Prednisone and mercaptopurine. Azathioprine/mercaptopurine/prednisone

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Prednisone and mercaptopurine.



 

Bruce C. Bostrom, Martha R. Sensel, Harland N. Sather, Paul S. Gaynon, Mei K. La, Katherine Johnston, Gary R. Erdmann, Stuart Gold, Nyla A. Heerema, Raymond J. Hutchinson, Arthur J. Provisor, Michael E. Trigg; Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Blood ; 10 : — Conventional therapy for childhood acute lymphoblastic leukemia ALL includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous IV over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine.

The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine.

Intrathecal IT methotrexate was the sole central nervous system—directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system—relapse rate of 3.

There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse. All patients received a 3-drug induction phase and experienced a 3-month consolidation phase with 6-mercaptopurine 6-MP , methotrexate, vincristine and steroid; a 2-month delayed intensification DI phase 2 ; and a or month maintenance phase for girls and boys, respectively.

The details of therapy are depicted in Figure 1. Boldface signifies differences in therapy. In CCG, 2 hypotheses were tested. The first hypothesis was that dexamethasone will be superior to prednisone in preventing central nervous system CNS relapse and provide better event-free survival EFS. Dexamethasone provides better CNS penetration than prednisone. Poor outcome has been linked to a lesser accumulation of intracellular thioguanine nucleotides.

All patients received dexamethasone during delayed intensification and daily oral 6-mercaptopurine during maintenance. CCG opened in March and closed in August Diagnosis of ALL was based on morphologic, biochemical, and flow cytometric features of leukemic cells, including lymphoblast morphology on Wright-Giemsa—stained bone marrow smears, negative staining for myeloperoxidase, and reactivity with monoclonal antibodies to B-lineage—associated or T-lineage—associated lymphoid differentiation antigens, as described before.

The National Cancer Institute and local institutional review boards approved the protocol. Written informed consent was obtained from guardians or patients, as per National Institutes of Health NIH guidelines. Details of therapy are listed in Table 1. Patients with a M2 day marrow required a M1 marrow status by day 14 of consolidation therapy to continue on study.

Girls were treated for approximately 26 months and boys for 38 months. Treatment was modified to adjust for morbidity and to optimize delivery. Therapy was not increased above prescribed doses for patients with persistent elevations of absolute neutrophil count. To evaluate better the morbidity anticipated from the experimental interventions, specific toxicity questions were added to the data forms 14 months after initiation of the study.

The specific toxicities evaluated included avascular necrosis, clinically significant infections determined by treating physician, grade 3 or 4 pancreatitis, steroid-associated proximal myopathy, any CNS toxicity, and hematuria or renal stones.

Leukemic karyotypes were accepted after central review of studies performed at the local institutions. Sample size and power calculations were based on a proportional hazard assumption for the treatment regimen, with few treatment failures assumed after 5 years of follow-up. The study was not designed to detect significant differences in bone marrow relapses. Assignments were randomized at study entry.

Data were analyzed in July using a January cutoff. The primary end point used for life table comparisons of treatment regimen outcomes and prognostic factor effects was EFS, which was defined as the time to first occurrence of any one of the following events: induction death, no response to induction therapy, relapse after remission at any site, death in remission, or second malignant neoplasm. A secondary end point of interest was incidence of isolated CNS relapse as the initial event. Analysis of CNS incidence was done using a cumulative incidence function.

Comparison of treatment regimen outcomes was done with the intent-to-treat approach. EFS and survival life table estimates were done with the Kaplan-Meier KM method, 22 and these estimates are provided at 6 years of follow-up. The standard deviation of the KM estimate was calculated using the Peto variance formula.

Chi-square tests for homogeneity of distributions were used in some comparisons similarity of patient characteristics, patterns of outcome events, etc. Multivariate analysis of prognostic factors was done with the Cox proportional hazards model. Among patients entered on study, 19 were deemed ineligible because of lack of adequate consent or incorrect diagnosis, and one was not assigned randomly.

Among the remaining patients, were assigned randomly to dexamethasone and to prednisone. Canadian institutions that participated in this study were unable to administer IV 6-mercaptopurine on an outpatient basis, and all 30 patients treated at Canadian institutions were not assigned randomly with respect to the 6-MP question.

Among patients assigned randomly with respect to the 6-MP route, were assigned to receive daily oral administration and were randomized to receive weekly IV administration. Presenting characteristics were not significantly different in the treatment groups and are detailed in Table 2. Moderately enlarged, enlarged but above the umbilicus; markedly enlarged, organ below the umbilicus. Normal, shoddy nodes; markedly enlarged, visible nodes; moderate enlargement, neither normal nor markedly enlarged.

