Successful Remission Induction Research Articles

P1165 Longitudinal observation of symptoms of fatigue, depression and anxiety in Crohn’s disease

Abstract Background In IBD, extraintestinal symptoms (EIS) such as fatigue, depression and anxiety are a major burden on the patients’ quality of life (QoL). These EIS are more prevalent in active disease but can persist in remission. A deleterious effect of depression and anxiety on the course of disease has already been confirmed in longitudinal studies, but to our knowledge the relevance and nature of fatigue symptoms in this regard have not been addressed longitudinally. We examined patients with Crohn’s disease (CD) in an active disease state and followed them up after 3-6 months to evaluate the presence, course and relationships of EIS. Methods We recruited patients with CD in active disease and healthy controls (HC). Patients were instructed to complete self-report questionnaires to measure clinical activity (HBI), fatigue (WEIMuS), anxiety and depressive symptoms (HADS-A, -D) and QoL (IBDQ) before a change of therapy (T1, n=49) and 3-6 months later (T2, n=46). HCs (n=25) answered the same questionnaires except IBDQ. We compared EIS scores between PAT and HC, as well as between T1 and T2, and evaluated EIS changes in PAT with regard to response vs. non-response at T2. Finally, we explored the influence of EIS on clinical activity at T2. Results At both visits and in each of the questionnaires analysed, patients showed higher scores for EIS compared to HC (all pcorr<0.004, FDR 0.05). In patients, fatigue scores were significantly lower at T2 compared to T1 (pcorr=0.034). Patients’ QoL improved (pcorr=0.003), while depression and anxiety didn’t change significantly between T1 and T2. When comparing remitted vs non-remitted CD at T2 (see Table 1), remitted patients had larger differences in EIS scores from T1 to T2 (all pcorr=0.012). Also, remitted patients showed significantly higher and more positive changes in QoL compared to non-remitted patients (pcorr=0.005). In multiple regression analysis, BMI, HADS-D and WEIMuS at T1 were positive predictors for the HBI at T2 (all pcorr<0.019). In contrast, HADS-A at T1 was a negative predictor for HBI at T2 with pcorr=0.002 (see Figure 1). Conclusion As expected, EIS were higher in CD compared to HC. Patients who responded to therapy changes showed higher decrease of fatigue, depression and anxiety and higher increases of QoL compared to non-responders. Higher BMI, depressive and fatigue symptoms at T1 were associated with non-response, higher anxiety at T1 could be associated with response. These findings need to be confirmed in larger studies but indicate the importance of successful induction of remission to improve not only intestinal inflammation and QoL, but also fatigue and affective symptoms.

Short-Term and Intermediate Efficacy of Tacrolimus for Active Ulcerative Colitis: A Single-Center Retrospective Analysis in Japan.

Background and aim Tacrolimus (tac) is used for induction therapy in refractory and severe ulcerative colitis (UC) cases. The aim of this study was to identify the factors contributing to the induction of remission and to assess the endoscopic or histologic improvement rates following induction of remission by tac. Methods This study examined data from 67 UC patients treated with tac for induction of remission out of 515 patients attending Dokkyo Medical University Hospital. The primary endpoint of the study was the analysis of factors contributing to successful induction of remission treatment with tac. The secondary endpoints were the corticosteroid-free remission rate at 52 weeks after tac induction and the endoscopic and histologic improvement rates following induction of remission. Results Analysis of factors contributing to successful induction of remission by tac showed the Lichtiger index at the beginning of remission induction therapy was 9.5 ± 2.5 for the successful remission group and 11.5 ± 2.4 for the unsuccessful remission group (p = 0.002). The proportions of patients who had used immunomodulators were 13/45 (28.9%) for the successful remission group and 14/22 (63.6%) for the unsuccessful remission group (p = 0.006). The proportions of patients who had used anti-tumor necrosis factor(TNF)α biologics were 4/45 (8.9%) for the successful remission group and 8/22 (36.4%) for the unsuccessful remission group (p = 0.006). Conclusion Patients with UC who are potential candidates for intensification of remission maintenance therapy are good candidates for induction of remission with tac. Moreover, improvement in endoscopic inflammation might be a predictive marker of response to remission induction therapy with tac.

