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© 2002 American Society for Clinical Oncology Therapy-Related Myeloid Leukemias Are Observed in Patients With Chronic Lymphocytic Leukemia After Treatment With Fludarabine and Chlorambucil: Results of an Intergroup Study, Cancer and Leukemia Group B 9011ByFrom the Veterans Affairs Medical Center, Minneapolis, MN; Long Island Jewish Medical Center, New Hyde Park, and North Shore University Hospital, Manhasset, NY; Cancer and Leukemia Group B Statistical Center, Durham, NC; University of New Mexico Health Sciences Center, Albuquerque, NM; Fred Hutchinson Cancer Research Center, Seattle, WA; The Case Western Reserve University School of Medicine, Cleveland, OH; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; University of Chicago Medical Center, Chicago, IL; and Wayne State University School of Medicine, Detroit, MI. Address reprint requests to Vicki A. Morrison, MD, Sections of Hematology/Oncology and Infectious Disease, 111E, Veterans Affairs Medical Center, One Veterans Dr, Minneapolis, MN 55417; email: morri002{at}tc.umn.edu
PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin’s lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication. PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML. RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P = .007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months). CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.
THERAPY-RELATED second malignancies remain an important late complication among patients who receive cancer chemotherapy. Among patients with chronic lymphocytic leukemia (CLL), the potential for disease transformation to diffuse aggressive non-Hodgkin’s lymphoma (also known as Richter’s syndrome) or the evolution to prolymphocytic leukemia is well known. However, the development of therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute myeloid leukemia (t-AML) is uncommon. In most trials, an incidence rate of  1% has been seen. We present data from an intergroup CLL treatment trial in which a possible increase in the number of cases of therapy-related myeloid leukemia was observed.
Five hundred forty-four patients with previously untreated B-cell CLL were enrolled onto an intergroup protocol entitled "A Phase III Comparison of Fludarabine Phosphate vs. Chlorambucil vs. Fludarabine Phosphate + Chlorambucil in Previously Untreated B-Cell Chronic Lymphocytic Leukemia" (Cancer and Leukemia Group B 9011). Participants in the study included the Cancer and Leukemia Group B, the Southwest Oncology Group, the Eastern Cooperative Oncology Group, and the National Cancer Institute–Canada Clinical Trials Group. This protocol was open for accrual from October 1, 1990, to December 7, 1994. A complete report of the clinical results of this trial has been recently published.1 Eligible patients had received no prior cytotoxic therapy; however, prior corticosteroid therapy for autoimmune problems was allowed. Patients were required to have had either intermediate-stage disease (stages I and II) with clinical evidence of progressive disease or high-risk disease (stages III and IV) by the modified Rai staging system.2 After signed informed consent was obtained, patients were randomly assigned to one of the following three treatments: arm 1, chlorambucil 40 mg/m2 orally on day 1, every 4 weeks; arm 2, fludarabine monophosphate 25 mg/m2/d intravenously on days 1 to 5, every 4 weeks; or arm 3, chlorambucil 20 mg/m2 orally on day 1 plus fludarabine phosphate 20 mg/m2/d intravenously on days 1 to 5, every 4 weeks. Therapy was continued for 3 months after a clinical complete remission (CR) or for 2 months after a stable best response. The maximum duration of therapy was 1 year. Patients on either arm 1 or 2 who had evidence of disease progression on therapy or had an intolerable or allergic reaction to the initial treatment drug were crossed over to the alternate treatment arm. The combined-therapy arm (arm 3) was closed to further accrual on May 2, 1994, because an interim analysis by an independent data safety monitoring board indicated that toxicities were significantly more frequent on this arm than on either of the single-agent treatment arms (arms 1 and 2). The concomitant use of corticosteroids was prohibited on this study. The use of growth factors to maintain dose-intensity or dose schedule was not allowed. The primary objective of this retrospective analysis was to determine whether the type of initial therapy received for CLL had an impact on the subsequent occurrence of either t-MDS or t-AML. A secondary objective was to examine the clinical features and chromosomal abnormalities (when available) found in the cases of either t-MDS or t-AML. Case report forms from the 544 enrolled patients were retrospectively reviewed for the occurrence of either t-MDS or t-AML. Available data from 521 patients (96%) were complete for the determination of second malignancies. Reasons for exclusion of the remaining 23 patients from this analysis were as follows: follow-up data were incomplete on available flowsheets (n = 19) and study registration was canceled because of ineligibility (n = 4). Treatment arm differences in probability of developing t-MDS or t-AML were tested with the proportional hazards model by constructing the outcome as the time to malignancy. A 2-df test of any difference among the three arms and 1-df tests of each single-agent arm against the combination arm were calculated.
