Months Of Maintenance Therapy Research Articles

The psychopharmacology algorithm project at the harvard south shore program: 2012 update on psychotic depression

Background: The Psychopharmacology Algorithm Project at the Harvard South Shore Program (PAPHSS) has published evidence-supported algorithms for the pharmacological treatment of major depressive disorder with psychotic features (psychotic depression) in 1998 and 2008. This article is an update for the 2008 algorithm. Method: Using similar methodology as with the 2008 update, PubMed and EMBASE searches were conducted to identity relevant literature in the English language from November 2007 through July 2012. Articles were evaluated for quality of the data and for whether they provided additional evidence support for previous recommendations or prompted changes to the prior algorithm. Results: Minor changes were made to the algorithm: most prior recommendations were upheld. The most effective treatment for hospitalized, severe psychotic depression patients remains electroconvulsive therapy (ECT). The combination of an antidepressant (tricyclic [TCA], selective serotonin reuptake inhibitor [SSRI], or serotonin-norepinephrine reuptake inhibitor [SNRI]) plus an antipsychotic continues to be the preferred pharmacological modality when ECT is an unavailable/deferred option. Since the last update, new evidence tends to support using venlafaxine ER, a SNRI, as the first choice antidepressant. Regarding the antipsychotic, both olanzapine and quetiapine have new data demonstrating efficacy. Nevertheless, it is suggested that it may be reasonable to try other atypical antipsychotics with more benign safety profiles (e.g. ziprasidone, aripiprazole) as the first choice antipsychotic. New data also suggest at least four months of maintenance therapy is effective. If the first antidepressant-antipsychotic combination produces an unsatisfactory outcome, and ECT is still not acceptable or appropriate, the second pharmacotherapy trial can be with a change in the antidepressant, as was recommended in the 2008 algorithm. After two trials of combination therapy have failed (and, again, ECT is not an option), the algorithm continues to recommend augmentation with lithium. Limited evidence also suggests consideration of a switch to clozapine monotherapy. Augmentation with methylphenidate is a newly mentioned possible option based on very small evidence. When combination therapy is deferred, evidence suggests monotherapy with a TCA may be more effective than an SNRI or SSRI. However, safety issues and possible increased risk of psychosis exacerbation are unfavorable factors for TCA monotherapy. ECT or addition of an antipsychotic should be reconsidered if antidepressant monotherapy failed. Conclusion: This heuristic further refines the previous PAPHSS analysis of the available evidence for pharmacological treatment of psychotic depression. The validity of the conclusions is limited by the quality and quantity of the literature available: the number of head-to-head prospective trials in psychotic depression is still relatively small. However, this algorithm m

Final Analysis of a Multi-Center Randomized Controlled Trial (IAPLSG04) to Study the Optimal Duration of Arsenic Trioxide Maintenance Therapy in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia

Abstract 426Single agent arsenic trioxide (ATO) has proven efficacy in the management of newly diagnosed cases of acute promyelocytic leukemia (APL). To validate findings of an initial single center experience (Blood 2006:107; 2627) with this low cost, well tolerated, effective regimen a multicenter study was undertaken in a resource constrained environment. Additionally, in an effort to improve on the earlier experience and study the role of duration of maintenance on reducing late relapses, patients who achieved molecular remission were randomized to 6 vs. 12 months of ATO maintenance.From July, 2004 to December, 2008, 186 patients were initially screened and enrolled based on morphological diagnosis of APL from 7 centers in India. Twenty seven cases were excluded from analysis (6 RT-PCR negative, 4 IC bleed at diagnosis, 5 septicemia/pneumonia at diagnosis, 9 withdrew consent prior to randomization and some were treated with other protocols, 1 withdrawn by investigator prior to randomization). Patients were treated with single agent ATO at standard doses for up to 60 days in induction; this was followed by 28 day consolidation after a 4 week break following induction. Four weeks after completion of consolidation patients who were in molecular remission were randomized to 6 vs. 12 months of maintenance therapy with ATO administered for 10 days/month. Anthracyclines were permitted in induction for patients presenting with or WBC count rising >20×109/L in the first week, >50×109/L in the second week and for those who developed a differentiation syndrome. Hydroxyurea was permitted for control of leucocytosis. Of the 159 patients who could be evaluated 138 (86.8%) achieved hematological remission (CHR), one patient had primary induction failure and was removed from the study the rest were induction deaths at a median of 17 days (range: 4 – 69). 52 (32.7%) received an anthracycline in induction while 116 (73%) received hydroxyurea in induction. A differentiation syndrome was documented in 25 (16%) cases and was fatal in one. Grade III/IV non hematological toxicity was seen in 26 (16.3%), in the majority they resolved after discontinuing ATO for a short period. A protocol change after randomization was done in 3 cases for persistent toxicity. Five (3.6%) patients did not complete the scheduled maintenance regimen due to poor compliance or was discontinued by the investigator. At a median follow up of 48 months the 5 year Kaplan-Meir estimate of overall survival (OS), event free survival (EFS) and disease free surivival (DFS) was 75.7±3.9%, 68±4% and 76.9±4.2% respectively. Twenty five patients relapsed, the median time to relapse was 19.2 months (range: 8.2–51). There were no relapses beyond 4 years of follow up.136 patients who achieved molecular remission after consolidation were randomized in to 6 months (n=63) or 12 months (n=73) of maintenance therapy. The baseline characteristics of the two groups were not significantly different. Post randomization, the two groups were analyzed on an intention to treat basis. The OS, EFS (Figure 1) and DFS of the two groups were not statistically different. There was no evidence that the group that received 12 months of maintenance had any increased incidence of toxicity.This study confirms that this low cost, low intensity single agent ATO based regimen, as reported previously, is well tolerated and results in durable remissions. However, there is no apparent clinical benefit from increasing the duration of maintenance from 6 to 12 months. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Abl Kinase Domain Mutations Leading to Relapse of Ph+ Acute Lymphoblastic Leukemia (ALL) Occur Commonly and Can Be Detected At Initial Diagnosis: Molecular Results From CALGB 10001

