Modern concepts in the treatment of chronic lymphocytic leukemia

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There has been considerable progress in the treatment of chronic lymphocytic leukemia (CLL) during last 10 years. Purine analogs and monoclonal antibodies ...
Modern concepts in the treatment of chronic lymphocytic leukemia Lukas Smolej Second Department of Internal Medicine, Department of Clinical Hematology, University Hospital and Medical School, Hradec Kralove, Czech Republic 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. Keywords: Chronic lymphocytic leukemia, treatment, rituximab, ofatumumab, fludarabine, alemtuzumab, monoclonal antibodies, lenalidomide, bendamustine

Introduction Chronic lymphocytic leukemia (CLL), the most common leukemic disorder in the Western world, is still considered incurable despite marked progress in treatment achieved in the recent years. Fludarabine combined with cyclophosphamide (FC) in three large

Correspondence to: Lukas Smolej, Second Department of Internal Medicine, Department of Clinical Hematology, University Hospital and Medical School, Sokolska 581, 500 05 Hradec Kralove, Czech Republic E-mail: [email protected] ß W. S. Maney & Son Ltd 2009 Received 10 February 2009; accepted 12 April 2009 DOI 10.1179/102453309X446153

randomized studies led to increase in overall response rate (ORR), complete responses (CR) and prolongation of progression-free survival (PFS) in comparison to fludarabine or chlorambucil monotherapy and has become the standard treatment in first line.1–3 Chemoimmunotherapy, with the addition of monoclonal antibodies to chemotherapy, appears to further enhance the therapeutic efficacy. The combination of fludarabine, cyclophosphamide and the anti-CD20 antibody rituximab (FCR) achieved more than 90% ORR, 70% CR and PFS around 80 months

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in first line treatment; in addition, overall survival (OS) was longer in comparison with historical controls. As the inital data came from open label single-center analysis, randomized studies were required for confirmation.4–6 Recently, results of two large international studies randomizing between FC and FCR in first line (CLL-8 study) and relapse (REACH study) showed that the FCR regimen was associated with a significantly higher ORR and CR as well as a longer PFS.7,8 Therefore, the FCR protocol can be now considered the gold standard in treatment of physically fit CLL patients in first line and (with some exceptions due to the design of REACH study) in relapse. A significant proportion of patients will achieve not only complete hematological but also molecular remission [i.e. minimal residual disease (MRD) negativity] using these approaches. Nevertheless, every patient will eventually relapse the disease will become more resistant with each subsequent therapeutic line, until eventually the disease becomes refractory. Allogeneic stem cell transplantation offers the possibility of a definite cure but despite recent developments (reduced-intensity conditioning, better supportive care) it is still associated with significant morbidity and mortality and thus feasible only in a minority of CLL patients.9 As the field of hematopoietic stem cell transplantation in CLL is very broad itself, we will not discuss it further due to space constraints and readers are referred to an excellent review published recently.9 Given the incurable nature of CLL, considerable efforts have been devoted in the recent years to further improvement of treatment efficacy. There are several possible concepts on how to achieve better outcomes in CLL treatment. They include: eradication of MRD, treatment of early-stage disease, novel therapeutic combinations and completely new agents. This article brings an overview of recent advances and future concepts in CLL treatment.

Treatment of early-stage disease Randomized studies conducted in 1990s have demonstrated that immediate treatment of early-stage CLL does not confer any benefit in comparison to the concept of ‘watch-and-wait’ and therefore, treatment is reserved for patients with progressive or advanced stage disease. However, this concept was developed based on studies using chlorambucil in monotherapy or in combination with steroids10,11 and no data is yet available on the efficacy of highly active protocols with purine analog combinations and/or chemoim-

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munotherapy. CLL-7, a randomized study of the German and French CLL Study Groups, is trying to solve the ultimate question whether early treatment with FCR will be beneficial for patient in early clinical stages but with unfavourable biological prognostic factors (defined as at least two of following: short lymphocyte doubling time, elevated serum thymidine kinase, unmutated IgVH genes or unfavourable genetic aberrations).12

