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• W2100093952 abstract "Background & Aims: Studies to date have not confirmed an association between neoplasms and inflammatory bowel disease (IBD) treated with 6-mercaptopurine (6-MP). We have observed the occurrence of some neoplasms in IBD patients who developed sustained leukopenia as a result of treatment with 6-MP. As a result, we sought to compare the incidence of neoplasms in patients who developed sustained leukopenia after taking 6-MP compared with patients treated with 6-MP without sustained leukopenia. Methods: A database containing the medical records of more than 600 patients treated with 6-MP for IBD at 1 center between 1965 and 2002 was searched. The patients were divided into 2 groups. The study group consisted of patients who developed sustained leukopenia, defined as a white blood cell count of less than 4000 for 20 or more days. The control group patients matched those in the study group for age and sex. There were 3 matched controls for each patient in the study group. Results: Eighteen patients developed sustained leukopenia and, of these, 4 developed neoplasms (22%)—2 leukemias, 1 non-Hodgkin’s lymphoma, and 1 breast cancer. Of the 54 patients in the control group, 4 developed neoplasms (7%) (P = .10). Post hoc analysis revealed a statistically significant difference in the number of hematologic malignancies in the group with sustained leukopenia (P = .014). There was no significant difference between the 2 groups for all confounding variables examined. Conclusions: There was a trend toward a greater number of total malignancies in the sustained leukopenic patients. The data suggest that it is those patients who develop sustained leukopenia while taking 6-MP/azathioprine who are most at risk. Background & Aims: Studies to date have not confirmed an association between neoplasms and inflammatory bowel disease (IBD) treated with 6-mercaptopurine (6-MP). We have observed the occurrence of some neoplasms in IBD patients who developed sustained leukopenia as a result of treatment with 6-MP. As a result, we sought to compare the incidence of neoplasms in patients who developed sustained leukopenia after taking 6-MP compared with patients treated with 6-MP without sustained leukopenia. Methods: A database containing the medical records of more than 600 patients treated with 6-MP for IBD at 1 center between 1965 and 2002 was searched. The patients were divided into 2 groups. The study group consisted of patients who developed sustained leukopenia, defined as a white blood cell count of less than 4000 for 20 or more days. The control group patients matched those in the study group for age and sex. There were 3 matched controls for each patient in the study group. Results: Eighteen patients developed sustained leukopenia and, of these, 4 developed neoplasms (22%)—2 leukemias, 1 non-Hodgkin’s lymphoma, and 1 breast cancer. Of the 54 patients in the control group, 4 developed neoplasms (7%) (P = .10). Post hoc analysis revealed a statistically significant difference in the number of hematologic malignancies in the group with sustained leukopenia (P = .014). There was no significant difference between the 2 groups for all confounding variables examined. Conclusions: There was a trend toward a greater number of total malignancies in the sustained leukopenic patients. The data suggest that it is those patients who develop sustained leukopenia while taking 6-MP/azathioprine who are most at risk. 6-mercaptopurine (6-MP) and azathioprine (AZA) are established therapies for the treatment and maintenance of remission in ulcerative colitis1Korelitz B.I. Wisch N. Long term therapy of ulcerative colitis with 6-mercaptopurine a personal series.Am J Dig Dis. 1972; 17: 111-118Crossref PubMed Scopus (23) Google Scholar, 2Adler D.J. Korelitz B.I. The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis.Am J Gastroenterol. 1990; 85: 717-722PubMed Google Scholar, 3Su C.G. Stein R.B. Lewis J.D. et al.Azathioprine or 6-mercaptopurine for inflammatory bowel disease do risks outweigh benefits?.Dig Liver Dis. 2000; 32: 518-531Abstract Full Text PDF PubMed Google Scholar and for the treatment, maintenance of remission, and prevention of postoperative recurrence in Crohn’s disease.3Su C.G. Stein R.B. Lewis J.D. et al.Azathioprine or 6-mercaptopurine for inflammatory bowel disease do risks outweigh benefits?.Dig Liver Dis. 2000; 32: 518-531Abstract Full Text PDF PubMed Google Scholar, 4Present D.H. Korelitz B.I. Wisch N. et al.Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (983) Google Scholar, 5Korelitz B.I. Adler D.J. Mendelsohn R.A. et al.Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease.Am J Gastroenterol. 1993; 88: 1198-1205PubMed Google Scholar, 6Hanauer S.B. Korelitz B.I. Rutgeerts P. et al.Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo a 2- year trial.Gastroenterology. 2004; 127: 723-729Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar Although we now have more than 35 years of experience with the use of these drugs in inflammatory bowel disease (IBD), questions still remain about their long-term safety, specifically regarding their potential predisposition to the development of malignancies.7Korelitz B.I. Mirsky F.J. Fleisher M.R. et al.Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.Am J Gastroenterol. 1999; 94: 3248-3253Crossref PubMed Google Scholar, 8Warman J.I. Korelitz B.I. Fleisher M.R. et al.Cumulative experience with short and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis.J Clin Gastroenterol. 2003; 37: 220-225Crossref PubMed Scopus (86) Google Scholar Most of the complications of 6-MP therapy seem to occur early and are reversible on discontinuation of the drug.8Warman J.I. Korelitz B.I. Fleisher M.R. et al.Cumulative experience with short and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis.J Clin Gastroenterol. 2003; 37: 220-225Crossref PubMed Scopus (86) Google Scholar Malignant tumors, however, sometimes have occurred many years after the institution of therapy and sometimes after the cessation of therapy.7Korelitz B.I. Mirsky F.J. Fleisher M.R. et al.Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.Am J Gastroenterol. 1999; 94: 3248-3253Crossref PubMed Google Scholar To date, there has been no confirmatory evidence that 6-MP and AZA predispose to malignancies in IBD,9Connell W.R. Kamm M.A. Dickson M. et al.Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.Lancet. 1994; 343: 1249-1252Abstract PubMed Scopus (466) Google Scholar, 10Fraser A.G. Orchard T.R. Robinson E.M. et al.Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.Aliment Pharmacol Ther. 2002; 16: 1225-1232Crossref PubMed Scopus (171) Google Scholar, 11Farrell R.J. Ang Y. Kileen P. et al.Increased incidence of non-Hodgkin’s lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low.Gut. 2000; 47: 514-519Crossref PubMed Scopus (198) Google Scholar although a recently published meta-analysis suggests an approximately 4-fold increased risk for lymphoma in IBD patients treated with AZA/6-MP.12Kandiel A. Fraser A.G. Korelitz B.I. et al.Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.Gut. 2005; 54: 1121-1125Crossref PubMed Scopus (672) Google Scholar This result must be tempered by the fact that IBD alone may predispose to a higher incidence of lymphomas and/or leukemias,13Bernstein C.N. Blanchard J.F. Kliewer E. et al.Cancer risk in patients with inflammatory bowel disease a population-based study.Cancer. 2001; 91: 854-862Crossref PubMed Scopus (1023) Google Scholar, 14Greenstein A.J. Mullin G.E. Strauchen J.A. et al.Lymphoma in inflammatory bowel disease.Cancer. 1992; 69: 1119-1123Crossref PubMed Scopus (139) Google Scholar, 15Arseneau K.O. Stukenborg G.J. Connors Jr, A.F. et al.The incidence of lymphoid and myeloid malignancies among hospitalized Crohn’s disease patients.Inflamm Bowel Dis. 2001; 7: 106-112Crossref PubMed Scopus (48) Google Scholar, 16Palli D. Trallori G. Bagnoli S. et al.Hodgkin’s disease risk is increased in patients with ulcerative colitis.Gastroenterology. 2000; 119: 647-653Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 17Askling J. Brandt L. Lapidus A. et al.Risk of haematopoietic cancer in patients with inflammatory bowel disease.Gut. 2005; 54: 617-622Crossref PubMed Scopus (173) Google Scholar although this has not been supported universally.18Lewis J.D. Bilker W.B. Brensinger C. et al.Inflammatory bowel disease is not associated with an increased risk of lymphoma.Gastroenterology. 2001; 121: 1080-1087Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Patients who develop leukopenia while taking 6-MP or AZA for IBD may have an earlier and more profound response to therapy.19Colonna T. Korelitz B.I. The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn’s disease.Am J Gastroenterol. 