To date, six (1.2%) of the 521 patients have developed t-MDS (n = 3), t-AML (n = 2), or t-MDS that evolved to t-AML (n = 1) after initial therapy for CLL. The median length of follow-up for a second malignancy ranged from 49 to 50 months within the three arms (ie, there was an almost identical length of follow-up across the arms). The clinical characteristics of the six patients at the time of study enrollment are listed in Table 1. These disorders were diagnosed from 27 to 53 months (median, 34 months) after study enrollment. There was a significant difference among the three treatment arms in the probability of developing t-MDS or t-AML (P = .007). Five (3.5%) of the 142 patients who received simultaneous fludarabine plus chlorambucil developed either t-MDS or t-AML, as compared with only one (0.5%) of the 188 patients treated with single-agent fludarabine (P = .04). None of the 191 patients who received single-agent chlorambucil developed t-MDS or t-AML (compared with the combination-therapy arm; P = .01). No case of t-MDS or t-AML has occurred among patients who received initial single-agent therapy and were crossed over to the alternative treatment arm, with a 4.2-year median follow-up period.
Of the five patients treated with fludarabine plus chlorambucil, four had achieved a CR with initial therapy, and one patient had stable disease. The one patient who received single-agent fludarabine achieved a partial response to this therapy. Patients no. 5 and 6 received additional second-line treatment after progression of CLL and before the diagnosis of t-MDS. Patient no. 5 received six cycles of fludarabine, followed by one cycle of cladribine. Patient no. 6, treated with single-agent fludarabine, subsequently received 12 cycles of chlorambucil plus prednisone given intermittently over an 18-month period, ending 5 months before the development of t-MDS. The chlorambucil was administered as a protocol cross-over therapy; none of the other five patients who developed t-MDS or t-AML were crossed over to a second therapeutic arm on this study. A single cycle of cladribine was administered 4 months before the diagnosis of t-MDS. Cytogenetic studies at study enrollment were not required. However, cytogenetic analysis was performed on one of the six patients (patient no. 4), a 72-year-old woman who later developed t-AML, at study entry. Twenty-five of 30 metaphase cells were normal. However, four metaphase cells were 45,XX, and one metaphase cell had a deletion 9p11 abnormality. Loss of a sex chromosome can be age related and have no clinical significance. These initial karyotypic abnormalities were not later observed at the time of evolution to t-AML. The bone marrow findings at diagnosis of t-MDS/t-AML are listed in Table 2. Residual evidence of CLL was present in only one case. Three patients had cytogenetic analyses performed at diagnosis of therapy-related leukemia. In patient no. 1, two related abnormal clones were present at diagnosis of t-MDS, which was characterized as refractory anemia with ringed sideroblasts. All 20 metaphase cells examined had monosomy 5 plus other abnormalities. A follow-up bone marrow examination 4 months later revealed evolution to a refractory anemia with excess blasts in transformation. One month later, the patient had acute leukemia. Cytogenetic analysis in patient no. 3 at diagnosis of t-MDS revealed a structurally abnormal X chromosome, a rearranged chromosome 1, and two metaphase cells with multiple aberrations that involved 5q, 7q, and 12p. Patient no. 4 developed t-AML of a French-American-British M1 subtype. Complex cytogenetic abnormalities, including monosomies of both chromosomes 5 and 7, were present in all 20 metaphase cells examined.