Eradication of MRD A landmark study using the monoclonal anti-CD52 antibody alemtuzumab demonstrated that patients who entered molecular remission (i.e., where residual leukemic cells disease were detectable by highly sensitive methods such as four-colour flow cytometry or PCR only) had not only significantly longer PFS but also overall survival (OS).13 In the CLL-4B, a GCLLSG study for patients younger than 65 years who achieved therapeutic response after fludarabine or FC in the first line, patients were randomized between the ‘watch-and-wait’ approach and consolidation treatment with at the classical dose of alemtuzumab of 30 mg thrice weekly for a maximum duration of 12 weeks. The study had to be closed early due to life-threatening infectious complications in seven out of 11 patients in the consolidation arm, although no toxic deaths occurred. Despite this, the majority of patients consolidated with alemtuzumab achieved MRD-negativity and had significantly longer PFS.14 A non-randomized Italian study used a lower dose and shorter duration of alemtuzumab treatment for consolidation (10 mg subcutaneously thrice weekly for 6 weeks). Results were remarkable: CR rate increased from 35 to 79% and MRDnegative status was achieved in 56% of patients without excessive toxicity.15 On the other hand, very severe infections including five toxic deaths occured in American Cancer and Leukemia Group B (CALGB) study. Patients treated in first line by fludarabinezrituximab (FR) were consolidated 4 months after the end of induction therapy by subcutaneous alemtuzumab (30 mg thrice weekly for 6 weeks).16 The use of rituximab in consolidation/maintenance treatment has been less well studied. Pilot data from an Italian study is very promising with a significant prolongation of response duration.17 Given the results of alemtuzumab consolidation studies, further research in terms of optimal treatment schedule (dose, timing etc.) is necessary in order to minimize the infectious complications. Therefore, consolidation treatment in CLL

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should be considered an experimental approach and as such used within a clinical trials setting only.

Management of fludarabine-refractory CLL patients Management of fludarabine-refractory CLL patients are one of the more challenging clinical groups. Despite impressive efficacy of fludarabine-based combination regimens, 5–10% patients will not respond to first-line treatment; others will become fludarabine-refractory following subsequent lines of therapy. Alemtuzumab is able to salvage y40% of these patients but responses are mainly short-lived. Patients who are refractory to both fludarabine and alemtuzumab or those fludarabine-refractory with bulky lymphadenopathy (in whom alemtuzumab is not likely to be effective) have a particularly poor prognosis with OS being only several months. Many of these patients can be shown to have abnormalities in the p53 apoptotic signalling pathway (caused by deletion and/or mutation) in their leukemic cells resulting in high probability of refractoriness to conventional treatment. An alternative approach in these is the use of high-dose corticosteroids which are independent of the p53 pathway. There are two recently published reports on the use of high-dose methylprednisolone together with rituximab. Bowebn et al used methylprednisolone 1000 mg/m2 IV day 1–5 with rituximab 375 mg/m2 IV day 1 repeated every 28 days in 14 heavily pretreated patients, most having bulky lymphadenopathy.18 Treatment response was 93% and two patients entered CR. However, the response was of short duration (median PFS 7 months) with major infectious toxicity despite combined prophylaxis (6/14 patients experienced a significant opportunistic infection on treatment). The Mayo Clinic regimen used the same dose of steroids but rituximab was repeated weekly (day 1, 8, 15 and 22). Seventyeight percent out of 37 patients responded to treatment. Median PFS was around 12 months. Again, infections were an issue: 29% of patients had an infection and there were five early deaths due to infection during the first month of treatment.19 Combination of high-dose methylprednisolone and alemtuzumab, i.e. two agents working independently of p53 pathway, was reported as a pilot study in five patients with del 17p. ORR was 100% and 3/5 patients achieved complete remission. However, every patient experienced an infectious complication.20

