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© 1999 American Society for Clinical Oncology Second Malignancies as a Consequence of Nucleoside Analog Therapy for Chronic Lymphoid LeukemiasFrom the The Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda; and the EMMES Corporation, Potomac, MD. Address reprint requests to Bruce D. Cheson, MD, National Cancer Institute, Executive Plaza North, Rm 741, Bethesda, MD 20892; email chesonb{at}ctep.nci.nih.gov
PURPOSE: The nucleoside analogs fludarabine, 2'-deoxycoformycin (DCF), and 2-chlorodeoxyadenosine (CdA), commonly used in the treatment of patients with indolent lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL), are associated with myelosuppression and profound and prolonged immunosuppression. These complications raise the possibility of an increase in secondary malignancies in patients whose disease already places them at greater risk. The purpose of the present study was to assess the frequency of second tumors in patients with CLL who are treated with fludarabine and in patients with HCL who are treated with DCF and CdA. PATIENTS AND METHODS: We reviewed the long-term follow-up data for 2,014 patients treated on National Cancer Institute Group C protocols with fludarabine for relapsed and refractory CLL and with DCF and CdA for HCL using a Second Cancer Report. The numbers of observed and expected secondary tumors were compared. RESULTS: Median follow-up periods for the DCF (n = 409), fludarabine (n = 724), and CdA (n = 979) studies were 6.9, 7.4, and 5.1 years, respectively. The 111 malignancies were most commonly lymphoma (25 patients), prostate (19), lung (15), colorectal (nine), bladder (six), and breast (six), but also CNS, stomach, ovary, head and neck, melanoma, sarcoma, testicular, and myeloid leukemias. Compared with age-adjusted 1994 Surveillance and Epidemiology End-Results rates for the general population, the observed/expected frequencies for DCF, fludarabine, and CdA were 1.43 (95% confidence interval [CI], 0.93 to 2.10), 1.65 (95% CI, 1.04 to 2.47), and 1.50 (95% CI, 1.14 to 1.93), respectively, indicating a significant (at P = .05) increase in risk for patients treated on the latter two protocols compared with a normal population. However, these values are consistent with the increase already associated with these diseases. CONCLUSION: Despite their immunosuppression, nucleoside analogs can be safely administered to patients with CLL or HCL without a significantly increased risk of secondary malignancies.
THE NUCLEOSIDE ANALOGS fludarabine, 2'-deoxycoformycin (pentostatin; DCF) and 2-chlorodeoxyadenosine (cladribine; CdA) have revolutionized our approach to the treatment of patients with indolent lymphoid malignancies. Fludarabine is the most effective agent for the treatment of alkylator-refractory chronic lymphocytic leukemia (CLL) and is being increasingly used as initial treatment for patients with this disease.1-3 DCF and CdA are comparably effective in hairy cell leukemia (HCL) and are the two preferred treatment options.4,5 The toxicity profiles are similar for all three of these drugs and include moderate myelosuppression and profound and prolonged immunosuppression. After administration, there is a rapid decrease in the number of circulating lymphocytes, particularly CD4+ cells, with a reduction in the other mononuclear cell subsets that seems to be less prominent and more transient. The number of CD4+ cells does not return to normal for a year or longer after fludarabine therapy,6 and for more than 3.5 years after treatment with DCF or CdA.5,7-11 One result of this immunosuppression is an increase in opportunistic infections.12-14 An additional potential consequence of the prolonged immunosuppression related to nucleoside analog therapy is an increased risk for a secondary malignancy in a group of patients whose disease already places them at a greater risk for second cancers.15-17 Because of this concern, the current study was designed to evaluate the incidence of secondary malignancies in patients with CLL and HCL who are exposed to nucleoside analog therapy on the National Cancer Institute (NCI) Group C protocols. The Group C mechanism was established in 1976 by an agreement between the NCI and the United States Food and Drug Administration to provide safe and effective therapies to patients who otherwise would not be able to receive them. Drugs placed in Group C have demonstrated safety and efficacy and are able to be administered by properly trained physicians without specialized supportive care facilities. All physicians with a Form 1572 on file with the United States Food and Drug Administration may request Group C agents. Patient-specific data for selected Group C agents are collected using a Group C protocol at the discretion of the Cancer Therapy Evaluation Program/NCI. Three purine analogs, DCF, fludarabine, and CdA, were selected for Group C protocols. In 1997, we first suggested that nucleoside analog therapy might increase the risk for second malignancies.18 The analyses that follow describe that our long-term follow-up of the second cancer experience after treatment on these three Group C protocols suggests that such an increase was not confirmed.