The outcome after diagnosis of t-MDS or t-AML was poor. Survival ranged from several weeks to 10.1 months, with a median survival of 3.5 months. The two patients (patient nos. 5 and 6) who presented with overt AML received cytotoxic therapy, but neither had a complete response.
There has been increasing recognition of the importance not only of the more traditional parameters of outcome with oncologic therapeutics, such as response rate, remission duration, and survival, but also of the early and late effects of these therapies, including the impact of irreversible injury to major organ function and the development of second malignancies.3 Our finding of six cases of therapy-related myeloid leukemia among this large cohort of patients with previously untreated B-cell CLL is of interest both with regard to the occurrence of these secondary disorders and, more importantly, to the distribution of cases by the type of therapy received. The preponderance of these cases occurred in patients who received simultaneous combination chemotherapy with fludarabine and an alkylating agent. Although patients with CLL have an increased risk for the development of second malignancies, solid tumors such as colorectal and lung cancer, melanoma, soft tissue sarcoma, and squamous cell skin malignancies are most common.4-6 With regard to second hematologic malignancies, the risk of multiple myeloma in patients with CLL is increased 10-fold over the incidence of myeloma in the general population. However, AML develops in 1% or fewer of patients with CLL, despite the frequent and long-term use of alkylating agents for therapy, the older age of many of these patients, and their relatively long survival with this disease process.7 In the retrospective review by Robertson et al8 of 1,374 CLL patients who received care at the M.D. Anderson Cancer Center from 1972 to 1992, only three cases of MDS or AML were found. Seventy-two percent of these patients had received prior alkylator therapy. An additional four patients with concurrent diagnoses of CLL and MDS/AML were not included in the incidence calculations. Three of these seven patients had received no prior alkylator therapy. Anecdotal cases of myelodysplasia or AML occurring in untreated patients with CLL have been reported,9 as have cases of concomitant diagnoses of CLL and AML, although these are quite uncommon.8,10-15 None of the CLL patients in our study treated with chlorambucil alone has developed t-MDS or t-AML to date. The leukemogenic potential of alkylating agents has been long recognized when they are used either as cytotoxic antitumor agents or as immunosuppressive agents, for example, in the therapy of rheumatologic disorders.16-20 Zarrabi et al21 described a low incidence of acute leukemia as a terminal event in CLL patients receiving prolonged therapy with chlorambucil. The Polycythemia Vera Study Group found in an interim analysis of its randomized treatment trial two decades ago that the risk of acute leukemia was significantly increased in polycythemia vera patients who received therapy with chlorambucil compared with those treated with either radioactive phosphorus or phlebotomy alone.22 Half of the acute leukemia cases in the chlorambucil-treated patients were diagnosed within 5 years after randomization onto this trial. However, in a follow-up report, it was found that additional cases of acute leukemia occurred in the patients treated with radioactive phosphorus, with the majority of these diagnosed more than 5 years after initial treatment.23 As in our patients, these cases of secondary leukemia were generally refractory to therapy, with a median survival after diagnosis of approximately 1 month. The incidence of t-AML was 4.7% among a series of 63 patients with advanced CLL treated at Memorial Sloan-Kettering Cancer Center with the M-2 protocol, consisting of vincristine, carmustine, cyclophosphamide, melphalan, and prednisone.24 Therapy-related leukemia was diagnosed in three patients after a median period of 40 months of therapy. In a 1996 summary published by Grunwald and Rosner,25 18 cases of secondary AML arising in CLL patients treated with chlorambucil were reported. These cases occurred at a median period of 57 months (range, 24 to 89 months) after CLL diagnosis. More recently, the French Cooperative Group on Chronic Lymphocytic Leukemia has reported their experience, in which previously untreated patients with