Blast percentage in marrow was determined on day 7 of induction therapy. There was no difference in day-7 marrow response or induction end marrow status by randomized steroid. A Event-free survival EFS by randomized steroid. B Event-free survival EFS by 6-mercaptopurine route randomization during consolidation. All patients received oral 6-mercaptopurine during maintenance.

We found no evidence of an interaction between the 2 assigned treatment comparisons. As such there was no difference in EFS between patients assigned to receive oral or IV 6-MP within the dexamethasone or prednisone subsets.

Likewise, the significant improvement in EFS for the overall cohort of patients assigned to receive dexamethasone compared with those assigned to receive prednisone was preserved among subsets of patients treated with daily oral or weekly IV 6-MP. The survival advantage observed among the overall cohort of patients treated with oral 6-MP was preserved among patients who received dexamethasone or prednisone.

Also, survival for patients who received dexamethasone or prednisone was similar within the subsets of patients treated with oral or intravenous 6-MP. The primary reason for treatment failure was marrow relapse. Table 3 lists first events by treatment regimen. As hypothesized, the cumulative incidence of isolated CNS relapse was lower for dexamethasone patients than for prednisone patients, with 6-year cumulative estimates of 3. In addition, dexamethasone patients had a trend toward fewer marrow relapses, with 6-year estimates of 7.

Thus far, 3 second malignancies have been reported Table 3. Univariate analysis of a large number of clinical and laboratory presenting features found adverse prognostic significance of age, spleen enlargement, hypodiploidy, and low hyperdiploidy.

Outcomes were similar for patients with or without acceptable karyotypes. None of the 29 patients with trisomy 10 who were assigned to dexamethasone have relapsed. Outcomes were similar within day-7 marrow status subsets for oral and IV 6-MP patients.

Fungal infections were found in 6 dexamethasone patients and 10 prednisone patients. Viral infections were found in 11 dexamethasone patients and 14 prednisone patients. Incidence of fever and neutropenia and duration of hospital stay were similar between steroid groups, as were supportive care interventions. Six patients died from infections during induction or the month after 0. During delayed intensification, when all patients receive dexamethasone, 5 patients died from infections: 4 prednisone-assigned patients and one dexamethasone-assigned patient.

Infectious deaths during maintenance included 2 patients in the prednisone group Pseudomonas ; alpha-streptococcus and one in the dexamethasone group varicella. Reversible proximal myopathy was seen during induction, early consolidation, and delayed intensification, but not in maintenance. No patient had grade 4 toxicity ie, respiratory embarrassment. Incidence of grades 1 to 3 steroid myopathy during induction and early consolidation was 1. Grade 3 weakness ie, inability to ambulate was seen in 22 dexamethasone patients 4.

Grade 3 myopathy was more common in younger children and boys. During delayed intensification, when all patients received dexamethasone, incidence of myopathy was 0. Weakness was reversible when the steroid was discontinued, and none recurred during monthly 5-day steroid pulses in maintenance.

Incidence of grade 3 or 4 amylase elevation in induction was 1. Symptomatic pancreatitis was reported in 5 dexamethasone patients and one prednisone patient.

All recovered without sequelae. The incidence of grade 3 or 4 ALT elevations was similar among prednisone and dexamethasone patients. Data on specific use of insulin for hyperglycemia was not collected.

Two prednisone patients and one dexamethasone patient were diagnosed with avascular necrosis of the ankles early in maintenance therapy. Two patients had consistent dysesthesia and agitation with each 5-day course of dexamethasone in maintenance.

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By using the site you are agreeing to this as outlined in our privacy notice and cookie policy. Abstract Available from publisher site using DOI. A subscription may be required. C Hermida Search articles by 'C Hermida'. Hermida C ,. Cantero-Perona J ,. Moreno-Otero R. Affiliations 1 author 1. A comment on this article appears in " Low-dose methotrexate in ulcerative colitis: still a matter of debate.

Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract Background As treatment of steroid-dependent patients with inflammatory bowel disease IBD is controversial, we analysed the efficacy and tolerance of 6-mercaptopurine 6-MP and methotrexate MTX added to prednisone in increasing and maintaining the disease remission rate.

Methods Seventy-two steroid-dependent IBD patients, 34 with ulcerative colitis UC and 38 with Crohn's disease CD , receiving treatment with prednisone were randomly assigned in a ratio to additionally receive, orally, over a period of 30 weeks 1. All patients who achieved remission were included in a maintaining remission study for 76 weeks.

With regard to maintaining remission, UC patients in group A Noticeable side effects appeared in Conclusions These results suggest that 6-MP or MTX added to prednisone could be effective in steroid sparing, as well as in achieving and maintaining remission in steroid-dependent IBD patients. MTX was less effective in maintaining remission in UC patients. Full text links Read article at publisher's site DOI : Smart citations by scite.

