Pulsed Dexamethasone Research Articles

A study on the outcome of pulse therapy in vesicobullous disorders at a tertiary care centre in Chidambaram, Tamilnadu

Introduction: With the advent of pulse therapy and adjuvant immunosuppressive drugs, the outcome and prognosis of vesicobullous disorders have been improved to a greater extent. Different regimen protocol has been tried and this descriptive study was carried out to assess the outcome of various pulse therapy regimens in vesicobullous disorder at our centre. Methods: A total of 26 vesicobullous patients were enrolled for the study. Diagnosis was made clinically and confirmed by histopathology. They received treatment with Dexamethasone-Cyclophosphamide pulse (DCP) or Dexamethasone -Azathioprine pulse (DAP) or Dexamethasone pulse (DP) therapy and were followed up for clinical remission and side effects of therapy. Results: There was a total of 26 patients comprising 69.23% females and 30.77% males and 50% were between the age group of 40-50 years. Pemphigus vulgaris was the commonest clinical type seen in 69.23%.DCP was given for 22(84.62%) patients, dexamethasone pulse in 3(11.54%) and DAP in one (3.85%). In DCP group 77.27% of patients were in Phase I and 22.73% achieved clinical remission. One patient was refractory to DCP and required rituximab infusion. Weakness, headache, vomiting and weight gain were the commonest side effects encountered in our study. Avascular necrosis of femur and reactivation of pulmonary tuberculosis were the major side effects noticed in one patient each. Conclusion: DCP therapy prove to be an excellent therapeutic regimen in case of vesicobullous disorders to attain faster recovery sparing the adverse effect of corticosteroids. DAP can be an useful therapeutic option in patients who were unmarried or in reproductive age group. Keywords: Pemphigus vulgaris, Dexamethasone-cyclophosphamide pulse. Dexamethasone-azathioprine pulse, Dexamethasone pulse

A Multicentre Randomised Trial of First Line Treatment Pathways for Newly Diagnosed Immune Thrombocytopenia: Standard Steroid Treatment Versus Combined Steroid and Mycophenolate. the Flight Trial

BACKGROUND Immune thrombocytopenia (ITP) is a rare autoimmune condition associated with bleeding risk and fatigue. Current first line ITP treatment is with high dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems, with only 20% remaining in sustained long-term remission. In the UK, mycophenolate (MMF) is frequently used as second line treatment, with retrospective data in ITP suggesting efficacy in 50-80% of patients with good tolerability, although responses are often delayed. The FLIGHT trial aimed to test the hypothesis that MMF combined with corticosteroid is a more effective first line ITP treatment than current standard of care, corticosteroid alone. METHODS In this multicentre, UK based, open label, randomised controlled trial, we randomly assigned 120 patients with ITP requiring first line treatment, to corticosteroid alone (standard care) versus combined corticosteroid and MMF (1:1 ratio). Patients >16 years old, with baseline platelet count <30 x109/L requiring first line treatment were eligible. Exclusions included HIV, Common Variable Immunodeficiency (CVID), pregnancy, breast feeding or an unwillingness to follow contraception advice if assigned to MMF. Dosing of corticosteroid followed international consensus guidance (either dexamethasone pulses or prednisolone initial daily dose of 1mg/kg then taper) and dosing of MMF included a strategy to taper and stop 6 months after starting treatment. The primary efficacy outcome was time from randomisation to treatment failure, defined as platelets <30x109/L and a clinical need for second line treatment (included refractory and relapsed ITP). Secondary outcomes included side effects, bleeding events, and patient reported outcomes (PROM) measured at baseline, 2, 4, 6 and 12 months, by validated questionnaires (SF36v2 (Your health & wellbeing): Quality of life (QoL), FACIT-Fatigue (v4): Fatigue, FACT-Th6 (v4): Bleeding and ICECAP-A v2: QoL) RESULTS Of the 120 ITP patients consented, recruited and randomised (52.4% male, mean age 54 years, range 17-87), mean baseline platelet count was 7 x109/L and mean follow up was for 18 months (maximum follow up 24 months, minimum follow up of 12 months). Patient demographics and baseline values are shown in table 1. Significantly fewer treatment failures occurred in patients randomised to MMF as shown in figure 1 (22% [n=13 of 59] vs 44% [n=27 of 61], aHR=0.41 [0.21, 0.80], p=0.0064, and when secondary ITP patients were excluded, aHR 0.37 [0.19, 0.71] p=0.0029). There were similar rates between the groups of significant adverse events, bleeding events, rescue treatments, hospital admissions and treatment side effects including infection (n=14 in each group), neutropenia (4 patients in corticosteroid group), and gastrointestinal side effects (table 2). However, some aspects of quality of life (QoL) were worse in those patients assigned to the MMF group including physical role, physical function and fatigue. CONCLUSIONS This is the first randomised trial using MMF to treat ITP, demonstrating good efficacy and tolerability, even with the inclusion of elderly patients (27.5% were >70 years, 15.8% >75 years). Therefore, MMF may be considered an effective, well tolerated first line treatment option, alongside a short course of steroids, for some patients with ITP, approximately halving the risk of refractory or relapsed ITP. At final follow up, 56% of patients treated with corticosteroid alone had not required 2nd line treatment, which is higher than previous reports. It is unclear why some aspects of QoL were worse in the MMF group. This is an important reminder that disease response and patient experience may not correlate and emphasises the importance of including PROM outcomes within trials. For ITP, to date, PROMs have only been systematically evaluated in the TPO-RA randomised controlled trials. The FLIGHT trial received ethical approval from NRES Committee South West and is registered, (EudraCT Number: 2017-001171-23. ClinicalTrials.gov number: NCT03156452). This abstract presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0815-20016). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Mycophenolate is unlicensed for ITP treatment

