Treatment of relapsed chronic lymphocytic leukemia: old and new therapies

There are several initial therapies available for chronic lymphocytic leukemia (CLL) that offer extended disease-free or treatment-free survival time. However, once patients relapse, particularly after fludarabine-based therapy, treatment choices have remained limited. Newer therapies have now become available, including alemtuzumab, fludarabine-based combinations, rituximab, methylprednisolone, alternative nucleoside analogs, flavopirodol, lenalidomide, signal transduction inhibitors/small molecules, and new monoclonal antibodies. We discuss selection of therapy for the relapsed patient using risk stratification and the role of clinical research in continuing to pursue therapeutic advances against CLL.     

Novel therapies for chronic lymphocytic leukemia in the 21st century

Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia diagnosed in the Western Hemisphere. Introduction of the purine analogs has improved outcome for patients with CLL as measured by improvements in disease-free survival and has made it possible to attain a complete remission in a minority of patients with this disease. The therapeutic success with the purine analogs in CLL has led to preclinical and early clinical investigation of a variety of other therapeutic agents. This, combined with advances in the understanding the genetic and immunobiology of CLL, leaves hope that CLL may become a curable disease in this century.     

Comparative efficacy of first-line therapies for advanced-stage chronic lymphocytic leukemia: A multiple-treatment meta-analysis

Since the introduction of chlorambucil as a treatment for chronic lymphocytic leukemia (CLL) in the 1960s, several alternative treatment regimens have been explored. We performed a multiple-treatment meta-analysis using direct and indirect data based on all available head-to-head randomized controlled trials (RCTs) to compare the benefits and harms of first-line treatments for untreated advanced-stage CLL. Two reviewers independently identified RCTs comparing overall survival and progression-free survival between two or more first-line treatments. Twenty-five trials involving 7926 patients were included. Of the 25 eligible RCTs, 30 (n = 7741 patients) and 12 (n = 3910 patients) treatment pairs were included in the multiple-treatment meta-analysis of overall and progression-free survival, respectively. Trials generally enrolled younger and less complicated patients than actual clinical practice. There was no evidence for inconsistency between direct and indirect data. Based on combined direct and indirect data, no single treatment showed significantly better overall survival than any other, and credible intervals were wide. Among six newer treatments with longer progression-free survival compared with chlorambucil, fludarabine-rituximab-based chemoimmunotherapy (HR = 0.24, 95% CrI: 0.13–0.51) and bendamustine (HR = 0.23, 95% CrI: 0.13–0.42) had the largest PFS benefit. Limited data on treatment-related mortality precluded multiple-treatment meta-analysis. In conclusion, published randomized evidence on overall survival is insufficient to recommend any particular first-line treatments. Any progression-free survival differences may be applicable to relatively young uncomplicated patients.     

New agents in chronic lymphocytic leukemia

Opinion statement For many years, alkylating agents, especially chlorambucil, have been considered the drugs of choice for first-line treatment of progressive and symptomatic chronic lymphocytic leukemia (CLL). More recently, treatment approaches have included purine nucleoside analogs (PNAs), fludarabine or cladribine (2-CdA), and monoclonal anti-bodies (MoAbs). PNAs are highly active in patients with CLL, previously treated and untreated. Significantly higher overall response and complete response in patients treated initially with fludarabine or 2-CdA than in those treated with chlorambucil- or cyclophosphamide-based combination regimens have been recently confirmed in prospective, randomized trials. However, the median survival times do not differ among the patients treated with PNA and alkylating agents. The MoAbs directed against CD52 antigen (alemtuzumab) and CD20 antigen (rituximab) also demonstrate significant activity in CLL and should be used in patients with disease that is refrac-tory to PNAs. Combination therapies with PNAs and cyclophosphamide, and especially with rituximab, are more active than monotherapy with PNAs in regard to response rate and possible survival. Because most patients are older and there is no survival time advantage for alkylating agents or PNA therapies, we recommend chlorambucil as the first-line treatment, with PNAs for consideration as the second-line therapy. PNAs alone or in combination with cyclophosphamide and rituximab as first-line treatment are an option in younger patients, who may be candidates for consolidation therapy with alemtuzumab and/or stem cell transplantation. Alemtuzumab may be an effective treatment for patients refractory to PNAs. Several biological parameters have been gaining increasing importance to evaluate the prognosis of patients with CLL and define optimal therapeutic strategy. Moreover, novel therapies are being evalu-ated, especially in patients refractory to PNAs, including those targeting the anti-apoptotic bcl-2 family of proteins and receptors, vaccines, and allogenic stem cell transplantation, especially after nonmyeloablative chemotherapy.     