Abstract 2541CALGB 10001 tested the feasibility of performing allogeneic or autologous stem cell transplantation (SCT) following combination chemotherapy and tyrosine kinase inhibition with imatinib in patients <60 years old with newly diagnosed Ph+ ALL. Patients received imatinib with each course of chemotherapy prior to SCT. A minimum of 12 months of maintenance therapy with imatinib was recommended following SCT or until minimal residual disease was no longer detected using quantitative real-time PCR (q-PCR). One goal of this study was to determine the incidence of ABL kinase domain mutations in patients who relapsed during or following treatment on CALGB 10001, and to evaluate the kinetics of the resistant clone. 58 patients (median age, 44 yrs) enrolled on CALGB 10001 between 11/2003 and 2/2010. After 3–4 courses of imatinib plus chemotherapy, 15 patients received TBI/etoposide and an alloSCT from a matched sibling donor; 9 (60%) remain in CR (median, 665+ days; range, 152+ to 1208+ days), 2 subsequently relapsed (days +236 and +354), and 4 had transplant-related mortality (TRM). 17 patients received TBI/etoposide/cyclophosphamide and autologous SCT; 10 (59%) remain in CR (median, 742+ days; range, 196+ to 1656+), 9 relapsed (range, 257–522 days), and none had TRM (updated from Wetzler et al, ASH 2007; abstract #2869). Thus, a total of 19 patients have relapsed (8 prior to SCT; 2 after alloSCT; 9 after autoSCT,) at a median of 5.9 months following SCT. All patients were monitored for BCR/ABL1 by q-PCR at sequential time points during and following treatment. Using direct sequencing methods (sensitivity 15–25%), an ABL kinase domain mutation was found in 12 of the 19 (63%) at relapse. The mutations included: 4 with Y253H, 3 T315I, 3 E255K, and 1 E255V. One patient had both a T315I and E255V mutation. All of these mutations are associated with imatinib resistance. To evaluate the kinetics of the resistant clone, we used a quantitative mutation-specific PCR assay (Gruber et al, Leukemia 19:2159, 2005). The sensitivity of the assay was shown to be 1% for T315I and E255V and 0.1% for Y253H and E255K. Using the q-PCR method, we found the resistant clone was detectable at diagnosis in 6 of the 12 patients with kinase domain mutations. In 4 patients, the resistant clone was not detectable until the time of relapse; however, for 3 of these cases the relapse occurred very early, within 2 months of starting treatment. In the remaining 2 cases, the resistant clone was first detected during treatment at 1 and 9 months prior to relapse (Figure 1). In most cases, the kinetics of the resistant clone mirrored the overall BCR/ABL1 population (Figure 2). Nevertheless, the resistant clone proportionally increased in size over time, and at relapse, the resistant clone became the dominant BCR-ABL1 clone. In summary, our series demonstrates that ABL kinase domain mutations occur commonly at relapse in Ph+ ALL despite aggressive therapy with imatinib plus combination chemotherapy followed by autoSCT and in some cases, alloSCT. The relapses appear to be due to the emergence of an imatinib-resistant subclone that is frequently present but subclinical at the time of diagnosis. Improved TKI-based therapies with activity against imatinib-resistant subclones instituted early during treatment of Ph+ ALL are needed to prevent emergence of clonal resistance and eventual relapse. Use of sensitive q-PCR assays to screen for these commonly pre-existing mutations at diagnosis, perhaps using a multiplex method, would provide useful clinical information to allow for optimal therapeutic management of Ph+ ALL. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia

Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL. Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient's files. Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24weeks of maintenance therapy. The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.

Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial

Adjuvant high-dose interferon alfa-2b improves relapse-free survival (RFS) in patients with high-risk melanoma, although benefits in overall survival are uncertain. Because of the toxic effects of high-dose regimens, intermediate doses are being explored. We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma. This randomised, open-label, phase 3, parallel-group trial was undertaken between 1996 and 2004. 855 patients were randomly assigned at 35 centres in the Nordic countries by block randomisation to three groups: observation only (group A); 4 weeks of induction (interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week) followed by 12 months of maintenance therapy (interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week; group B); or 1 month of induction and 24 months of maintenance (group C). Neither investigators nor patients were masked to treatment assignment. Patients were stratified for country and tumour stage; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse, palpable versus non-palpable lymph-node metastases, and number of metastatic lymph nodes. The primary endpoint was overall survival in the two interferon alfa-2b groups combined. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01259934. 284 patients were assigned to group A, 285 to group B, and 286 to group C; all patients were analysed. The median follow-up time was 72·4 months (IQR 46·9-98·0). We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation: median overall survival was 56·1 months (IQR 22·3 to >120·0) in group A, 72·1 months (25·8 to >120) in group B, and 64·3 months (24·7 to >120) in group C (p=0·600). Hazard ratios (HR) for overall survival were 0·91 (95% CI 0·74-1·10; p=0·642) for groups B and C combined versus observation; 0·91 (0·72-1·14; p=0·652) for group B versus observation; and 0·91 (0·72-1·15; p=0·858) for group C versus observation. Median RFS was 23·2 months (IQR 5·6 to <120) in group A, 37·8 months (10·8 to >120) in group B, and 28·6 months (8·6 to >120) in group C (p=0·034). HRs for RFS were 0·80 (0·67-0·96; p=0·030) for groups B and C combined versus observation, 0·77 (0·63-0·96; p=0·034) for group B versus observation, and 0·83 (0·68-1·03; p=0·178) for group C versus observation. The most common grade 3 and 4 adverse events were fatigue (five in group A [1·8%], 28 in group B [9·8%], and 32 in group C [11·2%]), myalgia (three [1·1%], 15 [5·3%], 14 [4·9%], respectively), and thrombocytopenia (15 [5·3%], 23 [8·1%], eight [2·8%], respectively). Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival. Interferon alfa-2b with 1-year maintenance therapy significantly improved RFS, but we recorded no significant effect for 2-year maintenance therapy. Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b. Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society.

Body mass index and blood pressure changes over the course of treatment of pediatric acute lymphoblastic leukemia

Obesity and hypertension are reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, little is known about the trajectory of body mass index (BMI) and blood pressure over the course of ALL therapy. In a retrospective cohort of 183 pediatric ALL patients diagnosed from 2000 to 2008, prevalence, severity, and risk factors for obesity and hypertension were assessed during treatment. At diagnosis, 36% of patients were overweight and 19% were obese. Median BMI increased during induction therapy with a return to baseline soon after, but increased again over the first 22 months of maintenance therapy. At the end of therapy, 49% were overweight and 21% were obese. Increased BMI z-score at diagnosis was associated with increased z-score during maintenance (P < 0.001). Elevated parental BMI was associated with elevated BMI at diagnosis. Median BMI z-score increased over the first 22 months of maintenance (P < 0.001). Patients with high risk disease had lower BMI z-scores regardless of cranial radiotherapy exposure (P < 0.001). Pre-hypertension was prevalent over the course of therapy (31.1% with systolic pre-hypertension and 18.6% with diastolic pre-hypertension). Hypertension was also highly prevalent with 41.5% meeting systolic criteria and 24.0% meeting diastolic criteria. During ALL therapy, patients are at risk for early development of elevated BMI and blood pressure, which places them at potentially increased risk for future adverse health conditions. Future studies are needed to develop strategies to mitigate these risks, such as potential reduction of corticosteroid pulses or a family-based diet and exercise intervention during maintenance therapy.

Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first‐line treatment of patients with glioblastoma multiforme

The current study was conducted to evaluate the efficacy of sorafenib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, when added to standard radiotherapy and temozolomide in the first-line treatment of patients with glioblastoma multiforme. After initial surgical resection or biopsy, patients with newly diagnosed glioblastoma multiforme received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and temozolomide (at a dose of 75 mg/m2 orally daily), followed by 6 months of maintenance therapy with temozolomide (at a dose of 150 mg/m2 orally on Days 1-5 every 28 days) and sorafenib (at a dose of 400 mg orally twice daily). Patients were re-evaluated every 2 months; the primary endpoint of the trial was progression-free survival (PFS). A total of 47 patients were treated; 34 had undergone previous debulking surgery. Nineteen patients withdrew from treatment before the initiation of maintenance therapy with temozolomide and sorafenib (12 because of early tumor progression). Twenty-eight patients (60% of enrolled patients) received 4 months of maintenance therapy with temozolomide and sorafenib, and 9 patients (19%) completed the planned 6 months of maintenance therapy. The median PFS for the entire group was 6 months (95% confidence interval [95% CI], 3.7-7 months), with a 1-year PFS rate of 16%. The median overall survival was 12 months (95%CI, 7.2-16 months). Maintenance therapy with temozolomide and sorafenib was found to be well tolerated by most patients, with no grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) reported to occur in >10% of patients. The addition of sorafenib did not appear to improve the efficacy of treatment when compared with the results expected with standard therapy. A substantial percentage of patients (40%) did not receive any maintenance sorafenib, most often because of early disease progression. The administration of angiogenesis inhibitors concurrently with radiotherapy and temozolomide may optimize the opportunity to improve therapy.