The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles. Explore citation contexts and check if this article has been supported or disputed. Evidence-based efficacy of methotrexate in adult Crohn's disease in different intestinal and extraintestinal indications.

Indeterminate Colitis - Update on Treatment Options. Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn's disease: a retrospective study. Use of thiopurines in inflammatory bowel disease: an update.

Pancreatitis associated with azathioprine and 6-mercaptopurine use in Crohn's disease: a systematic review. Similar Articles To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review. Methotrexate for maintenance of remission in ulcerative colitis.

Sample size and power calculations were based on a proportional hazard assumption for the treatment regimen, with few treatment failures assumed after 5 years of follow-up. The study was not designed to detect significant differences in bone marrow relapses. Assignments were randomized at study entry. Data were analyzed in July using a January cutoff. The primary end point used for life table comparisons of treatment regimen outcomes and prognostic factor effects was EFS, which was defined as the time to first occurrence of any one of the following events: induction death, no response to induction therapy, relapse after remission at any site, death in remission, or second malignant neoplasm.

A secondary end point of interest was incidence of isolated CNS relapse as the initial event. Analysis of CNS incidence was done using a cumulative incidence function. Comparison of treatment regimen outcomes was done with the intent-to-treat approach. EFS and survival life table estimates were done with the Kaplan-Meier KM method, 22 and these estimates are provided at 6 years of follow-up. The standard deviation of the KM estimate was calculated using the Peto variance formula.

Chi-square tests for homogeneity of distributions were used in some comparisons similarity of patient characteristics, patterns of outcome events, etc. Multivariate analysis of prognostic factors was done with the Cox proportional hazards model. Among patients entered on study, 19 were deemed ineligible because of lack of adequate consent or incorrect diagnosis, and one was not assigned randomly.

Among the remaining patients, were assigned randomly to dexamethasone and to prednisone. Canadian institutions that participated in this study were unable to administer IV 6-mercaptopurine on an outpatient basis, and all 30 patients treated at Canadian institutions were not assigned randomly with respect to the 6-MP question. Among patients assigned randomly with respect to the 6-MP route, were assigned to receive daily oral administration and were randomized to receive weekly IV administration.

Presenting characteristics were not significantly different in the treatment groups and are detailed in Table 2. Moderately enlarged, enlarged but above the umbilicus; markedly enlarged, organ below the umbilicus. Normal, shoddy nodes; markedly enlarged, visible nodes; moderate enlargement, neither normal nor markedly enlarged. Blast percentage in marrow was determined on day 7 of induction therapy. There was no difference in day-7 marrow response or induction end marrow status by randomized steroid.

A Event-free survival EFS by randomized steroid. B Event-free survival EFS by 6-mercaptopurine route randomization during consolidation. All patients received oral 6-mercaptopurine during maintenance. We found no evidence of an interaction between the 2 assigned treatment comparisons.

As such there was no difference in EFS between patients assigned to receive oral or IV 6-MP within the dexamethasone or prednisone subsets. Likewise, the significant improvement in EFS for the overall cohort of patients assigned to receive dexamethasone compared with those assigned to receive prednisone was preserved among subsets of patients treated with daily oral or weekly IV 6-MP.

The survival advantage observed among the overall cohort of patients treated with oral 6-MP was preserved among patients who received dexamethasone or prednisone. Also, survival for patients who received dexamethasone or prednisone was similar within the subsets of patients treated with oral or intravenous 6-MP. The primary reason for treatment failure was marrow relapse. Table 3 lists first events by treatment regimen. As hypothesized, the cumulative incidence of isolated CNS relapse was lower for dexamethasone patients than for prednisone patients, with 6-year cumulative estimates of 3.

In addition, dexamethasone patients had a trend toward fewer marrow relapses, with 6-year estimates of 7. Thus far, 3 second malignancies have been reported Table 3. Univariate analysis of a large number of clinical and laboratory presenting features found adverse prognostic significance of age, spleen enlargement, hypodiploidy, and low hyperdiploidy.

Outcomes were similar for patients with or without acceptable karyotypes. None of the 29 patients with trisomy 10 who were assigned to dexamethasone have relapsed. Outcomes were similar within day-7 marrow status subsets for oral and IV 6-MP patients. Fungal infections were found in 6 dexamethasone patients and 10 prednisone patients.