Successful Therapy Reduction in NCI Standard Risk (SR) Highly Favorable Subgroup of Childhood Acute Lymphoblastic Leukemia

Background: Acute Lymphoblastic Leukemia (ALL) is the most common cancer in childhood; it is curable in 80-90% of patients. Current efforts focus on therapy guided by sensitive and specific methods of minimal residual disease (MRD) monitoring, tailoring the type and intensity of chemotherapeutic agents to improve cure rates, quality of life and decrease morbidity. We sought to study the outcome of low risk (LR) ALL treated per modified St Jude total XV Study. Methods: We adopted the modified St Jude total XV study ,B-cell precursor patients with age between 1 and 10 years and presenting leukocyte count <50×10^9/L, leukemic cell DNA index ≥1.16, or TEL-AML1 fusion are classified to have low-risk ALL, provided that they do not have testicular or central-nervous-system (CNS-3) leukemia, hypodiploidy (<45 chromosomes), E2A-PBX1 fusion, or MLL rearrangement, and have a treatment response at day 15 by minimal residual disease (MRD) of <5% and at day 46 of remission-induction <0.01%. We further identified a subgroup of (LR) ALL; defined by presenting age between 2 and 6 years, leukocyte count of <10x 10^9/L and MRD of <0.01% at day 15 of remission induction as Very Low Risk ALL (VLR). Patients with St Jude Low Risk (LR) ALL were treated per St Jude total XV study with several modifications: On 2007; doxorubicin was omitted from reinduction II to lower the total cumulative dose of anthracycline to 80 mg/m2, pulses of dexamethasone and vincristine were stopped at week 72 of maintenance instead of 100. On 2012; for patients identified as VLR; pulses of vincristine /dexamethasone were stopped at week 52 and HDMTX given at week 10 and 12 of maintenance therapy was omitted, frequency of triple Intrathecal chemotherapy remained unchanged (13-18) for LR ALL based on CNS status. Results: We reviewed 184 patients with (LR) between May 2006 to Feb 2018, (the median age at diagnosis, 7.3 years; range, 1.5-9.8). Eighty-two patients (45%) and 102 patients (55%) were treated as VLR and LR ALL respectively. The only significant difference in patients of two groups were age at diagnosis 2-6 years(VLR, 100%; LR, 46%; p<0.001), initial count <10x 10^9/L (VLR, 100%; LR, 65%; p<0.001) and MRD at day 15<0.01%(VLR, 100%; LR, 61%; p<0.001). At median follow up of (48 months; range, 17 to 157), in the subgroups of NCI standard risk defined above; as very low risk(VLR) ALL and low risk (LR) ALL, the 5-year EFS were 92%±3.4; 85%±4 (p=0.12), and the 5-year OS were 98%±1.7; 93%±3.3 (p=0.2) respectively. Conclusion: Chemotherapy was substantially reduced safely in subgroup of children with low risk ALL who were selected on the basis of presenting age, leukocyte count and undetectable MRD levels early at day 15 and at day 46 of remission induction without jeopardizing the survival rate. Patients with St Jude LR ALL maintained outstanding outcomes despite reduction of chemotherapy. Disclosures No relevant conflicts of interest to declare.

Parental functioning during maintenance treatment for childhood acute lymphoblastic leukemia: Effects of treatment intensity and dexamethasone pulses.

During maintenance treatment, Dutch pediatric patients with medium-risk (MR) acute lymphoblastic leukemia (ALL) receive intravenous chemotherapy and cyclic dexamethasone. Dexamethasone affects child's sleep and behavior. Standard-risk (SR) patients only receive oral chemotherapy, without dexamethasone. Effects of stratified therapy on parents are not well known. This study compares parental sleep, distress and quality of life (QoL) with the general population, between MR and SR groups, and on- and off-dexamethasone (MR group). One year after diagnosis, parents of MR patients completed the Medical Outcomes Study (MOS) sleep, distress thermometer for parents and Short Form-12 (SF-12) twice; once on-dexamethasone and once off-dexamethasone. SR parents completed one measurement. Sleep problems, distress and QoL scores (off-dexamethasone) were compared to reference values and between MR and SR. Score differences on- and off-dexamethasone were assessed by multilevel regression analysis. Parents (80% mothers) of 121 patients (57% males; 75% MR, 25% SR) completed 191 measurements. Compared to reference values, parents reported more sleep disturbances, higher distress, and lower mental QoL. Additionally, MR parents reported clinical distress (score≥4), whereas SR parents (on average) did not (mean 4.8±2.4 vs 3.5±2.4, P=.02). Within the MR group, outcomes did not significantly differ on- and off-dexamethasone. Parents of ALL patients report sleep problems, high distress, and QoL impairment. Within the MR group, parental functioning did not differ on- and off-dexamethasone. However, MR parents reported clinical distress more often than SR parents, possibly reflecting differences in prognostic estimates and treatment burden. This perhaps includes the overall strain of cyclic dexamethasone. This study highlights the need for psychosocial support throughout treatment, regardless of risk stratification.