Monthly Itraconazole Versus Classic Homeopathy for the Treatment of Recurrent Vulvovaginal Candidiasis

When used to treat acute infections of vulvovaginal candidiasis as well as maintenance therapy to prevent recurrence, oral or topical antifungal agents of the azole group lower the incidence of and cure most of the infections. Cessation of maintenance treatment, however, results in recurrent vulvovaginal candidiasis (RVVC) within 6 months in about 50% of women. Classic homeopathy (CH) is a widely used controversial alternative treatment for RVVC, but there is little objective data demonstrating its effectiveness. Two previous studies reported that oral and intravaginal administration of Lactobacillus acidophilus in women with RVVC was associated with some subjective and objective improvements. This prospective, single center, randomized trial was a 12-month study that compared the effectiveness of monthly cycle-dependent itraconazole with and without lactobacilli and CH in reducing the frequency of clinical episodes of RVVC in 150 women with prior episodes. Patients positive for Candida albicans were randomly assigned to receive either itraconazole/lactobacilli (group 1), itraconazole monotherapy (group 2), or CH alone (group 3). Induction therapy for an acute infection for both group 1 and 2 patients consisted of single-day doses of itraconazole 200 mg b.i.d. This dose was continued during 6 months of maintenance therapy in groups 1 and 2; additionally, group 1 patients were given a suppository containing lactobacilli intravaginally. The women in groups 1 and 2 received no further treatment. Group 3 patients were treated using a single homeopathic remedy during the entire 12 months. Patients' RVVC related-complaints and their level of satisfaction with therapy was evaluated using a visual analogue scale. The absence of vulvovaginal candidiasis in vaginal culture was achieved significantly earlier among women in groups 1 and 2 than those in group 3 (log-rank test; P < 0.0001). Following induction therapy before the start of the maintenance regimen, 40 of 47 women (85%) in group 1 and 44 of 49 women (89.8%) in group 2 were free of Candida detectable in culture. Women in group 3 had a recurrence of the infection significantly earlier than women in the both groups 1 and 2 (log-rank test; P = 0.002). At 12 months, 78% (18/23) of the women in group 1, 76%, (19/25) of those in group 2, and 39% (9/29) of those in group 3 were free of Candida in culture. The level of discomfort from RVVC and dissatisfaction with therapy was significantly higher among women in group 3 than those in groups 1 and 2 (P < 0.001). These findings are consistent with other earlier studies showing that itraconazole is more effective for treatment of RVVC than classic homeopathy. There was no added benefit with lactobacilli.

Single Agent Arsenic Trioxide Regimen for the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Initial Results of a Multicenter Randomized Controlled Study From India to Study the Optimal Duration of Arsenic Trioxide Maintenance Therapy (IAPLSG04).

Abstract 2082Poster Board II-59Single agent arsenic trioxide (ATO) has proven efficacy in the management of newly diagnosed cases of acute promyelocytic leukemia (APL). To validate findings of an initial single center experience (Blood 2006:107; 2627) with this low cost, well tolerated, effective regimen, a multicenter study was undertaken in a resource constrained environment. Additionally, in an effort to improve on the earlier experience and study the role of duration of maintenance on reducing late relapses, patients were randomized to 6 vs. 12 months of ATO maintenance (ClinicalTrials.gov Identifier:NCT00517712).From July, 2004 to December, 2008, 182 patients were initially screened and enrolled based on morphological diagnosis of APL from 7 centers in India. Diagnosis was subsequently confirmed by molecular methods. Twenty seven cases were excluded from analysis (6 RT-PCR negative, 4 IC bleed at diagnosis, 5 septic/pneumonia at diagnosis, 9 withdrew consent prior to randomization and some were treated with other protocols, 1 withdrawn by investigator prior to randomization). Patients were treated with single agent ATO at standard doses (10mg/day for adults and 0.15mg/kg/day for pediatric patients) for up to 60 days in induction; this was followed by a 28 day consolidation after a 4 week break. Four weeks after completion of consolidation patients who were in molecular remission were randomized to 6 vs. 12 months of maintenance therapy with ATO administered for 10 days/month. Hydroxyurea was permitted for control of leucocytosis. Anthracyclines were permitted in induction for patients presenting with or WBC count rising >20×109/L in the first week, >50×109/L in the second week and for those who developed a differentiation syndrome. Of the 155 patients who could be evaluated 136 (87.7%) achieved hematological remission (CHR). One patient had primary induction failure and was removed from the study while the other 18 were induction deaths at a median of 17 days (range: 4 – 69). During induction, 52 (33.5%) patients received an anthracycline and 116 (75%) received hydroxyurea. A differentiation syndrome was documented in 25 (16%) cases and was fatal in one. Grade III/IV non hematological toxicity was seen in 26 (16.7%), which resolved in the majority after discontinuing ATO for a short period. One hundred and thirty six patients were randomized, 64 (47%) and 72 (53%) into a 6 and 12 month maintenance regimen respectively. A protocol change after randomization was done in 3 cases for persistent toxicity. Five (3.6%) patients did not complete the scheduled maintenance regimen due to poor compliance or was discontinued by the investigator. At a median follow up of 24 months, the 3-year Kaplan-Meir estimate of overall survival (OS), event free survival (EFS) and disease free survival (DFS) of the entire cohort was 76.87±4.33%, 71.57±4.64% and 80.69±4.77% respectively. Fourteen patients relapsed, the median time to relapse was 19.3 months (range: 9-51). The baseline characteristics of the two groups (6vs12 months) were not significantly different. Post randomization, the two groups were analyzed on an intention to treat basis. The OS, EFS and DFS of the two groups were not statistically significantly different. There was also no evidence that the group that received 12 months of maintenance had any increased incidence of toxicity.Single agent ATO based regimen as reported previously is well tolerated and results in durable remissions. Longer follow up is required to see if 12 months of maintenance therapy reduces risk of late relapses. Disclosures:No relevant conflicts of interest to declare.