Viral infections were found in 11 dexamethasone patients and 14 prednisone patients. Incidence of fever and neutropenia and duration of hospital stay were similar between steroid groups, as were supportive care interventions. Six patients died from infections during induction or the month after 0. During delayed intensification, when all patients receive dexamethasone, 5 patients died from infections: 4 prednisone-assigned patients and one dexamethasone-assigned patient. Infectious deaths during maintenance included 2 patients in the prednisone group Pseudomonas ; alpha-streptococcus and one in the dexamethasone group varicella.

Reversible proximal myopathy was seen during induction, early consolidation, and delayed intensification, but not in maintenance. No patient had grade 4 toxicity ie, respiratory embarrassment. Incidence of grades 1 to 3 steroid myopathy during induction and early consolidation was 1. Grade 3 weakness ie, inability to ambulate was seen in 22 dexamethasone patients 4. Grade 3 myopathy was more common in younger children and boys.

During delayed intensification, when all patients received dexamethasone, incidence of myopathy was 0. Weakness was reversible when the steroid was discontinued, and none recurred during monthly 5-day steroid pulses in maintenance. Incidence of grade 3 or 4 amylase elevation in induction was 1. Symptomatic pancreatitis was reported in 5 dexamethasone patients and one prednisone patient. All recovered without sequelae. The incidence of grade 3 or 4 ALT elevations was similar among prednisone and dexamethasone patients.

Data on specific use of insulin for hyperglycemia was not collected. Two prednisone patients and one dexamethasone patient were diagnosed with avascular necrosis of the ankles early in maintenance therapy. Two patients had consistent dysesthesia and agitation with each 5-day course of dexamethasone in maintenance. Both patients were switched to prednisone with no or less intense reactions.

Four patients were switched from dexamethasone to prednisone at their parents' requests because of similar reactions. There were no apparent differences in incidence of other rare toxicities by assigned treatment, including seizures, CNS hemorrhage, thrombotic stroke, hematuria, and renal stones.

Corticosteroids are one of the mainstays in therapy for acute lymphoblastic leukemia. The study was not designed with a sample sufficient to determine a statistically significant reduction in bone marrow relapses. Although no differences were found in duration of hospitalization or supportive care interventions, the substitution was not truly isotoxic. Published equivalency tables suggest that dexamethasone is approximately 7-fold more potent than prednisone.

However, in vitro assays of phytohemagglutinin-induced lymphocyte proliferation suppression have shown dexamethasone to be fold more active than prednisolone. We observed a higher incidence of reversible corticosteroid-induced side effects hyperglycemia and myopathy in dexamethasone patients. Hurwitz et al described an increased incidence of gram-negative bacteremia and induction death in a group of patients who received dexamethasone during induction compared with historical controls who received prednisone.

Hurwitz et al used doxorubicin during induction, unlike this trial, which might have deepened neutropenia and delayed neutrophil recovery. In addition, dexamethasone may blunt the febrile response to infection, delaying recognition of fever and initiation of antibiotic therapy, thus increasing risk of death. Although CCG and others have used dexamethasone with anthracycline in delayed intensification for more than 20 years, we concur with Hurwitz et al's caution about prolonged exposure to dexamethasone in conjunction with myelosuppressive chemotherapy.

Avascular necrosis of bone is a known complication of corticosteroids. Factors increasing risk include being older than 10, female, and white, as well as the number of dexamethasone-containing delayed intensification courses. However, there was no difference in this rare occurrence by randomized steroid received.

Patients who receive therapy for ALL are at risk of other skeletal abnormalities including osteopenia, osteoporosis, and symptomatic and asymptomatic fractures.

Disease status and use of intensive corticosteroids may contribute to that risk. We did not screen for subclinical fractures. Proximal myopathy is a complication of corticosteroid therapy.

Male sex and younger age were risk factors for development of more severe weakness. Weekly vincristine was given during induction. It may be difficult to clinically differentiate corticosteroid myopathy from vincristine neuropathy, so it is possible that those patients may have had weakness from both effects. In most affected patients, ambulation was impaired. However, all patients recovered completely without recurrence during corticosteroid pulses in maintenance.

Agitation and even frank psychosis are known complications of corticosteroid use. Although a rare occurrence, 2 patients in the current study were unable to tolerate dexamethasone pulses in maintenance because of severe agitation, and 4 others were switched to prednisone at their parents' requests.

In some cases, we found that concomitant sedatives and potassium supplements may decrease agitation level. Otherwise, a change to prednisone reduced or eliminated symptoms. Waber et al linked dexamethasone with cognitive dysfunction after comparing 2 cohorts of children who received one drug or the other. The dexamethasone patients were younger at diagnosis and fewer had parents who had gone to college.