Oral mycophenolate mofetil as a stabilizing treatment for progressive non-segmental vitiligo: results from a prospective, randomized, investigator-blinded pilot study

Dexamethasone oral mini-pulse (OMP) is commonly used to halt progression of non-segmental vitiligo (NSV). There is an unmet need for non-phototherapy, non-corticosteroid therapeutic options for stabilizing actively spreading NSV. To assess the efficacy of oral mycophenolate mofetil in stabilizing active NSV in comparison to OMP. In this prospective, randomized, investigator-blinded study, 50 patients of active vitiligo [baseline vitiligo disease activity (VIDA) score 4] were randomized into two groups in 1:1 ratio. Group A received oral dexamethasone (2.5mg on two successive days a week) and group B received mycophenolate mofetil (up to 2g) for 180days with a treatment-free follow-up period of 90days. Assessment was done using VIDA, number of new lesions in past 30days, and Vitiligo Area Scoring Index (VASI). Arrest of disease progression was defined as the absence of any new lesions in past 30days. Twenty-five patients received OMP (group A, 11 males, 14 females), and 25 received mycophenolate (group B, 12 males, 13 females). In both groups, Kruskal-Wallis revealed a significant trend for reduction in VIDA and the number of new lesions in last 30days, over the treatment and follow-up duration when compared to baseline (p < 0.001). The first significant reduction in VIDA was noticed on 90th day in groups A and B (p < 0.001). In both groups, VIDA reduced significantly at the 180th day compared to baseline (p < 0.001, WMP), only to increase significantly at the 270th day (p < 0.001, WMP). VIDA in group B was marginally higher at 270days than group A (p 0.03; Mann-Whitney). Eighteen and 17 patients achieved VIDA 2 + on the 180th day in groups A and B, respectively. The mean number of new lesions in last 30days reduced significantly in both groups at the 180th day (p < 0.001) and 270th day [p < 0.001; Wilcoxon matched pairs (WMP)] when compared to baseline; but increased significantly at the 270th day compared to the 180th day (p 0.006 WMP). Twenty patients in group A and 18 patients in group B had arrest of the disease activity with treatment. Mean duration to arrest disease progression was 47.2 ± 12.1days in group A, and 52.5 ± 9.3days in group B; p 0.21. The difference between VASI at baseline and VASI at the 180 and 270th days was non-significant in both groups (p 0.18 WMP). Five patients in each group failed the respective treatments. Acne (n = 3), weight gain (n = 3), headache, insomnia and menstrual irregularity (n = 1 each) were the important adverse effects noted with dexamethasone pulse; whereas nausea (n = 6) and diarrhea (n = 4) were the commonest adverse effects noted with mycophenolate. Two patients in group B discontinued treatment because of leucopenia (n = 1) and transaminitis (n = 1) that resolved after the discontinuation of mycophenolate. Both OMP and mycophenolate mofetil halt actively spreading vitiligo, and have distinct adverse effect profiles. These should be offered in progressive vitiligo, especially in circumstances precluding the use of phototherapy. Relapse occurred significantly earlier with mycophenolate, and relapse rate was higher (though non-significant) than dexamethasone OMP. The repigmentation potential is minimal for both therapies. This study was approved by Institute Ethics Committee, and retrospectively registered with clinical trial registry of India (CTRI/2018/02/011,664).

Immune Thrombocytopenia Purpura Secondary to COVID-19

A 73-year-old female with past medical history of essential hypertension, hyperlipidemia, seasonal allergies, and chronic back pain presented to the hospital with complaints of headaches, fevers, fatigue, generalized body aches, shortness of breath, and diarrhea. Initial complete blood count was remarkable for leukopenia with an absolute lymph count of 0.60 K/µL and severe thrombocytopenia (platelet count < 3 K/µL). She was tested for COVID-19 via nasopharyngeal swab polymerase chain reaction (PCR) testing and found positive. Additional labs showed an elevated D-dimer, C-reactive protein, fibrinogen, and lactate dehydrogenase. Vitamin B12 and folate levels were obtained and found to be normal. Peripheral smear showed no schistocytes or additional hematologic abnormalities apart from thrombocytopenia. The patient was transfused one unit of platelets with no improvement in platelet count. Fibrinogen count was obtained and found in normal range at 458 mg/dL. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were all found to be normal. Immune thrombocytopenia purpura (ITP) was suspected and intravenous immunoglobulin (IVIG) was administered at a dose of 1 g/kg/day for two doses. By day 4, the patient had marked response to treatment with platelet recovery to 105 K/µL and subsequently discharged by day 5 with complete resolution of symptoms and platelet count of 146 K/µL. Twenty-eight days after discharge, she presented to hematology clinic with platelet count of 8 K/µL. Repeat nasopharyngeal swab PCR COVID testing was negative and she was treated with IVIG and pulse dexamethasone with prompt response, confirming suspicion of underlying, undiagnosed ITP prior to COVID infection.

Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932.

10509 Background: Post-hoc analysis of COG P9904 identified a low risk (LR) group of SR B-ALL patients aged 1-9.99 years with WBC &lt; 50,000/µL, no CNS3, and either ETV6/RUNX1 or double trisomies (DT) of chromosomes 4 and 10 with day 8 peripheral blood (PB) and day 29 marrow (BM) minimal residual disease (MRD) &lt; 0.01% who had a 5-year event-free survival (EFS) of 97±2% and overall survival (OS) 98.8±0.8%. Outstanding results were also obtained for LR patients on COG AALL0331 using CCG-based ALL therapy. AALL0932 tested prospectively whether LR B-ALL patients could attain a 5-year EFS ≥95% with these regimens. Methods: Following a 3-drug induction, eligible AALL0932 LR patients had NCI SR B-ALL (no testicular leukemia, unfavorable genetics or Down syndrome) with DT or ETV6/RUNX1 fusion, CNS1, no steroid pre-treatment, with Day 8 PB and Day 29 BM MRD &lt; 0.01%. Between 2010-16, 603 LR patients were randomized to P9904-based regimen LR-M (n = 301) or CCG 1991/COG AALL0331-based regimen LR-C (n = 302). LR-M included 6 24-hour infusions of 1 gm/m2 of methotrexate (MTX) with leucovorin rescue, but no anthracyclines or alkylating agents. Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8. Boys and girls were treated for 2.5 years from diagnosis. LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose). LR-C Maintenance included daily 6-MP and weekly oral MTX with 5-day pulses of DEX and 1 dose of VCR given every 12 weeks. Girls received 2 years and boys 3 years of therapy from the start of IM I. Results: Both regimens achieved outstanding outcomes: 5-yr disease-free survival (±SE) 98.8%±0.8% for LR-M and 98.5%±0.9% for LR-C (p = 0.67). Both had 5-yr OS 100%. Therapies were well tolerated with higher rates of mucositis (12.9 vs 6.3%; p = 0.008) and allergic reactions (2.3% vs 0%; p = 0.02) on LR-C. Conclusions: AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Clinical trial information: NCT01190930.

Redundancy in circadian clocks?

Circadian Rhythms The transcription factor BMAL1 is a core component of the mammalian circadian clock; without it, circadian behaviors are abolished. However, Ray et al. found that in animals lacking BMAL1, peripheral tissues synchronized with a brief pulse of the glucocorticoid hormone dexamethasone appear to retain a 24-hour pacemaker that sustains rhythmic gene expression, protein abundance, and protein phosphorylation in excised liver cells and fibroblasts (see the Perspective by Brown and Sato). These oscillations persisted in the absence of cues from changes in light or temperature. The results raise intriguing questions about the possible nature of the oscillator that maintains the observed rhythms. Science , this issue p. [800][1]; see also p. [740][2] [1]: /lookup/doi/10.1126/science.aaw7365 [2]: /lookup/doi/10.1126/science.aba5336

Circadian rhythms in the absence of the clock gene Bmal1.

Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is a principal driver of a molecular clock in mammals. Bmal1 deletion abolishes 24-hour activity patterning, one measure of clock output. We determined whether Bmal1 function is necessary for daily molecular oscillations in skin fibroblasts and liver slices. Unexpectedly, in Bmal1 knockout mice, both tissues exhibited 24-hour oscillations of the transcriptome, proteome, and phosphoproteome over 2 to 3 days in the absence of any exogenous drivers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. We suggest that such oscillations might be underpinned by transcriptional regulation by the recruitment of ETS family transcription factors, and nontranscriptionally by co-opting redox oscillations.

Safety and efficacy of eltrombopag plus pulsed dexamethasone as first-line therapy for immune thrombocytopenia.

Current first-line treatments for immune thrombocytopenia (ITP) usually have transient effects and sustained platelet response off therapy remains low. We evaluated whether eltrombopag plus pulsed dexamethasone as first-line therapy can increase the proportion of patients maintaining platelet counts >50×109 /l for a prolonged period without further ITP therapy. Treatment consisted of eltrombopag 25-75mg daily according to platelet response for 12weeks plus dexamethasone, 40mg daily for four consecutive days every fourweeks for 1-3 courses. Primary endpoint was durable response off therapy defined as maintaining platelet counts >50×109 /l for more than sixmonths without further ITP therapy. Fifty ITP subjects were enrolled between November 2014 and March 2019. Out of 46 evaluable subjects, 26 (56·5%) had achieved the primary endpoint. The median platelet counts at sixmonths off-treatment follow-up were 158×109 /l. Only two out of 26 responders had relapsed at eight- and nine-month follow-up. The remaining 24 are still maintaining platelet counts >50×109 /l, the longest over threeyears. All subjects tolerated treatment well and no Grade 3 or above adverse effects were reported. Eltrombopag plus pulsed dexamethasone as a first-line therapy could result in durable response off therapy in a significant number of ITP subjects.