The Group C protocols sponsored by the NCI Cancer Therapy Evaluation Program using nucleoside analogs in lymphoid malignancies included a single trial in patients with alkylator-refractory CLL (I89-0018) and two sequential studies first using DCF (I88-0015) and then CdA (I91-0019) for patients with HCL, either as initial treatment, after splenectomy, or, in the case of some patients on CdA, after treatment with DCF. A total of 2,179 patients were registered to the three Group C trials by 1,334 physicians during the period of October 20, 1988, through March 26, 1993 (Table 1). Baseline and treatment information for the 2,014 treated patients is provided in Table 2. Patients were entered from 24 countries, with 28% of the participants registered from outside of the United States. Seventeen cases were treated on both HCL protocols (I88-0015 and I91-0019); information for these 17 cases is included only for their initial treatment on protocol I88-0015.
The recommended dose of fludarabine on I89-0018 was 25 mg/m2 administered intravenously for 5 consecutive days per month. DCF was to be delivered at a dose of 4 mg/m2 intravenously every 14 days, and CdA at 1 mg/kg by continuous intravenous infusion for 7 days. The patients, methods, and response data from these trials have been published previously.19-21 Baseline information was collected at the time of registration; follow-up (including toxicity and response assessment) was continued at 6-month intervals until patient death. During the spring of 1995, a decision was made to collect information on secondary malignancies. A Second Cancer Report Form was designed and distributed (one form for each of 2,014 treated patients); 1,793 (89%) were returned with information on second cancers. Additionally, the Long-Term Follow-Up Form for each of the studies was modified to prospectively collect information on new secondary malignancies. These forms were submitted by the investigators every 6 months until patient death. With these two mechanisms, we were able to obtain information on secondary malignancies for 1,814 patients (90%). Information was collected on malignancies occurring before and after Group C protocol therapy to identify recurrent disease. Malignancies occurring at least 2 months after the start of protocol treatment were included in the analyses. Patients who developed large-cell non-Hodgkin's lymphoma (Richter's syndrome) on protocol I89-0018 (fludarabine in CLL) were noted but were excluded from the analyses because of the possibility that this additional lymphoid malignancy represented a natural progression of CLL. Nonmelanotic skin cancers were also excluded from the excess risk calculation because the Surveillance and Epidemiology End-Results (SEER) rates used for the calculation of the expected number of cancers excludes these tumors. To estimate the risk of second malignancies, sex-specific person-years at risk were tabulated in 5-year categories. The time at risk for second malignancy was computed from 2 months after the start of protocol treatment. Expected numbers of cancer cases were obtained by multiplying SEER 5-year age- and sex-specific incidence rates by the accumulated person-years at risk. To determine whether there was an excess in the rate of second malignancies, an observed-to-expected ratio (O/E) was calculated. The 95% confidence intervals (CI) for O/E were based on the assumption that the observed numbers of second malignancies followed a Poisson distribution. The Cochran-Armitage trend test was used to test for dose response.22,23
A total of 150 second cancers occurring after the start of protocol therapy have been reported among 146 patients; 11 of these cancers (11 patients) occurred within 2 months of the start of treatment and are excluded from the analysis (Table 3). Eight events were nonmelanotic skin cancers, 18 were large-cell non-Hodgkin's lymphomas occurring on I89-0018 (fludarabine in CLL), and two of the events seemed to be recurrences of cancers that were diagnosed before the start of protocol therapy. These 28 are also excluded, leaving 111 events (among 109 patients) occurring at least 2 months after the start of protocol therapy. A breakdown by protocol and site is provided in Table 4.
The excess frequencies (O/E) of second malignancies for DCF, fludarabine, and CdA studies were 1.43 (95% CI, 0.93 to 2.10), 1.65 (95% CI, 1.04 to 2.47), and 1.50 (95% CI, 1.14 to 1.93), respectively (Table 5). For the fludarabine and CdA protocols, the lower boundary excludes 1, indicating a statistically significant (P = .05) increase in risk for this group of patients when compared with age-adjusted healthy controls. However, there is a known increase in risk of secondary malignancies for CLL and HCL patients as a whole, and the increase that occurs as a result of treatment cannot be evaluated with these data.24-32
The excess risk of second malignancies in women seemed to be greater than that of men: 1.67 versus 1.38 (DCF), 2.18 versus 1.52 (fludarabine), and 2.24 versus 1.36 (CdA) for women and men, respectively. No significant trend in frequency of second malignancies was detected with an increase in the number of courses of therapy (P = .53, .09, and .27 for DCF, fludarabine, and CdA, respectively). There were no significant differences in occurrence of secondary malignancies observed with respect to the specific agents or within subgroups based on the extent of prior therapy. The effect of potential prognostic factors was evaluated overall and within protocols; the results are presented in Table 2. No factors that were examined seemed to predict the occurrence of a second tumor.