In the current study, no patient received prophylactic cranial radiation. Dexamethasone doses differed from doses in the current study. Neuropsychologic testing in a cohort of long-term survivors of this trial would address the question most productively. Daily oral 6-mercaptopurine is a mainstay in the treatment of childhood ALL. Others have linked more myelosuppression during maintenance therapy with daily oral 6-MP and weekly oral methotrexate with better EFS, which suggests that biologic activity of these drugs has an important bearing on outcome.

Van Eys and coworkers were unable to improve outcome by escalating the dose of oral 6-MP to modest levels of leukopenia. The bioavailability of oral 6-MP is poor, and its interpatient variability is wide. Intravenous 6-MP has better bioavailability and less interpatient variability. We did observe a significantly improved overall survival for oral 6-MP patients because of an increased risk of death after relapse in IV 6-MP patients. Weekly IV 6-MP does not improve outcome despite reports of superior bioavailability in the literature.

In contrast, dexamethasone significantly improves outcomes of children with standard-risk ALL by decreasing relapses without causing undo short-term toxicity. This improvement was apparent even though all patients received dexamethasone during delayed intensification. In this standard-risk population younger than 10 years who received no anthracycline during induction, neither infectious complications nor avascular necrosis of bone were problematic. For older patients at higher risk of avascular necrosis, and for patients who receive anthracycline in induction, dexamethasone should be introduced only in the context of a clinical trial where benefits and harms may be assessed accurately.

The publication costs of this article were defrayed in part by page charge payment. Sign In or Create an Account. Sign In. Search Dropdown Menu. Skip Nav Destination Content Menu. Close Abstract. Patients, materials, and methods. Article Navigation. Bostrom , Bruce C. This Site. Google Scholar. Martha R. Sensel , Martha R. Harland N. Sather , Harland N. Paul S. Gaynon , Paul S. Mei K. La , Mei K. Katherine Johnston , Katherine Johnston.

Gary R. Erdmann , Gary R. Stuart Gold , Stuart Gold. Nyla A. Heerema , Nyla A. Raymond J.

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    Arthur J. Improvement was defined as a reduction in the score by 2 or more points, lasting for 3 months or longer. The bioavailability of oral 6-MP is poor, and its interpatient variability is wide. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.

It may be difficult to clinically differentiate corticosteroid myopathy from vincristine neuropathy, so it is possible that those patients may have had weakness from both effects. In most affected patients, ambulation was impaired.

However, all patients recovered completely without recurrence during corticosteroid pulses in maintenance. Agitation and even frank psychosis are known complications of corticosteroid use. Although a rare occurrence, 2 patients in the current study were unable to tolerate dexamethasone pulses in maintenance because of severe agitation, and 4 others were switched to prednisone at their parents' requests.

In some cases, we found that concomitant sedatives and potassium supplements may decrease agitation level. Otherwise, a change to prednisone reduced or eliminated symptoms. Waber et al linked dexamethasone with cognitive dysfunction after comparing 2 cohorts of children who received one drug or the other.

The dexamethasone patients were younger at diagnosis and fewer had parents who had gone to college. In the current study, no patient received prophylactic cranial radiation. Dexamethasone doses differed from doses in the current study. Neuropsychologic testing in a cohort of long-term survivors of this trial would address the question most productively. Daily oral 6-mercaptopurine is a mainstay in the treatment of childhood ALL.

Others have linked more myelosuppression during maintenance therapy with daily oral 6-MP and weekly oral methotrexate with better EFS, which suggests that biologic activity of these drugs has an important bearing on outcome. Van Eys and coworkers were unable to improve outcome by escalating the dose of oral 6-MP to modest levels of leukopenia. The bioavailability of oral 6-MP is poor, and its interpatient variability is wide. Intravenous 6-MP has better bioavailability and less interpatient variability.

We did observe a significantly improved overall survival for oral 6-MP patients because of an increased risk of death after relapse in IV 6-MP patients. Weekly IV 6-MP does not improve outcome despite reports of superior bioavailability in the literature. In contrast, dexamethasone significantly improves outcomes of children with standard-risk ALL by decreasing relapses without causing undo short-term toxicity.

This improvement was apparent even though all patients received dexamethasone during delayed intensification. In this standard-risk population younger than 10 years who received no anthracycline during induction, neither infectious complications nor avascular necrosis of bone were problematic.

For older patients at higher risk of avascular necrosis, and for patients who receive anthracycline in induction, dexamethasone should be introduced only in the context of a clinical trial where benefits and harms may be assessed accurately. The publication costs of this article were defrayed in part by page charge payment. Sign In or Create an Account. Sign In. Search Dropdown Menu. Skip Nav Destination Content Menu. Close Abstract. Patients, materials, and methods. Article Navigation. Bostrom , Bruce C.