Successful remission induction with reduced-dose all-trans retinoic acid for acute promyelocytic leukemia complicated by COVID-19

A 43-year-old man with pancytopenia was diagnosed with acute promyelocytic leukemia (APL). On the first day of induction therapy with all-trans retinoic acid (ATRA) alone, he presented with high fever and was found to have coronavirus disease 2019 (COVID-19) infection by SARS-CoV2 antigen test. While it is generally recommended to delay treatment for APL patients with COVID-19 unless urgent APL treatment is required, this patient needed to continue treatment due to APL-induced disseminated intravascular coagulation (DIC). Considering the challenge of distinguishing between differentiation syndrome (DS) and COVID-19 exacerbation, the ATRA dosage was reduced to 50%. The patient was able to continue treatment without development of DS or exacerbation of DIC, leading to his recovery from COVID-19 and remission of APL.

Successful remission induction of IgG4-related ophthalmic disease by obinutuzumab therapy: a retrospective study of 8 patients.

To evaluate the therapeutic efficacy and safety of obinutuzumab in remission induction for IgG4-related ophthalmic disease (IgG4-ROD) patients. Eight IgG4-ROD patients were retrospectively enrolled. They were intravenously administered 1000 mg obinutuzumab at baseline and examined for changes in physical signs, orbital structure imaging parameters, IgG4-related disease responder index (IgG4-RD RI), serological index, and adverse events during treatment. The number of treatment sessions was based on treatment response. The mean IgG4-RD RI scores of all patients at baseline (7.75 ± 2.92) and after treatment (2.00 ± 0.76) were highly significantly different (P < 0.001). Six patients achieved complete remission (CR) (75%) and two patients achieved partial remission (25%). The mean serum IgG4 levels at baseline (9.45 ± 6.95 g/L) and after treatment (1.55 ± 1.09 g/L) showed a mean decrease of 83% (P = 0.0079). The serum IgG4 level correlated well with IgG4-RD RI at baseline and that after each treatment (r = 0.852, P < 0.01; r = 0.78, P < 0.001). In patients with CR, the serum IgG4 levels at baseline correlated positively with dose numbers required for CR (r = 0.86, P < 0.05). Five patients (62.5%) experienced infusion-related reactions (IRRs) during the first obinutuzumab infusion, while only one (12.5%) experienced IRRs during all subsequent eight infusions. Obinutuzumab is a safe and promising therapeutic option for IgG4-ROD. It rapidly reduces ocular inflammation and serum IgG4 levels to avoid excessive corticosteroid usage and reduce potential risk of adverse events.

Ulcerative Colitis-associated Spondyloarthritis Successfully Treated with Infliximab in the Absence of Enhanced TNF-α Responses

Although concurrent occurrence of spondyloarthritis (SpA) and ulcerative colitis (UC) is sometimes seen, the profiles of cytokines have been poorly understood in UC-associated SpA. We herein report a case of UC-associated SpA successfully treated with infliximab. Profiles of cytokines in the serum and colonic mucosa were characterized by an enhanced expression of IL-6 but not TNF-α. Successful induction of remission by infliximab was associated with the downregulation of IL-6 expression but no significant alteration in TNF-α expression. These findings suggest that some cases of UC-associated SpA might be driven by IL-6, and infliximab might be effective in cases lacking enhanced TNF-α responses.

Treatment Options for Recurrent Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

Efficacy and safety of secukinumab in patients with giant cell arteritis: study protocol for a randomized, parallel group, double-blind, placebo-controlled phase II trial

BackgroundOne key pathological finding in giant cell arteritis (GCA) is the presence of interferon-gamma and interleukin (IL)-17 producing T helper (Th) 1 and Th17 cells in affected arteries. There is anecdotal evidence of successful induction and maintenance of remission with the monoclonal anti-IL-17A antibody secukinumab. Inhibition of IL-17A could therefore represent a potential new therapeutic option for the treatment of GCA.MethodsThis is a randomized, parallel-group, double-blind, placebo-controlled, multi-center, phase II study in which patients, treating physicians, and the associated clinical staff as well as the sponsor clinical team are blinded. It is designed to evaluate efficacy and safety of secukinumab compared to placebo in combination with an open-label prednisolone taper regimen. Patients included are naïve to biological therapy and have newly diagnosed or relapsing GCA. Fifty patients are randomly assigned in a 1:1 ratio to receive either 300 mg secukinumab or placebo subcutaneously at baseline, weeks 1, 2 and 3, and every 4 weeks from week 4. Patients in both treatment arms receive a 26-week prednisolone taper regimen. The study consists of a maximum 6-week screening period, a 52-week treatment period (including the 26-week tapering), and an 8-week safety follow-up, with primary and secondary endpoint assessments at week 28. Patients who do not achieve remission by week 12 experience a flare after remission or cannot adhere to the prednisolone tapering will enter the escape arm and receive prednisolone at a dose determined by the investigator’s clinical judgment. The blinded treatment is continued. Two optional imaging sub-studies are included (ultrasound and contrast-media enhanced magnetic resonance angiography [MRA]) to assess vessel wall inflammation and occlusion before and after treatment. The primary endpoint is the proportion of patients in sustained remission until week 28 in the secukinumab group compared to the proportion of patients in the placebo group. A Bayesian approach is applied.DiscussionThe trial design allows the first placebo-controlled data collection on the efficacy and safety of secukinumab in patients with GCA.Trial registrationClinicalTrials.gov NCT03765788. Registration on 5 December 2018, prospective registration, EudraCT number 2018-002610-12; clinical trial protocol number CAIN457ADE11C.