Evaluation of treatment plan by three-period pulses of high-dose dexamethasone among patients with primary immune thrombocytopenia on platelet count response and adverse events: A randomized Clinical trial.

Background:Primary immune thrombocytopenia (ITP) decreases platelet count as well as increases the risk of bleeding due to platelet destruction in an autoimmune disorder. For many years, prednisone (PDN) has been the standard first-line treatment in ITP practical guidelines. The current randomized clinical trial compared the efficacy of treatments between three-pulse high-dose dexamethasone (HD-DXM) and the traditional PDN regimen among untreated patients with ITP in accordance with platelet count responses and adverse events.Materials and Methods:We randomly assigned eligible patients with ITP to receive PDN or a three-pulse regimen of HD-DXM. In the HD-DXM group, 40 mg of DXM was administered intravenously for 4 consecutive days and was repeated in 14-day intervals for three pulses of treatment. Patients in the PDN group received 1.0 mg/kg of PDN orally per day for 4 consecutive weeks. The Mann–Whitney test was used for comparing the median of platelet count between the two groups, and logistic regression was used to evaluate odds ratio (OR) in the response rate of platelet count between the two groups. Blindness was not applied for both patients and physicians.Results:The initial response rate of platelet count in the HD-DXM group was significantly higher than the PDN group (P < 0.05). According to the results of logistic regression, the initial and sustained response (SR) rate of platelet count in the HD-DXM group was significantly higher than the PDN group (OR: 5.68 and 4.17, respectively, P < 0.05). In fact, in the HD-DXM group, more patients reached SR after the 8-month follow-up (88.9% vs. 66.6%, P < 0.05).Conclusion:In patients with ITP disease who have not received any kind of treatment, HD-DXM was more effective than conventional PDN therapy.

Giant pyoderma gangrenosum treated successfully with combination of dexamethasone pulse and cyclosporine

Giant pyoderma gangrenosum treated successfully with combination of dexamethasone pulse and cyclosporine

Lack of Benefit of Extended Vincristine and Dexamethasone Pulses during Maintenance Treatment of Childhood Acute Lymphoblastic Leukemia: A Multicenter Randomized Controlled Study of Chinese Children Cancer Group (CCCG)-ALL-2015

Introduction: The efficacy of extended duration of vincristine (VCR) and dexamethasone (DEX) pulses in the treatment of childhood acute lymphoblastic leukemia (ALL) is uncertain in the context of contemporary chemotherapy. By contrast, the long-term sequelae of vincristine-induced peripheral neuropathy and dexamethasone-related metabolic syndrome, osteonecrosis, and neurocognitive impairment are well recognized. We therefore conducted a randomized study in the CCCG-ALL-2015 protocol participated by 20 hospitals in China to compare the event-free survival (EFS) and overall survival (OS) between children with newly diagnosed ALL who did or did not receive extended duration of VCR+DEX pulses during maintenance treatment. Methods: After remission induction and consolidation treatment with high-dose methotrexate and mercaptopurine, all patients received antimetabolite-based maintenance treatment. During the initial 20-week of maintenance treatment, low-risk (LR) patients received two reinduction cycles and three pulses of VCR+DEX pulses, while intermediate-/high-risk (I/HR) patients received daily mercaptopurine interrupted every three weeks with PEG-asparaginase, mercaptopurine, daunorubicin, and VCR+DEX pulses for 5 courses followed by a reinduction treatment. During the subsequent maintenance treatment, all patients received VCR+DEX pulses every 4 weeks for 5 cycles. All Philadelphia chromosome (Ph)-negative patients were then stratified and randomized during the fifth cycle of maintenance course (between weeks 51 and 53) to or not to receive the VCR+DEX pulse every 8 weeks for 7 cycles between weeks 54 and 109; the remaining maintenance treatment between weeks 110 and 125 consisted of only mercaptopurine and methotrexate. Results: Between January 2015 and December 2018, 3985 eligible Ph-negative patients, including 2318 (58.2%) LR patients and 1667 (41.8%) I/HR patients, were enrolled in the study. With a median follow-up of 2.53 years (IQR 1.82-3.26), the 4-year event-free survival (EFS) and overall survival (OS) rates were 91.6% (95% CI 89.4-93.9) and 98.8% (95% CI 98.2-99.4) in the LR patients, and 85.9% (95% CI 83.2-88.7) and 95.4% (95% CI 93.8-96.9) in the I/HR patients, respectively. The 4-year OS were 99.0% (95%CI, 98.3%-99.8%) in the 1145 LR patients randomized to receive VCR+DEX pulse (LR-A) and 98.6% (95% CI, 97.7%-99.5%) in the 1173 LR patients not to receive the pulse (LR-B, hazard ratio 1.5, 95% CI 0.6-4.0; p=0.374, Fig 1A). The 4-year EFS were 91.1% (95% CI, 87.4%-95.1%) in LR-A group and 92.0% (95% CI, 89.6%-94.5%) in LR-B group (hazard ratio 1.3, 95% CI 0.8-1.9; P=0.27; Figure 1B). There were no significant differences between LR-A and LR-B group among patients with or without the t (12;21) (ETV6-RUNX1) in univariate analysis (Table1). Likewise, there was no significant difference in the 4-year OS between the 834 I/HR patients who did (I/HR-A) and the 833 I/HR patients who did not (I/HR-B) receive the pulse: 94.3% (95% CI, 91.7%-97.0%) versus 96.3% (95%CI 94.6%-98.0%, hazard ratio 0.8, 95% CI 0.4-1.4; P=0.421) (Fig 1C). The 4-year EFS were 83.6% (95%CI 79.2%-88.3%) for I/HR-A group and 88.1% (95%CI 85.1%-91.2%, P=0.372) for I/HR-B group (hazard ratio 0.9, 95% CI 0.6-1.2; P=0.37) (Figure 1D). There were no significant differences between I/HR-A and I/HR-B group among patients with B-ALL, T-ALL or t (1;19) (TCF3-PBX1) in the univariate analysis (Table1). Conclusion: The additional pulses of VCR+DEX pulse beyond one year of maintenance treatment had no impact on 4-year EFS or OS among LR or I/HR patients. If this finding remains unchanged with additional follow-up, the VCR+DEX pulses can be omitted after one year of maintenance therapy in childhood ALL. Disclosures No relevant conflicts of interest to declare.