This Site. Google Scholar. Martha R. Sensel , Martha R. Harland N. Sather , Harland N. Paul S. Gaynon , Paul S. Mei K. La , Mei K. Katherine Johnston , Katherine Johnston.

Gary R. Erdmann , Gary R. Stuart Gold , Stuart Gold. Nyla A. Heerema , Nyla A. Raymond J. Hutchinson , Raymond J. Arthur J. Provisor , Arthur J. Michael E. Trigg Michael E. Blood 10 : — Article history Submitted:. Connected Content.

A companion article has been published: Small steps to improve outcome in ALL. Cite Icon Cite. View large Download PPT. CCG schema. Table 1. Patients with CNS disease at diagnosis also received intrathecal methotrexate on days 7 and View Large. Table 2. Presenting features of children with standard risk acute lymphoblastic leukemia. Age, y. EFS by randomized treatment. Table 3. First event by randomized treatment regimen. Number randomized Marrow relapse 31 33 20 28 Isolated CNS relapse 17 20 10 10 57 Testicular relapse 2 1 1 0 4 Other relapse 0 1 0 0 1 Second malignancy 1 2 0 0 3 Death 6 3 4 4 17 Induction failure 0 1 2 0 3 Total events 57 61 37 42 Expected events Isolated central nervous system CNS relapse by randomized steroid.

EFS by trisomy status. EFS by day 7 bone marrow response. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. Search ADS. Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Children's Cancer Group phase III trial. Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia.

The use of glucocorticoids in acute lymphoblastic leukemia of childhood: molecular, cellular, and clinical considerations. Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia.

High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia: results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion.

A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study. Either your web browser doesn't support Javascript or it is currently turned off.

In the latter case, please turn on Javascript support in your web browser and reload this page. Read article at publisher's site DOI : Therap Adv Gastroenterol , , 23 Mar J Inflamm Res , , 30 Nov Therap Adv Gastroenterol , , 13 Sep Intest Res , 20 1 , 15 Apr Frontline Gastroenterol , 12 5 , 11 Jun To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Gastroenterology , 2 Cited by: 51 articles PMID: World J Gastroenterol , 25 9 , 01 Mar Review Free to read. Dig Liver Dis , 37 6 , 01 Jun Cited by: 25 articles PMID: Cited by: 23 articles PMID: Dig Dis Sci , 66 5 , 26 Jun Cited by: 0 articles PMID: Contact us.

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Abstract Available from publisher site using DOI. As our experience has grown, our practice has been to use a somewhat higher dosing of 6-MP, though perhaps not as high as some other centers.

The patients in our study experienced very little toxicity from 6-MP. However, it should be noted that our mean starting and maximum doses 51 mg and 61mg, respectively, see Table 1 were lower than usually prescribed today.

Response and remission may take longer to occur than without simultaneous steroids. Google Scholar. Azathioprine and 6-mMercaptopurine in Crohn disease: a meta-analysis. Ann Intern Med. Dig Dis. Am J Gastro. Thiopurine methyltransferase in a French population. Br J Clin Pharmacol. The importance of thiopurine methyltransferase for the use of azathioprine in transplant recipients.

Xanthine oxidase activity and gene expression in renal Epithelial cell: cytokine and steroid regulation. J Immunol. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Quality of Life. Browse all content Browse content in. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation.

Volume Article Contents Materials and Methods. Appendix I. Journal Article. Goldstein, MD , Eric S. Goldstein, MD. Oxford Academic. James F. Marion, MD. Daniel H. Present, MD. Cite Cite Eric S. Select Format Select format. Permissions Icon Permissions. Table 1. Open in new tab. Table 2. Table 3. Figure 1. Open in new tab Download slide. No caption available. Google Scholar Crossref. Search ADS. Google Scholar PubMed.

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Read article at publisher's site DOI : Therap Adv Gastroenterol, 23 Mar J Inflamm Res, 30 Nov Therap Adv Gastroenterol, 13 Sep Intest Res20 115 Apr Frontline Gastroenterol12 511 Jun To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Gastroenterology2 Cited by: 51 articles PMID: World J Gastroenterol25 901 Mar Review Free to read. Dig Liver Dis37 601 Jun Cited by: 25 articles PMID: Cited by: 23 articles PMID: Dig Dis Sci66 526 Jun Cited by: 0 articles PMID: Contact us. Europe PMC requires Javascript to function effectively. Recent Activity. Search life-sciences literature 41, articles, preprints and more Search Advanced search. This website requires cookies, and the limited processing of your personal data in order to function.

By using the site you are agreeing to this as outlined in our privacy notice and cookie policy. Abstract Available from publisher site using DOI. A subscription may be required. C Hermida Search articles by 'C Hermida'. Hermida C. Cantero-Perona J. Moreno-Otero R. Affiliations 1 author 1. A comment on this article appears in " Low-dose methotrexate in ulcerative colitis: still a matter of debate. Share this article Share with email Share with twitter Share with linkedin Share with facebook.