Distinguishing active from quiescent disease in ANCA-associated vasculitis using attenuated total reflection Fourier-transform infrared spectroscopy

The current lack of a reliable biomarker of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis poses a significant clinical unmet need when determining relapsing or persisting disease. In this study, we demonstrate for the first time that attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy offers a novel and functional candidate biomarker, distinguishing active from quiescent disease with a high degree of accuracy. Paired blood and urine samples were collected within a single UK centre from patients with active disease, disease remission, disease controls and healthy controls. Three key biofluids were evaluated; plasma, serum and urine, with subsequent chemometric analysis and blind predictive model validation. Spectrochemical interrogation proved plasma to be the most conducive biofluid, with excellent separation between the two categories on PC2 direction (AUC 0.901) and 100% sensitivity (F-score 92.3%) for disease remission and 85.7% specificity (F-score 92.3%) for active disease on blind predictive modelling. This was independent of organ system involvement and current ANCA status, with similar findings observed on comparative analysis following successful remission-induction therapy (AUC > 0.9, 100% sensitivity for disease remission, F-score 75%). This promising technique is clinically translatable and warrants future larger study with longitudinal data, potentially aiding earlier intervention and individualisation of treatment.

Characterization of microbiota in acute leukemia patients following successful remission induction chemotherapy without antimicrobial prophylaxis.

In the present study, we characterized the microbiomes of acute leukemia (AL) patients who achieved complete remission following remission induction chemotherapy (RIC) as outpatients, but who did not receive antimicrobials to treat or prevent febrile neutropenia. Saliva and stool samples from 9 patients with acute myeloid leukemia, 11 patients with acute lymphoblastic leukemia, and 5 healthy controls were subjected to 16S ribosomal RNA sequencing at baseline and at 3 months following RIC. Only patients who achieved remission at 3 months post-treatment were included. We excluded anyone who used antimicrobials within 2 months of enrollment or at any time during the study period. At baseline, the relative abundances of species of Prevotella maculosa (P=0.001), Megasphaera micronuciformis (P=0.014), Roseburia inulinivorans (P=0.021), and Bacteroides uniformis (P=0.004) in saliva and Prevotella copri (P=0.002) in the stools of controls were significantly higher than in AL patients. Following RIC, the relative abundances of Eubacterium sp. oral clone DO008 (P=0.012), Leptotrichia sp. oral clone IK040 (P=0.002), Oribacterium sp. oral taxon 108 (P=0.029), Megasphaera micronuciformis (P=0.016), TM7 phylum sp. oral clone DR034 (P<0.001), Roseburia inulinivorans (P=0.034), Actinomyces odontolyticus (P=0.014), Leptotrichia buccalis (P=0.005), and Prevotella melaninogenica (P=0.046) in saliva and Lactobacillus fermentum (P=0.046), Coprococcus catus (P=0.050), butyrate-producing bacterium SS3/4 (P=0.013), and Bacteroides coprocola (P=0.027) in the stools of AL patients were significantly greater than in controls. Following RIC, several taxa are changed in stool and salvia samples of AL patients. Our results warrant future large-scale multicenter studies to examine whether the microbiota might have an effect on clinical outcomes of AL patients.