Novel treatment combinations In high risk patients the addition of alemtuzumab to FCR, the CFAR regimen, is being tested in relapsed/

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refractory CLL as well as in first line.21,22 Though efficient, the major problems are significant hematological toxicity and the financial cost of the treatment. The combination of fludarabine with alemtuzumab (FluCam) was reported by GCLLSG in 36 patients with relapsed/refractory CLL. ORR was 83% but there were two mycotic pneumonias and one early death due to sepsis.23 Another logical option aiming at better therapeutic efficacy is addition of the anthracycline mitoxantrone to fludarabine-based regimens. The Spanish protocol FCM (FCzmitoxantrone 6 mg/m2 IV day 1 of the cycle) has been reported in 69 patients younger than 65 years as first-line treatment. Overal respose rate was 90% with 26% MRD-negative complete remissions and median response duration of 37 months. Severe neutropenia occured in only 10% and significant infections in 1%, respectively.24 The British phase II study CLL201 randomized 52 patients with relapsed CLL between FCM and rituximabzFCM (RFCM, classical dose of 375 mg/m2 IV day 1 of the cycle) with an increased CR rate (40 versus 12%) and MRD-negative responses (five versus three patients) present in the RFCM arm.25

Novel agents Bendamustine is a molecule with combined properties of an alkylating agent and a purine analog, originally developed in 1960s in the former German Democratic Republic. A landmark international phase III study randomized 305 untreated CLL patients between bendamustine (100 mg/m2 IV day 1–2 repeated every 28 days) and chlorambucil (0.8 mg/kg day 1 and 15, repeated every 28 days).26 Bendamustine demonstrated significantly higher OR/CR (68/30% versus 39/2%) as well as PFS (21.7 versus 9.3 months). Based on these results, bendamustine was approved in 2008 by US Food and Drug Administration for the firstline treatment of CLL. Monoclonal antibodies are increasingly being trialled in CLL because of the nature of the target cell. Ofatumumab is fully human anti-CD20 antibody binding to a different epitope of CD20 antigen than rituximab. In vitro experiments have shown better efficacy of ofatumumab in comparison to rituximab in the treatment of murine B-cell lymphomas. In addition, ofatumumab has been shown to effectively destroy cells insensitive to rituximab and CLL cells with low density of CD20 because of better complement-dependent cytotoxicity.27 Phase I/II study in relapsed CLL demonstrated 50% ORR in 27 patients treated by a schedule consisting of 500 mg IV plus

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three doses of 2000 mg IV once-weekly. Tolerability was very good – major toxicity was infusion-related (skin rash, fever, dyspnea, nausea, etc.) but manageable. Infections were noted in 51% of patients but predominantly (88%) of grade I/II.28 Given these promising results, a large phase III study is currently running worldwide in patients refractory to both fludarabine and alemtuzumab and to fludarabinerefractory patients ineligible to alemtuzumab because of bulky lymphadenopathy. The regimen consists of 300 mg plus seven doses of 2000 mg IV once weekly followed by four monthly infusions of 2000 mg IV. Results have been promising even in this highly unfavourable group of patients: ORR was 51% in the double-refractory patients and 44% (including one CR) in the bulky fludarabine-refractory group; Moreover, a significant number of patients achieved at least stabilization of the disease. Median OS was 14 and 15 months, respectively.29 Ofatumumab is also being currently tested in first-line therapy in randomized phase II study (BIFROST) in combination with FC (300 mgz56500 mg versus 1000 mg IV day 1 of the 28-day cycle).30 Lumiliximab, a chimeric human-macaque anti-CD23 antibody, showed some activity (decrease in peripheral lymphocyte count and/or shrinkage of lymph nodes) in a dose-escalation phase I study; however, there were no responses according to NCI-WG criteria.31 Treatment with lumiliximab (500 mg/m2 IV day 1) plus FCR in relapsed CLL led to an improvement in CR when compared to historical controls treated with FCR (48 versus 25%) without additional toxicity.32 This concept is therefore being further assessed in a large phase III study LUCID with randomization between six cycles of FCR¡lumiliximab.33 The bone marrow microenvironment is a logical target for a modern therapy because interactions between CLL cells and bone marrow stromal cells, endothelium and other cell types play a crucial role in the increased survival of the leukemic clone and its resistance against therapy. Thalidomide was banned in 1960s because of the widespread development of phocomelia in children whose mothers used it in pregnancy for morning sickness. The agent was rediscovered in the 1990s for the treatment of graft versus host disease and later in multiple myeloma. The mode of action of thalidomide is very complex and includes disruption of interleukin-6 and tumor necrosis factor-alpha pathways and inhibition of angiogenesis amongst a variety of postulated actions. In a pilot phase I/II study, 100–300 mg of thalidomide was administered daily for a total period of 6