Purine analog therapy induces profound and prolonged immunosuppression, which increases the risk for opportunistic infections and, potentially, secondary malignancies. CD4+ counts are primarily affected, decreasing within weeks of the start of treatment. CD4+ counts decrease below 150/µL during therapy and remain depressed for a year or longer after fludarabine treatment for CLL.6 A similar but more prolonged decrease in CD4+ counts is observed after therapy with CdA. Seymour et al10 reported their experience with CdA in patients with HCL. The median CD4 count before treatment was 743/µL, which attained a nadir CD4+ count of 139/µL. The median time to reach 365 CD4+ cells/µL, which represents the lower limit of normal, was 40 months. In a longer follow-up of 15 patients, the same investigators found that the median time to attaining the lower limit of normal for CD4+ and CD8+ cells were 54 months and 36 months, respectively.11 The duration of immunosuppression may be even longer after DCF therapy.7-9,11 Secondary malignancies occur with increased frequency in patients with HCL and CLL; such malignancies are related both to the immune defects associated with these diseases as well as the consequences of therapy.17,18,26,30-42 In CLL, the most frequent of these are lung cancers and melanomas; others include Hodgkin's disease, essential thrombocythemia, multiple myeloma, acute myeloid leukemia, and chronic myeloid leukemia (the latter two occur primarily after extensive alkylating agent therapy).34,36,38,43 Several studies have noted the increased frequency of secondary malignancies in patients with CLL treated with alkylating agents such as chlorambucil. The occurrence of secondary malignancies from these drugs may relate both to the specific agent as well as to the schedule of administration.42 The French Cooperative Group on CLL conducted two large successive trials in patients with early stage (Binet A) disease. In the first, 609 patients were randomized to either daily oral chlorambucil until disease progression or to no initial therapy. Not only was there no difference in survival, but there was a significantly higher frequency of secondary solid tumors in the group with initial therapy. These malignancies were primarily breast, skin, and colon cancer and acute leukemias. In their next study of 926 patients, the treated group received intermittent chlorambucil and prednisone delivered for 5 days per month for 3 years. Again, there was no survival advantage to early intervention; however, the increase in second tumors was not observed. Studies conducted before the use of interferon (IFN) or nucleoside analogs in HCL suggested that these patients are more likely to have second cancers.17,24 Genitourinary cancers occur with a marked frequency, notably prostate cancer, which is consistent with the present experience. Although these second malignancies are most often solid tumors, there are anecdotal reports of secondary lymphomas.27,44 Bernstein et al24 observed that second malignancies occurred in patients with HCL with an expected frequency that is twice that of a normal population. These tumors presented either concurrently or before a year of HCL diagnosis, which led the authors to speculate that the association was the result of an immune defect. In a study from the University of Chicago of 172 patients with HCL,17 there were 15 second tumors (most often of the skin, followed by lung cancer). The second malignancy was diagnosed before HCL in one patient, concurrent with the diagnosis of HCL in six, and after the diagnosis of HCL was established in eight. In another report from the same institution, of 69 patients who were treated with IFN, seven developed a second malignancy at a median follow-up of 79 months.28 At a median of 91 months (range, 0.2 to 109 months),45 the excess frequency was 4.33 compared with the SEER database. The risk was greater for hematologic malignancies, which behaved aggressively and were associated with a median survival duration of 8.8 months. The authors related these tumors to the prolonged survival of these patients, rather than to a direct oncogenic effect of the IFN. Several studies have evaluated the risk of secondary malignancies in patients with HCL after treatment with alpha interferon, DCF, or CdA.5,25,29,32,46-51 A report from the British Columbia Cancer Agency32 included 117 patients with HCL who were diagnosed between 1976 and 1996. Therapy included splenectomy in 23 patients, IFN in 65, DCF in 24, and CdA in 67. At a median follow-up of 68 months, a second malignancy was diagnosed in 36 patients (30.5%), with a total of 44 tumors. Multiple second malignancies were identified in 5% of patients. The tumor was diagnosed before the diagnosis of HCL in 12 patients (10.2%), concurrently with HCL in three patients (2.6%), and after HCL in 25 patients (21.3%). Second malignancies were diagnosed at a median of 40 months after HCL. As in the present series, prostate cancer was the most commonly encountered second tumor. The relative rate of a second malignancy