Azacitadine and Low-Dose Gemtuzumab Ozogamicin for the Treatment of Poor-Risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), Including Relapsed, Refractory Disease.

Abstract 1034Poster Board I-56 Background:Poor-risk groups with AML – defined as those above age 50, those with secondary or treatment-related disease, and individuals relapsing after or refractory to initial therapy – have a very disappointing response to therapy and a dismal overall survival, on the order of 6 months. Therapeutic options are limited by age, comorbidities and toxicities from prior treatment. Hypomethylating agents, such as Azacitidine (AZA) may induce remission in up to 20% of patients. We have previously published a pilot study of a regimen combining AZA and low-dose gemtuzumab ozogamicin (GO) for the treatment of newly diagnosed, elderly patients with AML or high-risk MDS. (Leuk Lymphoma. 2008:49:2141-7) The combination produced a 70% CR/CRi rate, a median OS of 10 months and formed the basis of a national cooperative group trial in this select population. Based on these results, our institution broadened the use of this regimen to patients not otherwise eligible for standard therapy or a clinical trial, including patients with relapsed or refractory disease. We have retrospectively analyzed the clinical characteristics and outcomes of 56 patients treated with this regimen at our institution between September 2006 and July 2009. Methods:With IRB consent, all off-study patients with AML and MDS as well as those with relapsed/refractory AML were included in this analysis. Patients were included if they received at least one full cycle of AZA at a dose of 75mg/m2 SQ or IV daily for seven days followed by GO 3mg/m2 IV on day 8. A second cycle could be given after a day 15 bone marrow (BM) if there was no evidence of a CR or aplasia. Patients could receive consolidation therapy with the same regimen for one or more additional cycles and/or could continue on monthly maintenance therapy with single-agent AZA.Results: Patient characteristics:Between September 2006 and May 2009, a total of 56 patients received the regimen, 26 (46%) for the treatment of relapsed or refractory disease and 30 (54%) as first-line therapy. Most were treated for AML, but 11 (20%) had high-risk MDS, including three with CMMoL. The average age of patients at the time of treatment was 63 yrs, range of 23-85 yrs. Following induction, 17 patients received AZA alone as monthly maintenance therapy and nine were treated with allogeneic transplantation. The treatment-related mortality was 10% (n=6). Grade 3 or 4 non-hematologic toxicities, primarily infection or infusion reactions related to GO, were recorded in 17 patients (30%). Response rate/Overall survivalOf the 56 patients, 15 (27%) achieved a CR or CRi. An additional seven patients cleared their peripheral blood blasts or had hematologic improvement but did not have BM documentation of remission. CR or CRi was achieved in five of 22 patients (22%) with poor-risk cytogenetics and seven of the 24 (29%) patients who had therapy-related disease or disease that had evolved from pre-existing hematologic malignancy. The median OS was 21 weeks (range: 1-118). In patients who achieved a CR or CRi, the median OS was 40 weeks (range: 9-118). Most notably, seven of 26 patients (26%) with relapsed or refractory disease achieved a documented CR or CRi – including two patients with primary refractory disease and two who had relapsed after allogeneic transplantation. The median OS of these seven patients was 40 weeks (range: 9-118). Maintenance therapy with monthly AZA monotherapy was administered to 17 patients, 11 of whom had achieved a documented CR or CRi. The mean number of months of maintenance therapy was four; 8 received 5-10 cycles. Patients receiving maintenance therapy after achieving CR or CRi had a median OS of 45 weeks (range 20-118). Conclusions:The combination of AZA and low-dose GO produced a CR/CRi of 27% and a low TRM in an extremely poor-risk group of patients with AML and high-risk MDS. Responses were seen in patients with primary refractory disease and those who relapsed following allogeneic stem-cell transplant. Patients who were able to achieve a CR or CRi appeared to benefit from several months of maintenance AZA and had a median survival of nearly one year. Based on these results we are opening a prospective trial of this regimen for patients with relapsed or refractory disease with responders continuing on azacitidine indefinitely or proceeding to allogeneic transplantation. Disclosures:Off Label Use: I will describe the use of Azacitadine for acute myeloid leukemia. Smith:Celgene: Speakers Bureau. Nand:Pharmion/Celgene: Consultancy, Research Funding, Speakers Bureau.

A single‐institution experience with induction and maintenance intravesical docetaxel in the management of non‐muscle‐invasive bladder cancer refractory to bacille Calmette‐Guérin therapy