Abstract Background As treatment of steroid-dependent patients with inflammatory bowel disease IBD is controversial, we analysed the efficacy and tolerance of 6-mercaptopurine 6-MP and methotrexate MTX added to prednisone in increasing and maintaining the disease remission rate. Methods Seventy-two steroid-dependent IBD patients, 34 with ulcerative colitis UC and 38 with Crohn's disease CDreceiving treatment with prednisone were randomly assigned in a ratio to additionally receive, orally, over a period of 30 weeks 1.

All patients who achieved remission were included in a maintaining remission study for 76 weeks. With regard to maintaining remission, UC patients in group A Noticeable side effects appeared in Conclusions These results suggest that 6-MP or MTX added to prednisone could be effective in steroid sparing, as well as in achieving and maintaining remission in steroid-dependent IBD patients.

MTX was less effective in maintaining remission in UC patients. Full text links Read article at publisher's site DOI : Smart citations by scite.

The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles. Explore citation contexts and check if this article has been supported or disputed. Evidence-based efficacy of methotrexate in adult Crohn's disease in different intestinal and extraintestinal indications. Indeterminate Colitis - Update on Treatment Options.

Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn's disease: a retrospective study. Use of thiopurines in inflammatory bowel disease: an update. Pancreatitis associated with azathioprine and 6-mercaptopurine use in Crohn's disease: a systematic review. Similar Articles To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review. Methotrexate for maintenance of remission in ulcerative colitis. Methotrexate for induction of remission in refractory Crohn's disease.

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Background & aims: Clinical experience suggests that 6-mercaptopurine (6-MP) is effective therapy for children with active steroid-dependent Crohn's disease. Comparing Mercaptopurine vs Prednisone ; Mercaptopurine has an average rating of out of 10 from a total of 30 ratings on localhost 47% of reviewers reported. Abstract. Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested. In people receiving Mercaptopurine PO, Methotrexate PO, IT Methotrexate, Prednisone, Vincristine, more than 20 and up to may have. A retrospective study identified eleven men and eleven women with inflammatory bowel disease (IBD), aged 21−78 years, who developed. A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors. No patient had grade 4 toxicity ie, respiratory embarrassment.

Reprints: Daniel H. Present, MD, 12 E. New York, NY e-mail: danjane1 aol. Eric S. Goldstein, MD, James F. Marion, MD, Daniel H. Sparse literature to date suggests that 6-MP is effective when used without steroids. We conducted a retrospective chart review of 24 patients who were treated with 6-MP but had never received any form of steroid treatment at any time. In addition to overall response, data were also analyzed according to the indication for treating with 6-MP disease activity, fistulae, or both.

The time to relapse and the treatments required were also analyzed. Drug effect required a median of 5. Thirteen of the twenty patients who improved or remitted on 6-MP eventually relapsed, usually due to stopping 6-MP, at a median of Relapse was less frequent if patients continued 6-MP. Relapses occur despite continued therapy, but are often easily treated, and do not require initiating steroids. Corticosteroids, both oral and intravenous, have been the standard therapy for inflammatory bowel diseases for many decades.

Studies have demonstrated the efficacy of 6-mercaptopurine and azathioprine when used in combination with steroids for treating active disease as well as maintaining remission. Some investigators insist that steroids are required to induce response prior to 6-MP initiation. A computer database, created in FileMaker 4. Patients treated with ACTH were also excluded. Topical corticosteroid creams for dermatologic purposes were allowed. In cases where the patient had received multiple courses of 6-mercaptopurine, only the first course was used for analysis.

The practice routinely uses 6-mercaptopurine, and no patient in the database who was steroid-naive had been treated with azathioprine. Patients were followed by phone weekly for the first month to obtain information regarding clinical condition and complete blood counts CBCs for the first month of therapy.

Data were obtained regarding the indication and efficacy of 6-mercaptopurine. Indications for 6-MP were disease activity, fistulizing disease, or both. Patients receiving 6-mercaptopurine for postoperative prophylaxis were excluded. Modified Harvey-Bradshaw Index scores mHBI; Appendix 1 were tabulated at the time of therapy inception and at every chart entry thereafter until we observed remission, a stable significant improvement, drug failure, or drug cessation for another reason such as toxicity.

This was defined as the treatment end point. Remission was defined as an mHBI score of zero. Improvement was defined as a reduction in the score by 2 or more points, lasting for 3 months or longer.