1994; 89: 362-366PubMed Google Scholar However, in the patients who develop a sustained leukopenia we suspect, as a result of our clinical observations, a higher incidence of the development of malignancies. Therefore, we set out to determine in this controlled study if sustained leukopenia, induced by 6-MP therapy for IBD, predisposes to an increased risk for the development of malignancy. The study design was a retrospective search of a database containing the medical records of more than 600 patients treated with 6-MP for IBD in 1 private practice of gastroenterology and at the Inflammatory Bowel Disease Center at Lenox Hill Hospital from 1965 to 2002. No patients were included in the study if they were referred to us because of an existing neoplasm or in whom a neoplasm was discovered within 1 year of our meeting the patient. 6-MP flow charts were reviewed for each patient. These charts contained all 6-MP dosing information, the results of all complete blood counts (CBCs) obtained during the monitoring period, the directions for continuing or changing the dose, and the recommended time until the next blood count. In the instances in which a flow sheet was unavailable, a thorough search of the entire chart was performed to obtain this information. Very few patients included in the study were on 6-MP before entering this study. In all cases, we were satisfied that we had obtained a complete history of their medication usage, including any history of leukopenia (and if there was a history of leukopenia, it was quantified). The patients subsequently were divided into 2 groups. The study group consisted of patients who developed sustained leukopenia, defined as a white blood cell count of less than 4000 for more than 20 days. To qualify for this group, the patient must have had at least 3 blood counts performed during the 20-day period or longer to satisfy the investigators that sustained leukopenia was indeed present. The control group patients, those without 20 or more consecutive days of leukopenia, were matched to the study group patients for age and sex (men vs women). Because we had only 18 patients in our sustained leukopenic group and many more control patients available to us, we decided to match 3 controls for each leukopenic patient to increase the power of our study. The rate of malignancy in the control group was 7%. Our study was designed to detect a 30% difference in malignancy rate between the leukopenic and control groups with an 80% power and a .05 error rate. Data collected for the 2 groups included type of IBD, disease location, CBCs, all 6-MP dosing information, patient malignancy history, family history for neoplasms, and smoking history. A 2.08 conversion factor was used to convert a dose of 6-MP to AZA.20Sandborn W.J. Rational dosing of azathioprine and 6-mercaptopurine.Gut. 2001; 48: 591-592Crossref PubMed Scopus (121) Google Scholar The lowest and highest listed doses of 6-MP were recorded. When the dose was listed in terms of the number of milligrams of 6-MP to be taken over the course of a week, that number was divided by 7 to arrive at the daily dosage. Basal cell carcinomas and malignancies that occurred in patients before starting 6-MP were excluded from the analysis. Continuous parametric data were analyzed using matched-samples t tests and are presented as mean ± SD, and nonparametric (categoric) data were analyzed using the Wilcoxon test and are presented as counts or proportions (percentage). Baseline demographic and clinical characteristics were examined for statistically significant differences. The Kaplan–Meier survival analysis was used to compare time from onset of 6-MP (Teva Pharmaceuticals, North Wales, PA) to malignancy between the 2 groups. A P value of less than .05 was a priori considered statistically significant. SPSS (11.5) statistical software (SPSS Inc., Chicago, IL) was used for all analyses. Eighteen patients were identified in the study group who satisfied our criteria for sustained leukopenia. Because each leukopenic patient was matched to 3 controls, there were 54 patients in the control group. The baseline characteristics of the patients in the 2 groups are listed in Table 1. There were an equal number of men (50%) and women (50%) in each group. In the study group there were 12 patients with Crohn’s disease and 6 patients