Binet stage A CLL were randomly assigned to either no treatment or a combination of chlorambucil and prednisone.26 With a median follow-up of 129 months in this series, six cases (1.5%) of acute leukemia were reported among the 422 patients who received daily chlorambucil as initial or secondary treatment, compared with no cases among the 145 patients who were randomized to receive no initial therapy. Although the numbers were quite small, the majority of the acute leukemia cases occurred among patients treated with daily, versus intermittent, chlorambucil. One of our six cases of therapy-related leukemia occurred in a patient treated with single-agent fludarabine. However, at the time of disease progression, this patient received subsequent alkylator therapy. Thus, the pathogenesis of t-MDS in this patient may be related to one or both of these agents. The experience with fludarabine in the therapy of CLL is as yet more limited than that with the more commonly used alkylating agents. Antimetabolites similar to fludarabine, such as methotrexate, cytarabine, pentostatin, and azathioprine, are generally thought to have a negligible risk of therapy-related myeloid leukemia, although a few cases of acute leukemia have been reported in polycythemia vera patients treated with hydroxyurea.27,28 Keating et al29 recently reported long-term follow-up results of 174 patients with CLL with Rai stage I to IV disease who received fludarabine as their initial therapy at the M.D. Anderson Cancer Center. None of these 174 patients had developed acute leukemia at the time of that report. No cases of MDS/AML were reported from two large series of CLL patients who received salvage therapy with fludarabine.30,31 In a report from the French Cooperative Group on CLL, in which 196 patients with advanced-stage CLL were randomized to therapy with either single-agent fludarabine or cyclophosphamide, doxorubicin, and prednisone (CAP), no second malignancies have yet been reported from either therapeutic arm, with a median follow-up period of 34 months (range, 1 to 61 months).32 In an initial report from this same group, in which 247 previously untreated CLL patients with Binet stage B or C disease were randomized to fludarabine, CAP, or cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, no late effects such as second malignancies have yet been reported.33 The occurrence of second malignancies in 791 alkylator-refractory CLL patients who received fludarabine through the National Cancer Institute Group C protocol mechanism was reported by Cheson et al.34 With a median follow-up of 7.4 years, only one case of acute leukemia and no cases of MDS were reported. However, Orchard et al35 reported significant marrow dysplastic changes in five of 31 chlorambucil-treated patients with low-grade lymphoproliferative disorders who subsequently received fludarabine. No cytogenetic abnormalities other than those related to the lymphoproliferative disorder were reported in this cohort. Anecdotal cases of AML and myelodysplasia occurring in CLL patients who received initial ther-apy with fludarabine have been reported from other centers,36 as have isolated cases presenting after initial chlorambucil therapy followed by subsequent treatment with fludarabine.37,38 The finding of five cases of t-MDS/t-AML among the 142 CLL patients (3.5%) who received combination therapy with fludarabine plus chlorambucil administered in a simultaneous manner in our study is of concern. It would have been of interest to have comparative bone marrow cytogenetic data on these six patients at the time of CLL study entry and at diagnosis of t-MDS/t-AML, but unfortunately, in retrospect, marrow cytogenetic analyses were not required as part of this protocol. In several phase I trials that preceded this intergroup study, no detailed information on second malignancies, specifically t-MDS/t-AML, was provided.39,40 The mechanism explaining the possible increase in leukemogenesis is uncertain. Patients who received the combination regimen had a 50% reduction in alkylator exposure compared with those patients treated with single-agent chlorambucil. In vitro evidence of the synergistic effect of the fludarabine-alkylator combination in inducing apoptosis of B-CLL cells has been reported.41 This synergistic activity is likely related to the occurrence of alkylator-induced DNA damage and inhibition of subsequent DNA repair by fludarabine. Thus, the