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months together with fludarabine in a classical fashion. Thirteen untreated CLL patients achieved ORR/CR in 100/55 % and at median follow-up of 15 months, no progression was noted.34 Polish authors arrived at similar results; moreover, 10/16 relapsed patients responded including one complete remission.35 Side effects of thalidomide include neurotoxicity, fatique and constipation. Lenalidomide, a second generation thalidomide analog, was tested in two phase II studies in CLL. The first study from Roswell Park, Buffalo, used a regimen used in multiple myeloma: 45 relapsed/refractory patients received 25 mg day 1–21 of a 28-day-cycle. There were 47% OR and 9% CR; however, hematological toxicity was significant with neutropenia/thrombocytopenia in 78%.36 In the second study, 44 patients with relapsed CLL were treated by continuous dose of 10 mg per day with optional escalation; this however was not feasible due to significant neutropenia and thrombocytopenia. Efficacy was somewhat lower: OR/CR 32/7% including 31% in patients with unfavourable cytogenetic aberrations.37 The principal side-effects of lenalidomide therapy included in addition to hematological toxicity a condition described as tumor flare – a painful swelling of lymph nodes which develops in many patients, especially those with bulky lymphadenopathy at the beginning of treatment. Optimal dosing schedule is therefore still under investigation.38 Flavopiridol (alvocidib) is a semi-synthetic flavonoid which acts through inhibition of cyclin-dependent kinases independently of p53 pathway. Therefore, it is a potentially suitable agent for refractory patients harbouring del 17p. Despite very promising preclinical experiments, the phase I/II study was disappointing. When administered as a continuous 24 h infusion repeated every 2 weeks there was no observed clinical activity.39 The schedule was modified after an extensive pharmacokinetic analysis to a 30 min loading dose followed by 4 h infusion repeated weekly for 4 out of 6 weeks. This led to 45% of partial responses including 5/12 patients with del 17p and 13/18 with del 11q. Median of response duration was 13 months. Treatment with flavopiridol was complicated by a hyperacute tumor lysis syndrome requiring hemodialysis in 5/8 patients with leukocyte counts over 2006109/l. Patients with hyperleukocytosis therefore had to be excluded from the treatment and others had to receive complex and strict preventive measures including massive prehydration, alkalization of urine and serum potassium monitoring.40

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Conclusions The current surge in clinical interest in CLL has an extraordinary array of future treatment options. Novel treatment combinations as well as completely new agents have achieved very promising results in phase I/II studies which await confirmation in randomized phase III studies. In addition, many other agents initally used in other malignancies are now being tested in CLL (e.g., dasatinib, imatinib, sunitinib, sorafenib, valproic acid and many others). Therefore, we can be optimistic that in the future our ultimate therapeutic goals in CLL, of prolongation of overall survival and an improvement in the quality of life will be significantly expanded with our increasing treatment options.

Acknowledgements The author receives honoraria from Roche and Bayer-Schering Pharma. The work was supported by research project MZO 00179906 from Ministry of Health, Czech Republic.

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