To analyse the durability of response for patients with non-muscle-invasive bladder cancer (NMIBC) refractory to bacille Calmette-Guérin (BCG) therapy and treated with intravesical docetaxel in a combined induction and maintenance regimen. A previous phase I trial showed docetaxel to be safe for intravesical therapy, with no systemic absorption and minimal toxicity after six weekly instillations for patients with BCG-refractory NMIBC. In that trial, docetaxel gave a 56% complete response (CR) rate at 12 weeks, but the durability was only 22%. Thus a second group of patients was treated with a 6-week induction and then given monthly maintenance therapy with intravesical docetaxel. Thirteen patients with BCG-refractory Ta, T1, or Tis transitional cell carcinoma were treated. Induction therapy was administered as six weekly intravesical instillations of 75 mg followed by single-dose monthly maintenance therapy for nine additional instillations in patients who had a CR. The initial response at 12 weeks from the start of induction therapy was evaluated by cystoscopy with biopsy, and urine cytology. The follow-up consisted of quarterly cystoscopy with biopsy and cytology, and periodic imaging. The median follow-up was 13 months; 10 of 13 patients had a CR after induction, and six have remained disease-free during the follow-up. Of those in who the treatment failed, six had transurethral resection of the tumour and one a cystectomy. All 10 initial responders completed at least three instillations of maintenance therapy to date (median nine instillations), of whom six have remained recurrence-free. Monthly maintenance therapy with intravesical docetaxel appears to extend the durability of response to induction treatment for a selected group of patients with BCG-refractory NMIBC, and might decrease the overall risk of recurrence in high-risk NMIBC.

Phase II Study of Thalidomide Plus Dexamethasone Induction Followed by Tandem Melphalan-Based Autotransplantation and Thalidomide-Plus-Prednisone Maintenance for Untreated Multiple Myeloma: A Southwest Oncology Group Trial (S0204)

PURPOSE Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%. PATIENTS AND METHODS Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance. Results Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion. CONCLUSION Both overall survival (P = .0002) and event-free survival (P < .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH.

Clinically Meaningful Improvement in Health-Related Quality of Life in a Randomized Controlled Trial of Certolizumab Pegol Maintenance Therapy for Crohn's Disease

Moderate-to-severe Crohn's disease (CD) is associated with important impairment in health-related quality of life (HRQOL). The aim of this study was to assess the effects of certolizumab pegol (CZP) maintenance therapy on HRQOL. During an open-label induction phase, study participants with moderate-to-severe CD were treated with 400 mg CZP every other week. Responders were randomized to monthly maintenance therapy with CZP or placebo. Clinically meaningful improvement in HRQOL was evaluated with three patient-reported outcome (PRO) instruments. Quality-adjusted life-years (QALYs) were calculated from utility scores derived from the EuroQoL-5 dimensions (EQ-5D). Normal life rating was measured by combining clinical disease activity, HRQOL, and measures of professional work productivity and daily activity. A total of 425 responders to induction therapy were randomized to CZP maintenance (n=215) or placebo (n=210). Participants assigned to CZP maintenance reported clinically meaningful improvements in HRQOL relative to baseline and to placebo-treated participants. More participants receiving treatment with CZP reported clinically meaningful improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score (60 vs. 43%, P<0.001) and in Short-Form 36-Item Health Survey (SF-36) physical (51 vs. 34%, P<0.001) and mental component summary responses (44 vs. 32%, P=0.016) than did those receiving placebo. The proportion of participants who achieved clinically meaningful improvement in the EQ-5D plus health status visual analogue scale (VAS) was significantly greater in those assigned to CZP maintenance than in those assigned placebo (57 vs. 38%, P<0.001). There was also a significantly greater gain in QALYs for the CZP group as compared with the placebo group (mean+/-s.d. 0.25+/-0.10 and 0.21+/-0.11; P=0.001). Significantly more participants receiving CZP maintenance reported living a normal life (21.4%) than did those receiving placebo (12.9%, P=0.019). Maintenance therapy with CZP resulted in statistically significant and clinically meaningful improvements in HRQOL, as assessed by multiple PRO instruments. CZP improved and maintained the quality and quantity of the remission and response, as measured by QALYs. Furthermore, a significant proportion of study participants who received CZP returned to a normal life compared with those who received placebo.

A single institution experience with induction and maintenance intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to BCG therapy

5080 Background: Our initial phase I trial showed docetaxel to be a safe agent for intravesical therapy with no systemic absorption and minimal toxicity after 6 weekly instillations. In that trial, docetaxel appeared to show a 56% complete response (CR) but the durability was only 22% (no additional therapy) to 39% (CR with additional TURBT). Owing to this excellent initial response rate, a second group of patients were treated with a 6 week induction and then given monthly maintenance therapy with intravesical docetaxel for BCG refractory high-grade, non-muscle invasive bladder cancer (NMIBC). Methods: 13 patients with recurrent Ta (n=1), T1 (n=6), and Tis (n=6) TCC who failed at least one prior BCG treatment were treated. Induction therapy was administered to all 13 patients as 6 weekly instillations of 75mg intravesical docetaxel followed by single-dose monthly maintenance therapy for 9 additional instillations in 9 of the patients who experienced complete initial response. Initial response at 12 weeks from the start of induction therapy was evaluated by cystoscopy with biopsy and urine cytology. Follow-up consisted of quarterly cystoscopy with biopsy and cytology and periodic CT scans. Results: The median follow-up was 14.4 months for the entire cohort. Median duration of maintenance treatment was 9 months. 10/13 patients (77%) from the entire cohort had a complete initial response after induction, and 6/13 patients (46%) have remained disease-free in follow-up. Of those who failed, 6 patients underwent TURBT and one underwent cystectomy. 9/10 initial responders completed at least 3 doses of maintenance therapy to date, of whom 6/9 (67%) have remained recurrence-free. Conclusions: Monthly maintenance therapy with intravesical docetaxel appears to extend the durability of response to induction treatment for a select group of patients with BCG refractory high risk NMIBC and may decrease overall risk of recurrence in NMIBC. No significant financial relationships to disclose.