Excellent Outcomes with Reduced Frequency of Vincristine and Dexamethasone Pulses in Children with National Cancer Institute (NCI) Standard-Risk B Acute Lymphoblastic Leukemia (SR B-ALL): A Report from Children's Oncology Group (COG) Study AALL0932

Background: A key component of COG maintenance chemotherapy for pediatric B-ALL has been the inclusion of vincristine/steroid pulses administered every 4 weeks. With the intensification of pre-maintenance therapy and modern risk stratification, there is uncertainty regarding the optimal frequency of these pulses in the context of modern ALL therapy. AALL0932 was designed to optimize maintenance therapy by asking two questions: (1) whether giving vincristine/dexamethasone (VCR/DEX) pulses every 12 weeks was non-inferior to every 4 week pulses; and (2) whether a starting weekly oral methotrexate (MTX dose) of 40 mg/m²/dose would be superior to the standard 20 mg/m2/dose. We previously reported that there was no benefit to intensifying oral methotrexate during maintenance therapy (ASH 2017). We now report on the outcomes of the VCR/DEX pulses. Methods: Average risk (AR) patients participating in the randomization had NCI SR B-ALL without CNS3 or testicular leukemia, unfavorable genetic characteristics or Down syndrome, AND either favorable genetics (trisomies of chromosomes 4 &amp;10 or ETV6/RUNX1 fusion) with Day 8 peripheral blood (PB) minimal residual disease (MRD) ≥ 0.01% or CNS2 status, Day 29 bone marrow (BM) MRD &amp;lt; 0.01%, OR if neutral cytogenetics, had Day 8 PB MRD &amp;lt; 1% and Day 29 BM MRD &amp;lt; 0.01%. AR patients were randomized to 1 of 4 Maintenance regimens using a 2 x 2 factorial design: (A): VCR/DEX pulses every 4 weeks and oral MTX 20 mg/m²/week (standard arm); (B): VCR/DEX pulses every 4 weeks and oral MTX 40 mg/m²/week; (C): VCR/DEX pulses every 12 weeks and oral MTX 20 mg/m²/week; and (D): VCR/DEX pulses every 12 weeks and oral MTX 40 mg/m²/week. Results from the MTX randomization have been previously reported (ASH 2017). Between 2010 and 2016, 2364 patients were randomized at the start of maintenance to VCR/DEX pulses every 4 weeks [Arms A and B (n=1186)] or VCR/DEX pulses every 12 weeks [Arms C &amp; D (n=1178)]. Results: The 5-year disease-free survival (DFS) (±SE) measured from the time of randomization for the AR subset of patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 94.1% ±1.0% vs. 95.1% ±0.9%, respectively (one-sided p=0.86 indicating no evidence of DFS inferiority for 12 week frequency). The 5-year overall survival (OS) (±SE) for the AR patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 98.3% ±0.5%, vs. 98.6% ±0.5%, respectively (one sided p=0.69). There was no evidence of significant interaction between the MTX and VCR/DEX pulses randomizations. Conclusions: AALL0932 demonstrated that the AR subset of patients with SR B-ALL who received VCR/DEX pulses every 12 weeks maintained outstanding outcomes similar to those who received pulses every 4 weeks. The decreased frequency of VCR/DEX pulses will be incorporated into frontline B-lineage COG ALL trials thereby dramatically improving patient and family quality of life. Disclosures Angiolillo: Servier Pharmaceuticals: Consultancy. Schore:Janssen Research &amp; Development, LLC: Research Funding; AMGEN INC: Research Funding. Zweidler-McKay:ImmunoGen: Employment. Borowitz:Beckman Coulter: Honoraria. Relling:Servier Pharmaceuticals: Research Funding. Raetz:Pfizer: Research Funding. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Hunger:Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership; Jazz: Honoraria; Novartis: Consultancy.