with ulcerative colitis. There was no significant difference between the 2 groups in terms of location of disease within the small and large intestine (Table 2), previous use of cigarettes (P = .38), and family history of cancer (P = .43) (see Supplemental Table 1 at www.cghjournal.org).Table 1Patient Demographics and Baseline CharacteristicsGroup 1 (N = 18)Group 2 (3 controls per study patient) (N = 54)P valuesMen:women9:927:27.607Patients with Crohn’s disease1233Patients with ulcerative colitis621Mean age at IBD diagnosis26.6 ± 8.428.3 ± 11.8.557Mean age at which 6-MP was started42.0 ± 11.338.0 ± 13.0.253Mean 6-MP low dose, mg14.6 ± 17.943.2 ± 18.8<.001Mean 6-MP high dose, mg89.4 ± 40.388.6 ± 28.5.928Cigarette smokers313.383Family history of cancer615.432 Open table in a new tab Table 2Location of DiseaseLocation of diseaseNumber of patients in group 1Number of patients in group 2Left colon13Right colon01Pancolitis525Small intestine and colon1224Small intestine alone01 Open table in a new tab Some patients had treatment with 6-MP that began after 2002; all but 1 of these patients also received 6-MP before 2002. There were 3 patients in the study group who had episodes of sustained leukopenia after 2002, but 2 of these patients also had episode(s) of sustained leukopenia before 2002. The range of 6-MP dosing for each patient (mg/kg) is provided in Supplemental Table 1. The mean 6-MP low dose was significantly lower in the sustained leukopenic group as compared with the control group, 14.56 mg/day (SD, 17.95; 95% confidence interval, 5.63–23.48) vs 43.19 mg/day (SD, 18.83; 95% confidence interval, 38.00–48.39) (P = .00). There was no significant difference in the mean 6-MP high dose in the sustained leukopenic group, 89.39 (±40.3) mg/day vs the mean 6-MP high dose in the control group, 88.60 (±28.5) mg/day (P = .928). There was no significant difference in the mean age at which 6-MP was started between the 2 groups (P = .253). Eleven of the 54 control group patients (20%) developed a nonsustained leukopenia (see Supplemental Table 1 at www.cghjournal.org). Duration of leukopenia for the study group patients and duration of exposure to 6-MP for all patients is provided in Supplemental Table 1. There were 4 malignancies per 157 patient-years of follow-up evaluation in the study group and 4 malignancies per 400 patient-years of follow-up evaluation in the control group (P = .10). The malignancies in the study group included 2 leukemias, 1 non-Hodgkin’s lymphoma, and 1 breast cancer, whereas those in the control group included 1 each of colon, breast, ovary, and brain cancer. Post hoc analysis revealed a statistically significant increase in the number of hematologic malignancies between the leukopenic and control groups (P = .014). Leukopenic patients developed malignancies at ages 54, 58, 65, and 57 for an average of 58.5 ± 4.6 years, and patients in the control group developed malignancies at ages 48, 68, 65, and 32 for an average of 53.3 ± 16.7 years. There was no difference between the 2 groups (P = .53) in age at onset of malignancy despite the patient in the control group who developed a malignancy at the age of 32 (see Supplemental Table 1 at www.cghjournal.org). There was no difference between the leukopenic and the control group in terms of the rapidity with which the malignancy developed after the patient began taking 6-MP (P = .22) (Figure 1). Two of the 4 patients developing a malignancy in both the study and control groups had a family history of malignancy, and 1 patient in each group had an additional malignancy. In the study group, the patient who developed breast cancer had a mother who had ovarian cancer and another first-degree relative with colon cancer; in addition, 1 of the patients who developed leukemia had a mother who had lung cancer. This patient with leukemia also had a skin cancer. No other study patients with malignancy also had a concurrent malignancy. In the control group, the patient who developed colon cancer had a grandfather who had Hodgkin’s lymphoma and a patient with breast cancer had a mother with lymphoma and a daughter with breast cancer. The patient with the brain tumor also had a history of prostate cancer. This study was terminated with patient visits ending in 2001 and no patient received infliximab. The only immunomodulators used were 6-MP and AZA, except for a rare instance of methotrexate. No patient taking methotrexate developed a neoplasm. We had preliminarily reported a statistically significant increase in the development of malignancies among IBD patients treated with 6-MP who developed sustained leukopenia.21DiSanti W. Rajapakse R.O. Korelitz B.I. et al.Increased incidence of neoplasms in patients who develop sustained leukopenia during or after treatment with 6MP for inflammatory bowel disease.Am J Gastroenterol. 