Pseudoprogression after radiotherapy with concurrent temozolomide for high-grade glioma: clinical observations and working recommendations

Background Treatment of newly diagnosed GBM with postoperative RT and concomitant TMZ followed by 6 months of TMZ maintenance therapy has been shown to significantly improve overall survival compared with RT alone. Standard clinical assessments of these patients include Gd-MRI as well as neurologic evaluation. Frequently, patients exhibit immediate post-RT changes in enhancement on Gd-MRI that mimic tumor progression (ie, pseudoprogression or radiation-induced imaging changes). With the introduction of concomitant RT plus TMZ for treatment of malignant glioma, there appears to be an increasing incidence of pseudoprogression. Case Description In our experience, pseudoprogression after concomitant RT plus TMZ is typically not observed at first imaging immediately after completion of the therapy; but delayed focal enhancement mimicking tumor progression frequently occurs during the 6 months of maintenance therapy with TMZ. Pseudoprogression may reflect the radiosensitizing effect of TMZ during concomitant therapy, and retaining patients on treatment allows them to have enhanced survival and preserved quality of life. We observed 3 cases of pseudoprogression among 54 consecutive patients who were treated with this regimen. These patients developed pseudoprogression within 2 to 6 months after completion of concomitant RT plus TMZ, but all 3 patients completed maintenance chemotherapy and remained progression free for at least 15 months after diagnosis. Conclusion Functional imaging may improve the noninvasive diagnosis of pseudoprogression, but randomized prospective studies are needed to evaluate the real impact of pseudoprogression and validate neuroradiological techniques able to make a reliable distinction between tumor recurrence and pseudoprogression.

Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial)

Although many women with recurrent vulvovaginal candidiasis initially benefit from prophylactic intermittent treatment with antimycotics, most of them experience relapse after cessation of therapy, and often they return to the pretreatment recurrence rate. The purpose of this study was to demonstrate the efficacy and safety of an individualized, degressive, prophylactic regimen in 136 women with recurrent vulvovaginal candidiasis. After an induction dose of 600 mg fluconazole during the first week, 117 women started maintenance therapy: 200 mg fluconazole weekly for 2 months, followed by 200 mg biweekly for 4 months, and 200 mg monthly for 6 months, according to their individual response to therapy. All women were tested for recurrences monthly with wet mount microscopy and vaginal culture during the first 6 months and bimonthly during the next 6 months. Patients were allowed to move on to the next level of maintenance therapy only if they were symptom free and microscopy and culture negative. Of the women who were cured successfully after the induction phase, 101 women (90%) were disease-free after 6 months of maintenance therapy with this degressive regimen, and 80 women (77%) were disease-free after 1 year. The weekly incidence of the first clinical relapse was 0.5% during any period of the maintenance phase, and the rate of all new relapses, which included evidence of mycologic or microscopic colonization, was 1% per week. Women who experienced several relapses (poor responders) had experienced more relapses before entering the study compared with the optimal responders (odds ratio, 4.9; 95% CI,1.8-13.7; P = .002), experienced the disease for a longer period of time (6.5 vs 3.7 years; P = .06), and harbored significantly more Candida non-albicans during maintenance therapy (P = .001). No serious side-effects were noted. Individualized, degressive, prophylactic maintenance therapy with oral fluconazole is an efficient treatment regimen to prevent clinical relapses in women with recurrent vulvovaginal candidiasis.

Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial

From April 2003 to December 2006, 195 patients with de novo symptomatic myeloma and younger than 60 years of age were randomly assigned to receive either tandem transplantation up front (arm A, n = 97) or one autologous stem-cell transplantation followed by a maintenance therapy with thalidomide (day + 90, 100 mg per day during 6 months) (arm B, n = 98). Patients included in arm B received a second transplant at disease progression. In both arms, autologous stem-cell transplantation was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m(2)) and granulocyte colony stimulating factor. Data were analyzed on an intent-to-treat basis. With a median follow-up of 33 months (range, 6-46 months), the 3-year overall survival was 65% in arm A and 85% in arm B (P = .04). The 3-year progression-free survival was 57% in arm A and 85% in arm B (P = .02). Up-front single autologous transplantation followed by 6 months of maintenance therapy with thalidomide (with second transplant in reserve for relapse or progression) is an effective therapeutic strategy to treat multiple myeloma patients and appears superior to tandem transplant in this setting. This study was registered at www.ClinicalTrials.gov as (NCT 00207805).

Adaptation of Augmented Berlin-Frankfurt-Munster (ABFM) Therapy in Adolescents and Young Adults with Acute Lymphoblastic Leukemia (ALL).