Sweet’s syndrome: A Therapeutic challenge

Sweet’s syndrome: A Therapeutic challenge - IJCED- Print ISSN No: - 2581-4710 Online ISSN No:- 2581-4729 Article DOI No:- 10.18231/j.ijced.2019.037, IP Indian Journal of Clinical and Experimental Dermatology-IP Indian J Clin Exp Dermatol

Managing the challenging cases of pemphigus vulgaris with modified pulse therapy: case series

&lt;p class="abstract"&gt;In pemphigus vulgaris, pulse therapy is a promising modality to achieve better therapeutic response and to minimize the side effects of daily steroids. Here we report 5 different challenging situations where we successfully managed with modification of pulse therapy. Our first case had multiple comorbidities with persistent skin infections managed with dexamethasone and cyclophosphamide pulse (DCP) and interval pulse. The second case was unmarried hypertensive male with poor DLQI managed with Azathioprine pulse therapy. The third case was uncontrolled diabetic patient with pulmonary tuberculosis managed with rituximab. The fourth case was diabetic and hypertensive was managed with one day dexamethasone cyclophosphamide pulse therapy (DCP). The fifth case was not completed family with cushingoid features managed with dexamethasone azathioprine pulse therapy (DAP). Pulse therapy is effective in controlling disease activity in pemphigus. But it can be modified in some situations according to the patient needs.&lt;/p&gt;

Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome

Background: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. Methods: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m²) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m² every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m² every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. Results: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. Conclusion: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

Eltrombopag Plus Pulsed Dexamethasone As First Line Therapy for Subjects with Immune Thrombocytopenic Purpura (ITP)

▪Background: Eltrombopag is an oral thrombopoietin receptor agonist that has been licensed for use as second line therapy in ITP patients. For most subjects, platelet counts usually return to baseline within 2 weeks of eltrombopag discontinuation, however, up to 15% of subjects may maintain a prolonged response after discontinuation (BJH Volume 165(6) 2014 865-869). Therefore, we conducted a pilot study to evaluate whether a 12-week course of eltrombopag plus pulsed dexamethasone as first line therapy can increase the proportion of patients with prolonged response.Methods: This multicenter, single arm, open-label pilot study was performed on subjects with newly diagnosed ITP. Eligible subjects had confirmed ITP and platelet counts <30×109/L or platelet counts < 50×109/L and significant bleeding symptoms (WHO bleeding scale 2 or above). Patients must have no prior ITP treatment except platelet transfusions. All patients provided written informed consent before enrolment. This study was conducted in accordance with the Declaration of Helsinki.Eligibility criteria included isolated thrombocytopenia with exclusions of secondary immune or drug-induced thrombocytopenia, cancer and pregnancy related thrombocytopenia and virus induced thrombocytopenia. Bone marrow examination is not mandatory but must be consistent with peripheral platelet consumptions with no features of dysplasia, extensive fibrosis, aplasia, marrow infiltration if performed.Treatment consisted of eltrombopag 25-75mg daily according to platelet response for 12 weeks plus pulsed dexamethasone, 40mg daily for 4 consecutive days every 4 weeks for 1-3 courses. The primary endpoint was prolonged response defined as platelet counts > 50×109/L for more than 6 months without any ITP therapy after completion of 12-week therapy.The reported prolonged response rate of dexamethasone alone is around 25%, a sample size of 60 subjects will be required to detect a doubling of the prolonged response rate at a significant level of 0.05 with power of 0.9. Differences between prolonged responder and relapsed subject groups were analyzed by the Student's t-test. P values <0.05 were considered significant.Results:46 subjects were enrolled from February 2015 to July 2018. The median age was 40 years, range 18 to 81; 29 were female and 17 were male. Median platelet counts at baseline were 18×109/L, range 1 to 44×109/L. One subject withdrew consent before starting treatment. One was withdrawn because of protocol violations. Three subjects did not have significant increase in platelet counts during the entire 12 weeks treatment despite a maximum of eltrombopag 75mg daily and 3 courses of pulsed dexamethasone. One of them subsequently turned out to be amegakaryocytic thrombocytopenia. These 5 subjects were still included in the final analysis.Twenty-nine subjects had good initial response to treatment and completed at least 6 months follow-up (Fig 1), 19 of them had achieved the primary end point of platelet counts count> 50×109/L for more than 6 months after discontinuation of eltrombopag. The median platelet counts at 6 months were 150×109/L (range 53 to 371×109/L), Average eltrombopag dose was 36.8mg daily and average pulsed dexamethasone was 2.2 courses. Eleven subjects maintained prolonged response for 12 months or more.Four subjects are still receiving treatment and 8 subjects are still on the 6 months off-therapy observation period (median follow up is 12 weeks, range 4 to 21 weeks).Ten subjects relapsed after discontinuation of eltrombopag(Table 1). The median time to relapse was 47.8 days, range 15 to 148 days. Average daily eltrombopag was 45mg and average pulsed dexamethasone was 2.5 courses.So far, the prolonged response rate of 56 % (19/34) among 34 evaluable subjects is very encouraging. According to statistical analysis, seven more prolonged responders among the remaining 26 subjects (14 yet enrolled and 12 pending final evaluation) would suggest that 12-week of eltrombopag plus pulsed dexamethasone as first line therapy may significantly improve prolonged response rate in ITP patients. All subjects tolerated the treatment well and no Grade 3 or above adverse effects were reported.Conclusions: Eltrombopag plus pulsed dexamethasone is an effective and safe treatment for ITP as a first line therapy that can provide sustained prolonged response in adults. This therapy could be a new treatment option for ITP subjects. DisclosuresCheng:Novartis: Research Funding; BMS: Honoraria, Speakers Bureau; Astrazeneca: Honoraria, Speakers Bureau.