2004; 99: A777Crossref PubMed Scopus (66) Google Scholar Analysis of both re-collected data from our original study patients and data obtained from the addition of new patients has led us to modify our initial conclusion. Although there was only a trend toward a greater number of total malignancies in the sustained leukopenic group, post hoc analysis of our data showed a statistically significant difference only in the number of hematologic malignancies in the group of patients who developed sustained leukopenia during or after treatment with 6-MP. As stated previously, published reports offer conflicting information as to whether IBD alone poses an increased risk for lymphoma and/or leukemia.13Bernstein C.N. Blanchard J.F. Kliewer E. et al.Cancer risk in patients with inflammatory bowel disease a population-based study.Cancer. 2001; 91: 854-862Crossref PubMed Scopus (1023) Google Scholar, 14Greenstein A.J. Mullin G.E. Strauchen J.A. et al.Lymphoma in inflammatory bowel disease.Cancer. 1992; 69: 1119-1123Crossref PubMed Scopus (139) Google Scholar, 15Arseneau K.O. Stukenborg G.J. Connors Jr, A.F. et al.The incidence of lymphoid and myeloid malignancies among hospitalized Crohn’s disease patients.Inflamm Bowel Dis. 2001; 7: 106-112Crossref PubMed Scopus (48) Google Scholar, 16Palli D. Trallori G. Bagnoli S. et al.Hodgkin’s disease risk is increased in patients with ulcerative colitis.Gastroenterology. 2000; 119: 647-653Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 17Askling J. Brandt L. Lapidus A. et al.Risk of haematopoietic cancer in patients with inflammatory bowel disease.Gut. 2005; 54: 617-622Crossref PubMed Scopus (173) Google Scholar, 18Lewis J.D. Bilker W.B. Brensinger C. et al.Inflammatory bowel disease is not associated with an increased risk of lymphoma.Gastroenterology. 2001; 121: 1080-1087Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Furthermore, there has been no consensus as to a causative role of AZA/6-MP in the development of hematologic malignancies.9Connell W.R. Kamm M.A. Dickson M. et al.Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.Lancet. 1994; 343: 1249-1252Abstract PubMed Scopus (466) Google Scholar, 10Fraser A.G. Orchard T.R. Robinson E.M. et al.Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.Aliment Pharmacol Ther. 2002; 16: 1225-1232Crossref PubMed Scopus (171) Google Scholar, 11Farrell R.J. Ang Y. Kileen P. et al.Increased incidence of non-Hodgkin’s lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low.Gut. 2000; 47: 514-519Crossref PubMed Scopus (198) Google Scholar, 12Kandiel A. Fraser A.G. Korelitz B.I. et al.Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.Gut. 2005; 54: 1121-1125Crossref PubMed Scopus (672) Google Scholar In our study group we had 2 leukemias out of 18 patients. One patient was diagnosed in 1996 and the other in 2001. According to the National Institutes of Health Surveillance, Epidemiology, and End Results (SEER) data base, the age-adjusted incidence rate for leukemia was 12.2 per 100,000 men and women per year from 1998 to 2002. The higher rate observed in our study supports the potential link between 6-MP and hematologic malignancies and also raises the possibility that it is only within the subset of 6-MP or AZA patients who develop sustained leukopenia in whom the risk for hematologic malignancy is increased. This is a finding that should provoke larger studies on this topic. Of the 3 patients with hematologic malignancies, 2 developed their episode of sustained leukopenia within a few months of their malignancy diagnosis. This raises the possibility that the sustained leukopenia did not predispose these patients to malignancy but actually was the earliest indication of their malignancy. One patient had been on 6-MP for 7 years before developing sustained leukopenia and shortly thereafter was diagnosed with a non-Hodgkin’s lymphoma. The second patient also was on 6-MP for 7 years before developing