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Originally published as JCO Early Release 10.1200/JCO.2005.11.932 on February 28 2005 © 2005 American Society of Clinical Oncology.
Treatment of Chronic Lymphocytic Leukemia: Achieving Minimal Residual Disease–Negative Status As a GoalInstitute of Hematology and Oncology, Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain For many years, primum non nocere ("First, do no harm") dictated the treatment of patients with chronic lymphocytic leukemia (CLL). This approach came from the idea that, in most cases, CLL had an indolent course (a frequently unfortunate misconception) and that there were no effective therapies for this disease (regrettably, true). However, in the 1970s, the development of staging systems and other prognostic factors allowed the identification of subsets of patients with different outcomes ranging from a normal life span to a short survival. This advance, coupled with the appearance of more effective therapies, renewed interest in CLL and its treatment. Today, therapy for CLL is based on the use of purine analogs alone or in combination with other agents, including monoclonal antibodies. This strategy has resulted in an important increase in the complete response (CR) rate from less than 10% with chlorambucil to 60% to 70% with some of the regimens currently under investigation. Even though there is no proof yet of an improvement in overall survival, disease-free progression has been prolonged. Significantly, not only has the CR rate dramatically increased but it has also proved possible to eradicate minimal residual disease (MRD) in an increasing proportion of patients. Is achieving MRD-negative status a desirable goal in the treatment of CLL? A necessary condition to cure any type of neoplasia is to eradicate it; that is, to achieve CR. The fact that response to therapy is associated with a better outcome in patients with CLL had already been established in trials conducted in the 1980s using National Cancer Institute Working Group (NCI-WG) or International Workshop on CLL criteria to assess response.1,2 In these trials, the better the response, the longer the survival.3-5 However, these criteria are not accurate enough. For example, patients with less than 30% lymphocytes in bone marrow aspirate may be classified as complete responders, provided that clinical and laboratory findings return to normal. In addition, patients with lymphoid aggregates in bone marrow biopsy are considered to be in nodular partial response (nPR), yet the nodules may represent either leukemic or non-neoplastic T cells. In other words, many patients considered to be in CR by current criteria can still harbor leukemic cells, whereas others who are deemed to be in PR may have achieved CR. A step forward in evaluating the response in CLL is the assessment of MRD by either allele-specific polymerase chain reaction or four-color cytofluorometry.6,7 Although polymerase chain reaction has a slightly higher sensitivity than four-color cytofluorometry, both methods are considered to be similarly useful from the clinical point of view, and four-color cytofluorometry is more widely applicable. In this issue, Moreton et al8 describe the outcome in 91 previously treated patients with CLL who received alemtuzumab to best response followed by either combined alemtuzumab with fludarabine and/or stem-cell transplantation for patients not achieving MRD negativity. MRD was assessed, as previously described by the same authors, by a highly sensitive four-color cytofluorometry method.7 According to NCI-WG criteria, 32 patients (36%) achieved CR and 17 patients (19%) achieved PR. Detectable leukemic cells were eradicated from blood and bone marrow in 18 patients (20%), including six patients classified as being in PR by NCI-WG criteria. Patients achieving MRD-negative status had longer disease-free survival and, notably, longer overall survival than the remaining patients. Interestingly, 14 of the 32 patients in CR by NCI-WG criteria had detectable MRD; these patients had an outcome equivalent to those in NCI-WG PR. These results point to the importance of achieving MRD-negative status in patients with CLL and also to some of the weaknesses of current methods for evaluating response to therapy in CLL. It is worth noting that six MRD-negative patients in the series by Moreton et al8 were classified as PR by NCI-WG criteria because of therapy-related cytopenias. This indicates that with the newer, more effective but also more myelotoxic treatments, a time window that would allow patients to recover from treatment-related cytopenias should be mandated before evaluating response, and that treatment-related cytopenias should not necessarily disqualify patients for CR. However, the most important question from Moreton et al8 and other similar studies9,10 is whether response criteria for CLL therapy should be modified to incorporate a new response category: MRD-negative CR. Although the existing data are convincing, the benefits of achieving MRD-negative status in patients with CLL should be further investigated in large controlled trials in which, incidentally, patients should be stratified not only according to clinical stages but also according to biologic parameters such as cytogenetics, IgVH mutations or ZAP-70 expression.11 This, however, cannot be envisaged without incorporating MRD-negative CR as a new response category that would facilitate the evaluation of trials with eradication of MRD as the end point. It is therefore necessary to standardize methods for assessing MRD in CLL, a field in which important work has already been done.6,7,12 On the basis of the above-described reasons, it seems clear that the time has come for a change in the objectives of CLL therapy and in the criteria by which response to treatment in this disease is evaluated. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research funding: Emili Montserrat, Amgen, Roche. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES 1. International Workshop on Chronic Lymphocytic Leukemia: Chronic lymphocytic leukemia: Recommendations for diagnosis, staging, and response criteria. Ann Intern Med 110:236-238, 1989
2. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored working group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996 3. Montserrat E, Alcala A, Parody R, et al: A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone. Cancer 56:2369-2375, 1985[CrossRef][Medline] 4. Catovsky D, Fooks I, Richards S: Prognostic factors in chronic lymphocytic leukaemia: The importance of age, sex, and response to treatment in survival. Br J Haematol 72:141-149, 1989[Medline]
5. Keating MI, O'Brien S: Kantarjian H, et al: Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood 81:2878-2884, 1993 6. van Dongen JJM, Langerak AW, Brüggemann M, et al: Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17:2257-2317, 2003[CrossRef][Medline]
7. Rawstron AC, Kennedy B, Evans PA, et al: Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 98:29-35, 2001
8. Moreton P, Kennedy B, Lucas G, et al: Eradication of minimal residual disease in b-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23:2971-2979, 2005
9. Provan D, Bartlett-Pandite L, Zwicky C, et al: Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood 88:2228-2235, 1996 10. Bosch F, Ferrer A, López-Guillermo A, et al: Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol 119:976-984, 2002[CrossRef][Medline]
11. Montserrat E: Assessing prognosis in patients with chronic lymphocytic leukemia a quarter of century after Rai and Binet staging systems. Ann Oncol 15:450-451, 2004 12. Rawstron AC, Villamor N, Zehnder JL, et al: International standardized approach to molecular and flow cytometric disease monitoring in CLL. Blood 104:8a, 2004 (abstr)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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