Elsevier

Blood Reviews

Volume 23, Issue 5, September 2009, Pages 217-224
Blood Reviews

REVIEW
Emerging therapies for patients with advanced chronic lymphocytic leukaemia

https://doi.org/10.1016/j.blre.2009.07.001Get rights and content

Summary

Chronic lymphocytic leukaemia is a common lymphoid malignancy with a variable clinical course. While some patients never require treatment or can be managed effectively with palliative chemotherapy, others experience early disease progression and death. The development of new prognostic markers has helped in the identification of patients with high risk disease, even among those diagnosed at early stage. Recent prospective trials have established chemo-immunotherapy combinations as the new standard of care for CLL patients requiring therapy. Unfortunately, patients whose tumour cells have certain genomic aberrations, such as a chromosome 17 deletion, have a disease that is frequently refractory to conventional therapy and should have their treatment tailored accordingly. Younger patients with high risk disease should be referred for allogeneic haematopoietic cell transplantation if they have an appropriate donor. For the remaining high risk patients, a number of new compounds are emerging, which could lead to further improvement in their outcome.

Introduction

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries, accounting for over 15,000 new cases and 4000 deaths in the United States every year.1 According to recent Surveillance, Epidemiology and End Results (SEER) data, the median age at diagnosis is 72 years.2 A significant proportion of CLL patients never require treatment or can be managed effectively with palliative chemotherapy. In contrast, other patients have a very aggressive clinical course and experience early disease progression and death.

The clinical staging systems devised by Rai et al.3 and Binet et al.4 have a limited value in the prediction of early-stage disease progression, but remain the basis of the updated National Cancer Institute (NCI) criteria for initiating treatment in CLL patients. As such, patients with Binet stage C and patients with stage A or B plus other features of disease progression (B symptoms, progressive lymphocytosis, massive lymphadenopathy or splenomegaly) should be considered for therapy.5 The development of new prognostic markers in the last decade has helped in the identification of patients with high risk disease, even among those diagnosed at early stage.6 Furthermore, recent prospective trials revealed that patients whose tumour cells have specific genomic aberrations, such as a chromosome 17 deletion, have a disease that is frequently refractory to conventional therapy and should have their treatment tailored accordingly.[7], [8], [9]

Section snippets

Frontline therapy

In patients with early disease (i.e. not fulfilling the NCI criteria) therapy is not recommended regardless of prognostic markers. Although there are several clinical trials under way to confirm whether this affirmation remains true for modern therapeutic combinations, several trials and a meta-analysis have shown that treating patients at early stage is not beneficial.10

For patients with advanced disease, the treatment choice should be based on the patient’s age and co-morbidities.[11], [12]

Salvage therapy

Even modern chemo-immunotherapy combinations, e.g., FCR, able to achieve objective responses in 95% of patients when given upfront, have a PFS around 50% at six years with no plateau in the curve.17 In patients with relapsed CLL, second-line therapy will depend on the age and co-morbidities at the time of relapse, prior treatment and, very importantly, the duration of response to that treatment. Patients with F-refractory disease, defined as treatment failure or disease progression within six

Therapeutic approaches for high risk disease

The development of reduced intensity conditioning (RIC) regimens for allogeneic haematopoietic transplantation (allo-HCT) opened a new era for older patients with haematological malignancies. With a median age at diagnosis around 72 years, CLL patients certainly benefited from the appearance of these regimens. Accordingly, the number of patients undergoing RIC allo-HCT has progressively increased over the past years. However, RIC allo-HCT is associated with a non-relapse mortality (NRM) ranging

Conclusions

In the past, CLL was considered an incurable disease of the elderly and was somewhat “neglected” by physicians and haematologists alike. For many years, no real progress was made on the diagnosis, prognosis and treatment of these patients. Nowadays, the management of CLL is no longer straightforward for the practicing haematologist. In the last decade, remarkable improvements in laboratory methods for diagnosis and prognosis prediction, a better understanding of the natural history of the

Practice points

  • •

    FCR is considered the standard of care for younger patients requiring therapy.

  • •

    Chlorambucil remains a valid alternative for elderly patients or those with significant co-morbidities.

  • •

    Allogeneic HCT should be considered for patients with high risk disease (i.e. p53 abnormalities requiring therapy, fludarabine-refractoriness and early relapse after autologous HCT).

  • •

    Patients with high risk disease ineligible for allogeneic HCT should be entered into clinical trials. If not, alemtuzumab is the only

Research agenda

  • •

    Development of less toxic therapeutic regimens for younger patients with standard risk disease.

  • •

    Development of more effective regimens for elderly patients with standard risk disease.

  • •

    Reduction of non-relapse mortality in patients undergoing allogeneic HCT.

  • •

    Development of more effective therapies for patients with high risk disease not eligible for allogeneic HCT.

Conflicts of interest

J.D. has received lecturing fees from Bayer Schering Pharma and Roche, and consulting fees from Bayer Schering Pharma, Roche and GlaxoSmithkline. J.B and J.S. have no conflicts of interest to disclose.

References (90)

  • M.L. Sorror et al.

    Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia

    Blood

    (2008)
  • J. Delgado et al.

    Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British society of blood and marrow transplantation study

    Blood

    (2006)
  • J. Delgado et al.

    The effect of in vivo T cell depletion with alemtuzumab on reduced-intensity allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia

    Biol Blood Marrow Transplant

    (2008)
  • H. Döhner et al.