most likely explanation for the phenomenon that we have observed is increased DNA damage. Fludarabine is also an immunosuppressive agent, and loss of immunosurveillance may play an additional role. Cases of t-MDS/t-AML are also being recognized as an emerging problem in other malignancies, which are potentially curable. In a series of 77 patients with acute promyelocytic leukemia who achieved a CR after induction/consolidation chemotherapy (including idarubicin and cytarabine, alone or with all-trans-retinoic acid), five cases (6.5%) of t-MDS/t-AML were recently reported.42 These cases were characterized by a median latency period of 46 months, t-MDS preceding t-AML in four cases, and abnormalities in chromosomes 5 or 7 in two of four cases—findings similar to cases of t-MDS/t-AML after alkylator therapy. Three of the five patients died soon after diagnosis, similar to the poor outcome found in our series. On the basis of encouraging pilot studies, fludarabine-alkylator combinations are being investigated in low-grade lymphoproliferative disorders and in CLL, both in single-institution and cooperative group trials.43-46 In some of these trials, the alkylating agent therapy has been intensified beyond that used in our trial. Preliminary analyses from these trials have focused on early measures of outcome, such as response rate. Limited data from these trials on late complications, including the incidence of therapy-related myeloid malignancies, are available but will be of greater relevance with longer periods of follow-up. In a phase I study from the Eastern Cooperative Oncology Group of 27 patients with low-grade non-Hodgkin’s lymphoma who received initial therapy with fludarabine plus cyclophosphamide, no cases of t-MDS/t-AML were reported after a median follow-up of 61 months.44 Likewise, with a brief period of follow-up, no cases of t-MDS/t-AML have occurred among 60 patients with indolent lymphoid malignancies receiving initial therapy with fludarabine, cyclophosphamide, and filgrastim.45 Finally, in the recent report of O’Brien et al46 of 128 CLL patients, including both chemotherapy-naïve and previously treated patients, who received fludarabine plus cyclophosphamide, no mention of t-MDS/t-AML was commented on, with a median follow-up of 41 months. It has been suggested that the leukemogenic potential of cyclophosphamide is less than that of other alkylating agents, which may have a potential impact on the frequency of t-MDS/t-AML with fludarabine/cyclophosphamide combination therapy.47 Although the patient numbers are small and the preliminary incidence figures of t-MDS/t-AML from our series are not overwhelming, this has been seen with only a 4.2-year median follow-up period, and this incidence is likely to increase with a longer duration of follow-up. In addition, it is possible that the incidence of second malignancies such as these may be underreported or underdiagnosed, both in this study and in other CLL trials, depending on the scrutiny of follow-up by an individual institution enrolling patients onto these trials. In future trials in which potent immunosuppressive agents, such as monoclonal antibodies and cytokines, are combined with DNA-damaging agents, the incidence of therapy-related myelodysplasia and myeloid leukemias may well increase, and continued monitoring of these toxicities is warranted.
The appendix listing participating institutions is available online at www.jco.org.
Cancer and Leukemia Group B 9011 was supported in part by National Cancer Institute grant no. CA31946 to the Cancer and Leukemia Group B, grant no. CA32102 to the Southwest Oncology Group, and grant no. CA21115 to the Eastern Cooperative Oncology Group, and by the National Cancer Institute of Canada. Research was also supported by a grant from Berlex Laboratories, Inc, to The CALGB Foundation.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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42. Latagliata R, Petti MC, Fenu S, et al: Therapy-related myelodysplastic syndrome: Acute myelogenous leukemia in patients treated for acute promyelocytic leukemia—An emerging problem. Blood 99: 822-824, 2002 43. Weiss M, Glenn M, Maslak P, et al: Consolidation therapy with high-dose cyclophosphamide reduces minimal residual disease in patients with chronic lymphocytic leukemia. Blood 88: 481a, 1996 (suppl 1, abstr 1911)
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