Comparisons of survival of adolescents up to age 21 years of age treated on either pediatric or adult ALL protocols so far show improved survival for patients (pts) treated with pediatric therapies. ABFM therapy has been shown to be effective therapy for teen-aged pts up to age 21, and is the standard therapy arm of the current Children's Oncology Group high-risk ALL trial. We have initiated a trial of ABFM based therapy for pts up to the age of 30 with lymphoblastic leukemia. Pts receive four drug induction with prednisone 60 mg/m2 daily for 28 days, daunorubicin 25 mg/m2 weekly for four doses, vincristine 2 mg weekly for four doses, and a single dose of intravenous pegylated asparaginase (PEG-asp) in week one of therapy. Intrathecal (IT) cytarabine is given on day one, and IT methotrexate is given on days 8 and 29. IT therapy is intensified depending on the presence of spinal fluid blasts. Induction is extended by two weeks for patients who do not acheive a bone marrow morphologic remission (MR) by day 29. Pts that are in MR by day 15 are rapid early responders; they receive one phase of delayed intensification. Pts who are not in MR by day 15 but enter MR by day 29 or 42 are slow early responders; they receive two delayed intensifications. Upon completion of induction, pts continue with intensive phases of chemotherapy for approximately 6 months. They then start 24 months of maintenance therapy. 13 patients with newly diagnosed ALL have been enrolled with a planned enrollment of 80. The median age is 20 (range 14–28). 10(77%) have pre-B ALL and 3(23%) have T-ALL. 12(92%) are rapid early responders. All pts are in MR by day 29. Minimal residual disease (MRD) status is evaluated at day 29 and day 84 by four-color flow cytometry. 8(62%)pts are MRD negative by day 29. All pts so far are MRD negative by day 84. One pt has relapsed. There are no treatment related deaths. Treatment delays for bone marrow suppression are common. There has been 1 allergic reaction to PEG-asp and 2 cases of clinical pancreatitis. 2 pts have had stroke-like symptoms with MRI findings compatible with treatment toxicity; complete clinical resolution has occurred in both. 4 pts have had grade (Gr) 3–4 hyperglycemia. 2 pts have had Gr 3–4 hyperbilirubinemia. 2 patients have been non-compliant. One pt has had Gr 4 sepsis. Other infectious complications are not common. Early evaluation indicates that ABFM therapy is effective in inducing rapid MR in young adults with ALL. The regimen appears tolerable, but morbidity is frequent. Gr 3–4 toxicity occurs more often than recently reported for similar therapy in adults with ALL (Douer D, et al. Blood , 1 Apr 2007, 2744050).

Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?

The activity of thiopurine S-methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter-subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time-consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype. We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL). Eighty-nine per cent of the children had a homozygous wild-type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 (P < 0.001) but inter-group levels overlapped considerably. There was considerable heterogeneity in the percentage increase in TPMT activity after therapy, and little correlation between metabolites ratio [6-methylmercaptopurine derivative/6-thioguanine nucleotides (6-TGN)] and TPMT activity at the end of 6 months' maintenance treatment. These results show that TPMT activity cannot be used as an accurate tool for 6-mercaptopurine monitoring. Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life-threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6-TGN) and methylated metabolites.

The Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years (PREVENT) Study

To report second-year results from the 2-year maintenance phase of a long-term study to evaluate the efficacy and safety of venlafaxine extended release (ER) in preventing recurrence of depression. Outpatients with recurrent unipolar depression (DSM-IV criteria; N = 1096) were randomly assigned in a 3:1 ratio to 10 weeks of treatment with venlafaxine ER or fluoxetine. Responders (17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score <or= 12 and >or= 50% decrease from baseline) entered a 6-month, double-blind continuation phase on the same medication. Continuation-phase responders were enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo, and fluoxetine responders were continued for each period. The second 12-month maintenance phase compared the time to recurrence of depression with venlafaxine ER (75 to 300 mg/day) versus placebo as the primary efficacy measure. The primary definition of recurrence was a HAM-D(17) total score > 12 and < 50% reduction from baseline (acute phase) at 2 consecutive visits or at the last valid visit prior to discontinuation. The time to recurrence was evaluated using Kaplan-Meier methods and compared between the venlafaxine ER and placebo groups using log-rank tests. Secondary outcome measures included rates of response and remission (defined as HAM-D(17) </= 7). The study was conducted from December 2000 through July 2005. The cumulative probabilities of recurrence through 12 months in the venlafaxine ER (N = 43) and placebo (N = 40) groups were 8.0% (95% CI = 0.0 to 16.8) and 44.8% (95% CI = 27.6 to 62.0), respectively (p < .001). At month 12, using last-observation-carried-forward analysis, the rate of response or remission was significantly higher in the venlafaxine ER group (93%) than in the placebo group (63%; p = .002). Overall discontinuation rates were 28% and 63% in the venlafaxine ER and placebo groups, respectively. Adverse events were the primary reason for discontinuation for 1 patient (2%) in the venlafax-ine ER group and 4 (10%) in the placebo group. An analysis of the combined maintenance phases, which compared the risk of recurrence over 24 months for patients assigned to venlafaxine ER (N = 129) or placebo (N = 129) for the first maintenance phase, showed a significantly greater cumulative probability of recurrence through 24 months for the placebo group (47.3% [95% CI = 36.4 to 58.2]) than for the venlafaxine ER group (28.5% [95% CI = 18.3 to 38.7]; p = .005). In this study, an additional 12 months of maintenance therapy with venlafaxine ER was effective in preventing recurrence of depression in patients who had been responders to venlafaxine ER after acute (10 weeks), continuation (6 months), and initial maintenance (12 months) therapy. ClinicalTrials.gov identifier NCT00046020 (http://www.clinicaltrials.gov).