    P53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias

    Blood

    (1995)
  • M.J. Keating et al.

    Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study

    Blood

    (2002)
  • G. Lozanski et al.

    Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions

    Blood

    (2004)
  • D. Huhn et al.

    Rituximab therapy of patients with B-cell chronic lymphocytic leukemia

    Blood

    (2001)
  • J.L. Teeling et al.

    Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas

    Blood

    (2004)
  • B. Coiffier et al.

    Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study

    Blood

    (2008)
  • A. Chanan-Khan et al.

    Results of a phase I clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia

    Blood

    (2005)
  • A. Ferrajoli et al.

    Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia

    Blood

    (2008)
  • J.C. Byrd et al.

    Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53

    Blood

    (1998)
  • I.W. Flinn et al.

    Flavopiridol administered as a 24-h continuous infusion in chronic lymphocytic leukemia lacks clinical activity

    Leukemia Res

    (2005)
  • J.C. Byrd et al.

    Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia

    Blood

    (2007)
  • M.A. Phelps et al.

    Clinical response and pharmacokinetics from a phase I study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia

    Blood

    (2009)
  • R. Chen et al.

    Mechanism of action of SNS-032, a novel cyclin dependent kinase inhibitor, in chronic lymphocytic leukemia

    Blood

    (2009)
  • C. Pepper et al.

    Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers

    Blood

    (2008)
  • S.M. O’Brien et al.

    Phase I study of obatoclax mesylate (GX15–070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia

    Blood

    (2009)
  • A. Raval et al.

    Epigenetics in chronic lymphocytic leukemia

    Semin Oncol

    (2006)
  • J.C. Byrd et al.

    A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia

    Blood

    (2005)
  • A. Jemal et al.

    Cancer statistics, 2008

    CA Cancer J Clin

    (2008)
  • Ries LAG, Melbert D, Krapcho M et al. SEER Cancer statistics review, 1975–2005, National Cancer Institute. Bethesda,...
  • J.L. Binet et al.

    A clinical staging system for chronic lymphocytic leukemia: prognostic significance

    Cancer

    (1977)
  • M.R. Grever et al.

    Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997

    J Clin Oncol

    (2007)
  • Stilgenbauer S, Zenz T, Winkler D et al. Genomic aberrations, VH mutation status and outcome after fludarabine and...
  • G. Dighiero et al.

    Chlorambucil in indolent chronic lymphocytic leukemia. French cooperative group on chronic lymphocytic leukemia

    N Engl J Med

    (1998)
  • B. Eichhorst et al.

    Treatment of elderly patients with chronic lymphocytic leukemia

    Leukemia Lymphoma

    (2009)
  • Eichhorst BF, Busch R, Stauch M et al. No significant clinical benefit of first line therapy with fludarabine in...
  • I.W. Flinn et al.

    Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US intergroup trial E2997

    J Clin Oncol

    (2007)
  • Bosch F, Abrisqueta P, Villamor N et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) a new,...
  • Hallek M, Fingerle-Rowson G, Fink A-M et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab...
  • N. Lamanna et al.

    Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses

    J Clin Oncol

    (2009)
  • K.A. Foon et al.

    Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia

    J Clin Oncol

    (2009)
  • K.R. Rai et al.

    Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia

    N Engl J Med

    (2000)
  • P. Hillmen et al.

    Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia

    J Clin Oncol

    (2007)

    • Cited by (14)

    • How I treat chronic lymphocytic leukemia in older patients

      2015, Journal of Geriatric Oncology
      Citation Excerpt :

      Significant progress has been made in the past two decades in the management of chronic lymphocytic leukemia (CLL), which is a disorder predominantly of the elderly, with median age at diagnosis of 72 years (yrs) [1–3].

    • Active fraction from Ganoderma lucidum with apoptosis activity on peripheral blood mononuclear cells from chronic lymphocytic leukemia

      2012, European Journal of Integrative Medicine
      Citation Excerpt :

      B-CLL occurs primarily in middle-aged and elderly adults [2]. Several chemotherapy strategies have been used to promote malignant cell death but new therapeutic agents more effective and selective on tumor cells are required for a better control of the disease [3]. Fludarabine (FAMP), a purine analog, is one of the currently most effective compounds against B-cell malignancies.

    • Interleukin-15 enhances rituximab-dependent cytotoxicity against chronic lymphocytic leukemia cells and overcomes transforming growth factor beta-mediated immunosuppression

      2011, Experimental Hematology

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

      2011, Blood
      Citation Excerpt :

      The FCR combination is an effective regimen for treatment of relapsed patients with CLL. The estimated median PFS of 21 months compares favorably with published data of therapies for relapsed patients including purine analog combinations.23-25 Historical comparison of patients with relapsed or refractory CLL at MDACC, demonstrated improvement in quality of responses, duration of response and OS with FCR therapy, compared with FC9; this is confirmed in this updated analysis.

    • The prognostic impact of minimal residual disease in patients with chronic lymphocytic leukemia requiring first-line therapy

      2014, Haematologica

    • Small lymphocytic lymphoma/chronic lymphocytic leukemia

      2013, Lymphoma: Diagnosis and Treatment
    View all citing articles on Scopus
    View full text
    Copyright © 2009 Elsevier Ltd. All rights reserved.