Failure was defined as the need for steroids, cyclosporine, or surgery. Data regarding concurrent medications, disease extent, and relapse after remission or improvement were also collected. Relapse was defined as an increase in the mHBI score of two or more above the study end point score. Relapse rates were tabulated for the group as a whole, and then again post-hoc according to whether or not the patient continued 6-mercaptopurine. Chart analysis was current as of July 30, the end of the study period.

Data were tabulated, and Student t tests were performed, using Microsoft Excel Data were analyzed as one large cohort and again after being sorted by indication for 6-mercaptopurine. Two patients were excluded because chart review revealed the use of rectal steroids prior to coming to our practice, and one was excluded because of a short course of ACTH prior to 6-mercaptopurine therapy.

Three patients were excluded because their indication for 6-mercaptopurine was postoperative prophylaxis. Twenty-four patients were therefore eligible for study. No patient taking 6-mercaptopurine for both activity and fistula achieved complete remission. The mean mHBI score for all patients at the time of entry was 5.

At the study end point, the mean mHBI score for all patients was 1. See Table 2 for further details and subgroup tabulations. The effect of 6-mercaptopurine was seen at a median of 5. Efficacy was seen at a median 3. If patients continued 6MP, 2 of 4 relapsed whereas all 3 who stopped the drug eventually relapsed.

If patients continued 6-MP, 4 of 10 remained well, whereas 2 of the 3 who stopped treatment worsened. No patient required steroids, and only one patient required surgical intervention the incision and drainage of a perianal abscess. Six of the 7 patients who did not relapse remained on 6-MP at the end of the study period Table 3.

Toxicity was infrequently encountered during the treatment of steroid-naive patients with 6-mercaptopurine. Two patients experienced allergic symptoms fever, with or without rash and arthralgias. One patient developed glossitis, which resolved without interruption of drug therapy. Thus, only one patient had 6-mercaptopurine permanently withdrawn because of toxicity. One patient, with ileocolitis and in complete remission on 6-MP, underwent colectomy for low-grade dysplasia found during surveillance colonoscopy.

She had no disease flares after surgery and did not require 6-MP. Clinical course of study patients. Numbers in parentheses indicate the number of patients in each group. Abbreviations: LGD, low-grade dysplasia; Abx, antibiotics metronidazole,ciprofloxacin, others. In the NCCDS, 10 of the 59 patients randomized to the azathioprine monotherapy group had never received prior steroids. This difference was not statistically significant; this was perhaps due to the short duration of the study 17 weeks , since our median time to respond was 5.

This efficacy is similar to that found in some previous trials, 1 , — 4 , 8 , — 10 and superior to others. Although steroid-naive patients seem to have the classic lag from initiation of therapy to benefit, the time to improvement of fistulizing disease appears to be longer without steroids. Previous literature suggests that azathioprine and 6-mercaptopurine take effect in approximately 2 to 4 months, and prior studies do not either investigate or demonstrate a temporal difference between fistulizing disease and all other indications.

They show that a fourth of patients achieved remission at 8 weeks. The reason for this is unclear. Quicker effects may have been seen with higher dosing ie, 1. Our practice has evolved over time toward using higher doses of 6-MP and toward keeping patients on the drug for much longer periods of time.

Some patients now take moderate or high doses of 6-MP for years. The pharmacology of 6-MP and prednisone, and their interactions on a cellular level, are beginning to be understood. According to several in vitro experiments, prednisone does not induce thiopurine methyltransferase TPMT , the enzyme that converts 6-MP to 6-methyl-mercaptopurine 6-MMP, a metabolite of uncertain immunomodulatory capability and away from the 6-thioguanine 6-TG pathway.

As this did not occur, it is unlikely that a difference in the metabolism of 6-MP in steroid-naive patients accounts for the lengthened time to response. In view of newer long-term safety and efficacy data, we currently advise chronic continuous administration. It is possible that remission induced without steroids requires higher doses of 6-MP to be maintained, and may be enhanced by enzyme or metabolite testing.

As our experience has grown, our practice has been to use a somewhat higher dosing of 6-MP, though perhaps not as high as some other centers. The patients in our study experienced very little toxicity from 6-MP. However, it should be noted that our mean starting and maximum doses 51 mg and 61mg, respectively, see Table 1 were lower than usually prescribed today. Response and remission may take longer to occur than without simultaneous steroids.

Google Scholar. Azathioprine and 6-mMercaptopurine in Crohn disease: a meta-analysis. Ann Intern Med. Dig Dis. Am J Gastro. Thiopurine methyltransferase in a French population. Br J Clin Pharmacol. The importance of thiopurine methyltransferase for the use of azathioprine in transplant recipients. Xanthine oxidase activity and gene expression in renal Epithelial cell: cytokine and steroid regulation.

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