sustained leukopenia and shortly thereafter was diagnosed with leukemia. The other study patient who developed leukemia was on 6-MP for the better part of 4 years and had 4 separate incidents of sustained leukopenia, the longest of which lasted almost 6 months. This last episode of sustained leukopenia preceded the diagnosis of acute myelogenous leukemia by 3 months. A possible explanation for the overall finding of only a trend toward an increase in any malignancies at all in the sustained leukopenic group is that patients in the control group may have had a higher rate of malignancy than other IBD patients taking 6-MP. In 1999,7Korelitz B.I. Mirsky F.J. Fleisher M.R. et al.Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.Am J Gastroenterol. 1999; 94: 3248-3253Crossref PubMed Google Scholar we reported the malignancy rate in 550 patients in our database who had taken 6-MP. The rate of colon cancer in that study, which also may have included patients with sustained leukopenia, was 1.3%, which was similar to the rate in our control group of 1.9%. The rate of breast cancer in that study, .5%, also was similar to the rate of 1.9% seen in the present study. There was 1 patient with ovarian cancer in that study and 1 in the present study. Judging from these results, we cannot attribute our lack of statistical association as being the result of a higher than usual rate of malignancy for patients in the control group. The mechanism by which 6-MP induces sustained leukopenia and may induce a predisposition to neoplasia is unknown. 6-MP is metabolized along competing routes to 6-thioguanine (6-TG) and to 6-methylmercatopurine, among other metabolites.22Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (905) Google Scholar Many studies have indicated that rates of clinical remission correlate with 6-TG levels.22Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (905) Google Scholar, 23Achkar J.P. Stevens T. Easley K. et al.Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 339-345Crossref PubMed Scopus (44) Google Scholar Studies also have indicated that the levels of 6-TG and 6-methylmercatopurine are responsible for producing both the myelotoxicity and hepatotoxicity of 6-MP.22Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (905) Google Scholar It is possible that both the level of 6-TG and the level of 6-methylmercatopurine effect the development of leukopenia. Measurement of thiopurine methyl transferase (TPMT) genotypes is available to help predict which patients are at a higher likelihood to develop toxicity from 6-MP treatment, although the degree to which this information would be helpful is limited. The majority of patients who develop myelosuppression while taking 6-MP have no detectable TPMT mutations.24Colombel J.F. Ferrari N. Debuysere H. et al.Genotypic analysis of thiopurine S- methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy.Gastroenterology. 2000; 118: 1025-1030Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar Theoretically, low or absent TPMT levels would influence the decision to initiate 6-MP and certainly might prompt a lower starting dose should the decision be made to proceed.25Lobel E.Z. Korelitz B.I. Vakher K. et al.Prolonged remission of severe Crohn’s disease after fever and leukopenia caused by 6-mercaptopurine.Dig Dis Sci. 2004; 49: 336-338Crossref PubMed Scopus (12) Google Scholar On the other hand, the possibility of an acceleration of remission of IBD being achieved as the patients white blood cell count decreases might prompt the clinician to dose 6-MP more aggressively when faced with low TPMT levels.19Colonna T. Korelitz B.I. The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn’s disease.Am J Gastroenterol. 1994; 89: 362-366PubMed Google Scholar, 25Lobel E.Z. Korelitz B.I. Vakher K. et al.Prolonged remission of severe Crohn’s disease after fever and leukopenia caused by 6-mercaptopurine.Dig Dis Sci. 2004; 49: 336-338Crossref PubMed Scopus (12) Google Scholar Because 6-TG, 6-methylmercatopurine, and TPMT levels were not measured, we were unable to compare their levels in our patients with and without sustained leukopenia. It would have been especially interesting to compare these levels in our sustained leukopenic patients vs those patients who developed a more transient leukopenia that resolved with no, or very small, 6-MP dosing modifications. Whether enzyme levels