Novel treatment strategies in chronic lymphocytic leukemia

The recent introduction of new active agents has led to a renaissance of clinical investigation in chronic lymphocytic leukemia (CLL). These agents include three purine analogues, (pentostatin, fludarabine, and cladribine) and two monoclonal antibodies (rituximab and CAMPATH I-H). Careful clinical studies have allowed for the development of novel combinations of two and even three non-crossresistant agents. These preliminary studies indicate that such combinations can induce complete responses in a larger proportion of patients than can single-agent therapy. In CLL, survival is superior for patients achieving a complete response compared with patients achieving a partial response. Therefore, strategies designed to induce high-quality responses in the majority of patients may one day lead to improved survival or posibly even cure in patients with chronic lymphocytic leukemia.     

Therapeutic efficacy of theophylline in chronic lymphocytic leukemia

Theophylline, a methylxanthine commonly used as a treatment for asthma, has been shown to induce apoptosis in chronic lymphocytic leukemia (CLL) cells both in vitro and in vivo. We have treated three advanced CLL patients with theophylline, and seen responses in two. The clinical courses of the responders are presented, and the literature concerning theophylline as therapy for CLL is reviewed.     

Purine nucleoside analogues and combination therapies in B-cell chronic lymphocytic leukemia: dawn of a new era

Purine nucleoside analogues are unique drugs that are effective in a variety of hematologic malignancies. Fludarabine and 2-chlorodeoxyadenosine (2-CdA) are active in chronic lymphocytic leukemia (CLL) both as salvage therapy and in newly diagnosed patients. These agents have revolutionized therapeutic strategies for patients with CLL that had remained unchanged for many years and included alkylating agents-based therapy with no potential for long-term remission or cure. Purine analogues have also been successfully combined with a variety of other chemotherapeutic drugs such as mitoxantrone, cyclophosphamide, corticosteroids, and monoclonal antibodies, specifically Rituximab and CAMPATH-1H. These agents are immunosuppressive and have been associated with opportunistic infections, the incidence of which can be significantly reduced by early recognition and administration of prophylactic antibiotics. In this review, the activity and toxicity of 2-CdA, fludarabine, and pentostatin in CLL as single agents and in combination with conventional chemotherapy are discussed. These drugs are increasingly used as initial therapy in CLL. Such strategies are associated with higher remission rates than have been previously achieved and in some cases, molecular remission, suggesting an important step towards cure.     

Novel therapies for patients with chronic myeloid leukemia

The most immediate issues that will have a major impact on the long-term survival of patients with chronic myeloid leukemia is the optimal use of imatinib mesylate (Gleevec, Novartis) and the development of effective therapies for those patients who are intolerant of, or become resistant to, optimal doses of this agent. Of the multiple new agents that are currently being developed for patients with chronic myeloid leukemia, most are being investigated in patients who have developed resistance to imatinib, which is a confounding factor in itself. The mechanisms of action of novel agents are diverse and they may have a variably synergistic therapeutic relationship with imatinib. The complete blockade of the intracellular pathways that are triggered by Bcr-Abl, combined with successful reversal of apoptotic and/or angiogenic abnormalities in chronic myeloid leukemia, may well lead to a cure for the majority of patients.     

Novel therapies for patients with chronic myeloid leukemia

The most immediate issues that will have a major impact on the long-term survival of patients with chronic myeloid leukemia is the optimal use of imatinib mesylate (Gleevec^®, Novartis) and the development of effective therapies for those patients who are intolerant of, or become resistant to, optimal doses of this agent. Of the multiple new agents that are currently being developed for patients with chronic myeloid leukemia, most are being investigated in patients who have developed resistance to imatinib, which is a confounding factor in itself. The mechanisms of action of novel agents are diverse and they may have a variably synergistic therapeutic relationship with imatinib. The complete blockade of the intracellular pathways that are triggered by Bcr-Abl, combined with successful reversal of apoptotic and/or angiogenic abnormalities in chronic myeloid leukemia, may well lead to a cure for the majority of patients.     

A network meta-analysis of therapies for previously untreated chronic lymphocytic leukemia

Background

Several therapy options are available for symptomatic, treatment-naïve chronic lymphocytic leukemia (CLL). Many of these therapies have been compared against chlorambucil, but have not been directly compared against each other. There is currently no agreed upon standard therapeutic regimen for treatment-naïve CLL.