Corticosteroids in chronic inflammatory demyelinating polyneuropathy

BackgroundChronic inflammatory demyelinating polyneuropathy (CIDP) can be treated with corticosteroids or intravenous immunoglobulins. Various corticosteroid regimens are currently used in CIDP, but it is unknown whether they are equally efficacious. In this retrospective study, we compared efficacy and safety of three corticosteroid regimens in CIDP patients.MethodsWe included treatment naïve patients that fulfilled the EFNS/PNS criteria for CIDP. Patients were treated with corticosteroids according to the local protocol of three CIDP expertise centres. Corticosteroid regimens consisted of daily oral prednisolone, pulsed oral dexamethasone, or pulsed intravenous methylprednisolone. Outcomes were number of responders to treatment, remission rate of treatment responders, overall probability of 5-year remission, and the occurrence of adverse events.ResultsA total of 125 patients were included. Sixty-seven (54%) patients received daily prednisone or prednisolone, 37 (30%) pulsed dexamethasone, and 21 (17%) pulsed intravenous methylprednisolone. Overall, 60% (95% CI 51–69%) responded to corticosteroids, with no significant difference between the three treatment regimens (p = 0.56). From the 75 responders, 61% (95% CI 50–73%) remained in remission, during a median follow-up of 55 months (range 1–197 months). The probability of responders reaching 5-year remission was 55% (95% Cl 44–70%), with no difference between the three groups. Adverse events leading to a change in treatment occurred in ten patients (8%). Two patients had a serious adverse event.ConclusionCorticosteroids lead to improvement in 60% of patients and to remission in 61% of treatment responders. There were no differences between treatment modalities in terms of efficacy and safety.

Imaging Cobalamin Uptake within Malignant Breast Tumors In Vivo

PurposeTo image the uptake of cobalamin (Cbl) within malignant breast tumors in vivo.ProceduresPrior to surgery 20 female patients with clinically suspected breast tumors were intravenously administered 0.25 μg of an In-111 labeled 5-deoxyadenosylcobalamin (AC) analog ([111In]AC) and sequentially imaged with whole-body planar (WBP) and single-photon emission computed tomography (SPECT) between 2–5 h and 20–24 h post-injection (P.I.). The tumor to background (T/B) ratio for [111In]AC in breast tumors at 2–5 h was correlated to its expression of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors. Subsequent pulse chase (PC) experiments in nude mice burdened with the MDA-MB-231 triple-negative (TN) breast tumor xenograft measured the effect that pulses of AC or dexamethasone (DEX) had on [111In]AC uptake in both normal murine tissue and the TN breast tumor.ResultsThe mean [111In]AC T/B ratio of the patients’ 18 resected tumors was 5.8. Comparing ER- and PR-positive tumors (n = 11) to TN and HER2-positive tumors (n = 7), the mean [111In]AC T/B ratios at 2–5 h P.I. were 3.2 (range 1.8–5.6) and 10.4 (range 3.3–22.5), respectively. Pulses of 2.0 μg of AC at 2, 8, or 24 h; or 40.0 μg of DEX at 24 h prior to injecting 0.5 μg of [111In]AC, increased mean tracer uptake in the MDA-MB-231 tumors by 26.4, 71.5, 92.6, and 49.1 %, respectively. Only the 2- and 24-h PC intervals concomitantly suppressed [111In]AC uptake in normal murine tissue while enhancing [111In]AC uptake in MDA-MB-231 tumors.ConclusionThe uptake of Cbl within malignant breast tumors can be imaged clinically. Cbl uptake is greatest in TN and HER2-positive breast tumors. A solitary bolus of AC or DEX increases the [111In]AC uptake within a breast tumor in vivo. Investigating the cytogenetic mechanisms controlling the endocytosis of Cbl in malignant breast tumors is warranted.