compared with age- and sex-matched controls was 2.91 (P < .001) among men and 1.85 (P = .23) among women. The relative risk (RR) did not differ among the various treatment groups (RR = 0.21 to 3.81 for splenectomy, 0.60 to 5.59 for nucleoside analogs, 1.60 to 4.31 for IFN followed by purine analogs, and 1.57 to 8.40 for IFN alone). The risk of cancer risk peaked at 2 years and decreased steadily after that point. The authors concluded that the risk of second tumors was related to the underlying disease rather than to treatment effect. Kurzrock et al29 reported on the M.D. Anderson experience with 350 patients with HCL and compared their risk of second tumors with data from the Connecticut Tumor Registry. The median age of their patients was relatively young (50 years), and the median follow-up was 6 years. There were 26 patients with a second tumor after the diagnosis of HCL (O/E of 1.34, which was P =.08). However, the increase in lymphoproliferative disorders was significant (two cases of myeloma, two of lymphoma, and one of Waldenström's macroglobulinemia) because of the low expected rate. An additional 14 patents had a tumor diagnosed before the diagnosis of HCL. The solid tumors occurring after HCL were primarily prostate, head and neck, and melanoma. There were no synchronous tumors, but two patients who had a tumor before HCL developed another after HCL. There was no apparent increase when analyzed by treatment (IFN, n = 146 and O/E = 1.04; DCF, n = 15 and O/E = 0.83; or CdA, n = 126 and O/E = 1.22). In a report of the long-term follow-up of 24 patients with HCL treated with DCF, there was one case of stage IA Hodgkin's disease that was diagnosed 70 months after therapy, as well as a recurrence of basal and squamous cell carcinomas of the skin; two other patients developed a basal cell skin cancer at 5 years and multiple squamous cell tumors at 4 years.48 In the North American Hairy Cell Leukemia trial, which involved a comparison between IFN and DCF in previously untreated patients, second malignancies other than skin cancers were noted in 25 of 241 patients who received DCF; these were solid tumors in 18 patients and leukemia or lymphoma in seven.49 In a long-term follow-up of the original CdA experience,5 there were 349 patients; 27 (8%) developed a second malignancy at an O/E of 1.88 (95% CI, 1.24 to 2.74). They interpreted these data to suggest an increase in second tumors, which they attributed to the older age of the patients, patient sex (a preponderance of males and frequency of prostate cancer), and the longer survival of these patients resulting from newer and more effective therapy. Almost one half of these tumors were of the prostate. The median time from CdA treatment to the development of the second tumor was 21 months (62 months from diagnosis of HCL). The survival time from the onset of the second malignancy was a median of 36 months. Hoffman et al51 treated 49 patients with CdA for HCL and found five second tumors in four patients; two tumors were genitourinary. Tallman et al50 treated 50 patients, with the single second malignancy being prostate cancer in a 70-year-old man. The present study assessed the frequency of second tumors in 2,014 patients treated on NCI Group C protocols using fludarabine for patients with CLL and DCF and CdA for patients with HCL. A significant increase (P < .05) in second malignancies was noted for the fludarabine and CdA protocols when compared with the NCI/SEER data (1994). These tumors were mostly lymphomas, genitourinary tumors (primarily prostate), and gastrointestinal and lung cancers. However, the RR seems to be similar to that which has been reported previously for these diseases before the nucleoside analog era. These results suggest that there is only a minor increase in the frequency of second cancers in this patient group compared with the general population. Although differences in populations and methodology do not allow for a formal statistical comparison, there seems to be no additional risk of second malignancies associated with the use of these highly effective agents. Nevertheless, continued observation and reporting for living patients are ongoing. There is no clear explanation for why such immunosuppressive agents do not increase the risk of secondary tumors. This discrepancy may reflect the shorter duration of treatment, the intermittent nature of the therapy, and the fact that, whereas CD4 counts decrease rapidly with each of the analogs, the other mononuclear cell populations return to normal sooner. In addition, cytogenetic abnormalities may occur subsequent to therapy with drugs such as alkylating agents; these defects have not yet been reported in association with nucleoside analogs. The nucleoside analogs do not seem to meaningfully add to the risk of secondary malignancies that is already associated with the diagnosis of CLL or HCL. These agents should continue to be considered the most effective treatment available for these disorders.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests. Biometrics10:417-451, 1954
