patients received alemtuzumab (30 mg IV three times per week, for up to 12 weeks) or chlorambucil (40 mg/m² PO every 28 days, for up to 12 months). The OR was 83% with alemtuzumab (24% CR) versus 55% with chlorambucil (2% CR); differences in OR and CR were highly statistically significant. Superior PFS with a 42% reduction in risk of progression or death and significantly longer median time to progression (TTP) was reached.
Infusion-related reactions were common but mild with grade 3 or 4 reactions in only 14% of patients. The most common grade 3 or 4 toxicities were hematological, with grade 3 or 4 neutropenia and thrombocytopenia reported in 42% and 18% of patients, respectively. Meanwhile the drug has been approved by FDA as front-line therapy for CLL. In a phase II trial of subcutaneous (SC) administration of alemtuzumab an OR of 87% (19% CR) was reported. Infusion-related reactions (except for fever and local injection site reactions) were reduced compared with IV delivery. Hematological toxicities were similar between IV and SC administration. No patient developed febrile neutropenia and no bacterial infections grade >1 were noted. Thus, SC administration is safe, easy to perform and appears equally effective compared with intravenous infusion with a more favorable toxicity profile.
Alemtuzumab monotherapy in relapsed and refractory CLL:
Alemtuzumab was initially approved for the treatment of patients with CLL who have failed both alkylating agents and fludarabine therapy. In these patients monotherapy with alemtuzumab (IV 30 mg TIW up to 12-16 weeks) has produced response rates of 33% to 54%, with a median duration of response ranging from 8.7 to 18 months, in patients with relapsed/refractory CLL. The median overall survival was significantly prolonged up to impressive 36 months for responders.[27-30]
Alemtuzumab combination therapy in untreated or relapsed and refractory CLL with poor prognostic features:
Phase II trials assessed the combination therapy with alemtuzumab and fludarabine (FCam) or fludarabine in combination with cyclophosphamide (FCCam) or fludarabine in combination with cyclophosphamide and rituximab (CFAR) in relapsed or refractory CLL. The OR was between 65 and 83%. The FCCam regime appeared to be highly effective in reducing bulky lymph nodes (>5 cm), whereas the CFAR protocol showed high activity in patients with 17p deletion and in relapsed patients after prior chemoimmunotherapy (See Table 4). Alemtuzumab is especially effective in patients with high-risk genetic markers such as deletions of chromosome 11 or 17 or p53 mutations., An ongoing phase II trial of the GCLLSG assesses SC alemtuzumab combined with oral dexamethasone, followed by alemtuzumab maintenance or allogeneic stem-cell transplantation, in CLL with 17p deletion or refractory to fludarabine.
The presence of residual malignant cell clones after suboptimal therapy probably underlies eventual disease relapse. Moreover, clonal selection may result in enrichment of clones with resistant genotype like 17p deletion. MRD eradication and consolidation therapy with alemtuzumab are therefore promising tools to eliminate the disease under the detection limit of one in 104 -105 leucocytes in bone marrow or peripheral blood. Two phase II and III trials are published with different regimes of alemtuzumab. In a randomised phase III trial, median PFS was significantly prolonged after alemtuzumab consolidation therapy compared to observation only (not reached versus 27.7 months).
According to recent guideline recommendation alemtuzumab combination therapy and consolidation therapy shall not be used outside carefully controlled clinical studies.
The armantarium of agents for the treatment of CLL has been significantly enriched by many new agents and combination strategies. The clinical difficulty now is to decide about the optimal therapy of the individual patient according to the aim of treatment, either cure or palliation. Only the thoroughful review of molecular and clinical prognostic factors, expected toxicities and patient`s preference guide to the right treatment decision.
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