Methods

We performed a systematic literature review to identify randomized controlled trials (RCTs) published prior to November 2011 of therapies for previously untreated CLL. We conducted a network meta-analysis using fixed and random effect statistical models to estimate differences between shape and scale parameters of progression-free survival (PFS) curves for each competing therapy. We used the parameter estimates and a Weibull distribution to project mean PFS for each therapy option.

Results

Five RCTs were included in our comparison network. Overall, patients were younger (59–65 years), had good performance status based on the Eastern Cooperative Oncology Group scale (ECOG 0-1), and earlier stage disease (Rai 0–II or Binet A or B). The combination regimen fludarabine with cyclophosphamide and rituximab (FCR) was estimated to yield mean PFS of 76 months (95% CrI: 60, 91), FC 60 months (46, 73), fludarabine 38 months (27, 49), alemtuzumab 24 months (15, 32), and chlorambucil 23 months (15, 32).

Conclusion

Our results suggest that FCR has relatively higher potential of preventing disease progression in younger, healthier, treatment-naïve CLL patients and should be considered an optimal initial treatment strategy for this patient population. However, because estimates are based on model simulation, additional studies of FCR are necessary to clinically validate its therapeutic potential.     

Immunomodulatory drugs in chronic lymphocytic leukemia: a new treatment paradigm

Immunomodulating drugs belong to a new class of therapeutic agents that have immunomodulatory, antiangiogenic and antiproliferative effects. Although the basis of anti-tumour activity of immunomodulating agents are not clear, results of clinical trials have demonstrated impressive activity in certain hemalogical disorders such as multiple myeloma (MM) and myelodysplastic syndromes (MDS). The peculiar properties of immunomodulating agents prompted investigators to test their role in patients with chronic lymphocytic leukemia (CLL). The efficacy of single-agent thalidomide in refractory CLL is disappointing, although its combination with fludarabine seems promising. Lenalidomide, a thalidomide analogue, is showing anti-tumour activity with durable response in refractory CLL. These preliminary results represent the basis for investigating the potential of lenalidomide in association with established chemotherapy regimens or as maintenance therapy.     

Novel immune-based treatment strategies for chronic lymphocytic leukemia.

Immune-based treatments represent a new group of therapeutic strategies for patients with cancer, including chronic lymphocytic leukemia (CLL), that employ immune effector mechanisms. Among these strategies is passive immunotherapy with monoclonal antibody, alone or in combination with chemotherapy. Active immunotherapy strategies currently under development include vaccines, administration of expanded and activated T cells, and allogeneic stem cell transplantation. These immune-based strategies represent new treatments with potentially complementary mechanisms of action to standard therapies and signify major advances in treatments for patients with CLL.     

Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia

Over the last few years, several monoclonal antibodies have been investigated in patients with B-cell lymphoid malignancies. Rituximab is the most important monoclonal antibody of clinical value in these disorders. Rituximab is an IgG1 chimeric antibody containing murine light- and heavy-chain variable region sequences and human constant region sequences. Since approval in 1997, rituximab has become the standard of care in follicular B-cell lymphoma, chronic lymphocytic leukemia (CLL) and aggressive lymphoma when combined with chemotherapy. Higher clinical benefits of rituximab can be seen in patients with CLL when it is added to other chemotherapeutic agents. Several recent reports have suggested that in patients with CLL, rituximab combined with purine nucleoside analogs (PNAs) or PNAs and cyclophosphamide may improve the results with acceptable toxicity, both in previously untreated and refractory/relapsed patients. The randomized, multinational Phase III study (REACH trial) has shown that rituximab combined with fludarabine and cyclophosphamide (R-FC regimen) results in 10 months longer progression-free survival, and higher overall response and complete response rates than fludarabine and cyclophosphamide (FC regimen) in previously treated patients. The German CLL study group initiated a multicenter, multinational Phase III trial, CLL8, to evaluate the efficacy and tolerability of R-FC versus FC for the first-line treatment of patients with advanced CLL. The overall response rate was significantly higher in the R-FC arm (95%) compared with FC (88%). The complete response rate in the R-FC arm was 44% compared with 27% in the FC arm. The recently updated analysis has demonstrated longer overall survival in the R-FC group. Recent clinical observations have revealed that combinations of rituximab with pentostatin and cyclophosphamide, or cladribine and cyclophosphamide are also highly active regimens in previously untreated CLL. In addition, the results of treatment with high-dose methylprednisolone in combination with rituximab in advanced CLL resistant to fludarabine have been reported recently by several groups. However, available therapies are only partially effective in CLL, exposing an obvious need to develop new, more specific and active drugs. Recently, several new anti-CD20 monoclonal antibodies have been developed and are now being evaluated in clinical trials.     