are measured or not, ultimately patients must be monitored very closely clinically and with frequent CBCs while being treated with 6-MP; the appropriate dose adjustments then can be made. We chose to report patients’ high and low doses of 6-MP (in mg and mg/kg) merely to provide a framework of 6-MP exposure for each patient. In our practice, we do not dose 6-MP by body weight; we believe that doing so offers no correlation with efficacy. There also is no conclusive evidence that most toxicity is related to dose. We start all patients at 50 mg/day and alter dose based on leukopenia, toxicity, or lack of efficacy. The cumulative effects of escalating 6-MP exposure over the course of a lifetime increasingly may predispose patients to the development of a malignancy. Supplemental Table 1 shows the total number of days each patient took 6-MP until the conclusion of our study. There are no clear published guidelines by which to define sustained leukopenia. We chose to define sustained leukopenia as a white blood cell count of less than 4000 for more than 20 days, based on the initial observation that many malignancies in our IBD patients on 6-MP had the minimum length of leukopenia of 3 weeks. Our data show that 1 of the 4 patients with sustained leukopenia who developed malignancy had leukopenia in her history lasting 20 and 21 days, and another patient lasting 23 and 25 days. For this reason, we searched our database for those patients with 20 or more days of leukopenia, which then became our definition of sustained leukopenia, and then matched controls, without sustained leukopenia, to this group. The number of CBCs performed within the period of sustained leukopenia was dependent on how low the white blood cell count was and on the length of time that it remained depressed. At the very least, a period of 20 days allowed for 3 CBCs and thus for the development of a trend. In our practice, patients without leukopenia have a progressively increased time interval between CBCs. We chose 4000 to separate leukopenia from nonleukopenia. One of the limitations of our study was that our sample size was limited by the number of sustained leukopenic patients available in the database. The study was designed to detect a 30% difference in the malignancy rate between the sustained leukopenic and control groups. We observed a trend toward increased malignancy in the sustained leukopenic group. Larger studies are required. Only 1 of the 8 malignancies in the study was a colon cancer and it was present in a control patient with a documented history of pancolitis. There were no colon cancers among the sustained leukopenia group. The fact that no colon cancers were found in our study suggests that by maintaining patients in a state of remission, 6-MP might help prevent colon cancer. Even if that state of remission comes at the expense of sustained leukopenia, this study shows that the risk for developing colon cancer is not increased. In conclusion, although the results of this study show only a trend toward a greater number of total malignancies in the group of patients who developed sustained leukopenia during or after treatment with 6-MP, post hoc analysis of the data does support a statistically significant increase in the number of hematologic malignancies in the sustained leukopenic group. With a recent meta-analysis citing an increased risk for lymphoma among IBD patients treated with 6-MP/AZA,12Kandiel A. Fraser A.G. Korelitz B.I. et al.Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.Gut. 2005; 54: 1121-1125Crossref PubMed Scopus (672) Google Scholar this study offers an intriguing corollary to this conclusion—perhaps it is those patients who develop sustained leukopenia while taking 6-MP/AZA who are most at risk for developing these hematologic malignancies. Download .pdf (.04 MB) Help with pdf files Supplemental Table 1. Radiologic, Surgical, and Pathologic Findings of Confirmed Neoplasms in High-Risk Patients" @default.
• W2100093952 created "2016-06-24" @default.
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• W2100093952 date "2006-08-01" @default.
• W2100093952 modified "2023-09-23" @default.
• W2100093952 title "Incidence of Neoplasms in Patients Who Develop Sustained Leukopenia During or After Treatment With 6-Mercaptopurine for Inflammatory Bowel Disease" @default.
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