Coexistence of chronic myelogenous leukemia and chronic lymphocytic leukemia

A 55-year-old man is reported who initially developed chronic lymphocytic leukemia. Seven years later, after chemotherapy with chlorambucil, chronic myelogenous leukemia was diagnosed in addition to the chronic lymphocytic leukemia. Four previously reported cases with the same sequence of events are reviewed as well as cases of chronic myelogenous leukemia following chemotherapy alone.     

Antibody therapy for chronic lymphocytic leukemia: a promising new modality

Therapeutic options for chronic lymphocytic leukemia (CLL) have been limited, with low complete response rates (CR) and no treatments demonstrating a survival advantage. The recent introduction of the monoclonal antibodies rituximab and alemtuzumab into clinical trials for patients with CLL has generated promising results. Rituximab targets the CD20 antigen and demonstrates varied single-agent activity that is highly dependent upon the dosing schedule and treatment status of the patient. More importantly, when rituximab is combined with fludarabine or fludarabine and cyclophosphamide, a high frequency of CR and prolonged progression-free survival are observed without an appreciable increase in significant toxicity. Alemtuzumab targets the more ubiquitously expressed CD52 antigen and is therefore associated with a higher frequency of toxicity, particularly immunosuppression, but has appreciable activity in fludarabine refractory CLL. Additionally, alemtuzumab is effective against CLL clones that have p53 mutations or deletions. Future efforts in developing combination strategies with rituximab, alemtuzumab, and potentially other new antibodies offer great promise for the future treatment of CLL.     

Epigenetics in chronic lymphocytic leukemia

Enormous evidence has accumulated in the past decades that establishes the importance of epigenetic modifications in cancer and has resulted in shifting the focus from entirely genetic-based studies to integrated studies involving both genetic and epigenetic alterations. Chronic lymphocytic leukemia (CLL) is one such example where studies involving epigenetic aberrations have accelerated the search for affected genes, which was initially restricted to commonly deleted chromosomal regions. Many novel genes that are epigenetically silenced in CLL have been identified. Advances in the understanding of post-translational histone modifications and DNA methylation in normal and in CLL cells have proven to be extremely beneficial in finding powerful diagnostic markers, as well as in exploring novel therapies. At present, the field of epigenetics is at an evolving stage, but there is no doubt that further unraveling of its cause and effects in transformed cells will bring a new revolution in cancer therapeutics.     

Oncogenes in chronic lymphocytic leukemia

Oncogenes, in the context of retroviruses, are a common cause of leukemia in animals. Recently, activation of cellular oncogenes has been shown to be associated with leukemia in humans. Relatively few studies of oncogene activation in chronic lymphocytic leukemia (CLL) have been reported. In most instances, rearrangement of oncogenes has not been detected. Exceptions include the bcl-1 oncogene in B-cell prolymphocytic leukemia, the tcl-1 oncogene in T-cell CLL, the Hu-ets-1 and Hu-ets-2 oncogenes in small cell lymphocytic lymphoma and c-myc in a Sezary cell leukemia cell/line. Overall, it appears that oncogene abnormalities are less common in CLL than in other leukemias. The reason for it is uncertain and may relate to the relatively few cases evaluated. Alternatively, novel mechanisms of oncogene involvement or gene other than oncogenes may be important in the etiology or pathogenesis of CLL.     

Transplantation in chronic lymphocytic leukemia

Although there have been no randomized trials comparing the outcome of stem cell transplantation (SCT) with standard chemotherapy for patients with chronic lymphocytic leukemia (CLL), increasingly, both autologous and allogeneic SCT approaches are being explored in this disease. Clinical trials have demonstrated that these approaches are feasible, but current data suggest that autologous transplantation is not curative and myeloablative SCT, although offering the potential for cure, is associated with high treatment-related mortality. There is a clear demonstration of a graft-versus-leukemia effect in CLL, with encouraging results seen after SCT with reduced-intensity conditioning. Because no other treatment modalities are curently capable of improving survival in this disease, the treatment of choice for younger patients with poor-risk CLL may well be SCT, but continued enrollment of appropriate patients into well-designed clinical trials is vital to compare advances in SCT with the advances occurring in chemoimmunotherapy in CLL.