Monosomy 7 and Co-Occurrent Genomic Aberrations Determine Chemotherapy Response in Acute Myeloid Leukemia (AML) Patients Using the Cellworks Omics Biology Model (CBM): Mycare-021-04

Background: Monosomy 7/Del 7 (-7) or its long arm (del(7q)) is one of the most common cytogenetic abnormalities in pediatric and adult myeloid malignancies, particularly in adverse-risk acute myeloid leukemias (AMLs). In general, (-7) is associated with poor response to induction chemotherapy (PMID 12393746). At the same time, not all patients fare poorly so the ability to identify responders and non-responders remains a high priority. Aim: To predict the response for induction chemotherapy in AML patients with (-7) and identify novel genomic signatures of response and resistance. Methods: Genomic data from 13 consecutive patients with (-7) were analyzed using the Cellworks Omics Biology Model (CBM) to generate patient-specific protein network models. All data was anonymized, de-identified and exempt from IRB review. For each model, disease simulations were performed and patients were segregated into HOXA-upregulated and HOXA-downregulated cohorts based on the simulation levels of HOXA5 and HOXA9. Digital drug simulations for induction chemotherapy were accomplished by measuring the impact of drug effect on a cell growth score, a composite of cell proliferation, viability and apoptosis indices. Each patient-specific model was analyzed to identify mechanisms underlying treatment outcomes. Results: 7/13 (54%) of (-7) patients failed to achieve remission after induction chemotherapy (Table 1) which highlighted that (-7) alone does not confer resistance to chemotherapy. CBM identified other genomic alterations that determine chemotherapy response, including DNA repair deficiency genes, mismatch repair (MMR), and homologous recombination repair (HRR) genes. DNA methylation and histone methylation (H3K27me) impacting HOXA gene expression, mainly HOXA5 and HOXA9, were identified as upstream regulators of DNA repair genes. Loss or reduced levels of EZH2 is associated with lower H3K27 methylation and thereby higher expression of HOXA5 and HOXA9 gene targets. High active levels of HOXA correlated with low rates of successful remission induction (22%, n=7) and lower activity levels of HOXA correlated with successful induction chemotherapy (100%, n=4) (Table 1). CBM identified that (-7) results in a decreased expression of EZH2, CARD11, EIF3, PMS2, HUS1, KMT2C (MLL3), CDK5 and IKZF1 genes. Since EZH2 abnormalities alone are not implicated in poor prognosis for AML patients, we sought other aberrations that prevent HOXA upregulation. Using CBM, we identified multiple accompanying aberrations which regulate HOXA genes. Deletions of KAT6A, ASXL1, DNMT3B, DNMT3L genes and high KMT2A-partial tandem duplication correspond to HOXA-upregulation whereas EED amplification, gain of function mutations in DNMT3A, mutations in IDH1/2, MYC and KAT6A amplification and KDM4A deletion result in HOXA-downregulation. Conclusion: Alterations of chromatin regulation have consequences for transcription factors that regulate expression of DNA repair genes. Under conditions where DNA repair is enhanced, induction chemotherapy was 78% less likely to effect remission in (-7) AML patients undergoing induction chemotherapy. Loss of H3K27 methylation associated with loss of PRC2 function by any means resulted in HOXA-upregulation and upregulation of DNA repair genes induced resistance to induction therapy. On the other hand, CBM analysis identified genetic signatures associated with a 100% remission rate from AML induction therapy despite the presence of (-7). Generation of H3K27me caused by PRC2 activation resulting from numerous mechanisms led to HOXA-downregulation and 100% response to induction therapy. Stratification of patients harboring (-7) by HOXA biomarker analysis could inform treatment planning, avoid drug-related adverse events and reduce treatment costs after validation with a larger prospective dataset. Disclosures Castro: Cellworks Group Inc: Consultancy. Watson:Cellworks Group Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellmax Life Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mercy Bioanalytics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; SEER Biosciences, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioAI Health Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar:Cellworks Research India Private Limited: Current Employment. Nair:Cellworks Research India Private Limited: Current Employment. Grover:Cellworks Research India Private Limited: Current Employment. Sahu:Cellworks Research India Private Limited: Current Employment. Mohapatra:Cellworks Research India Private Limited: Current Employment. G:Cellworks Research India Private Limited: Current Employment. Agarwal:Cellworks Research India Private Limited: Current Employment. Suseela:Cellworks Research India Private Limited: Current Employment. Ganesh:Cellworks Research India Private Limited: Current Employment. Sauban:Cellworks Research India Private Limited: Current Employment. Kumar:Cellworks Research India Private Limited: Current Employment. Raman:Cellworks Research India Private Limited: Current Employment. Singh:Cellworks Research India Private Limited: Current Employment. Basu:Cellworks Research India Private Limited: Current Employment. Lunkad:Cellworks Research India Private Limited: Current Employment. Mundkur:Cellworks Group Inc.: Current Employment. Macpherson:Cellworks Group Inc.: Current Employment. Kapoor:Cellworks Research India Private Limited: Current Employment. Howard:Servier: Consultancy, Other: Speaker; Boston Scientific: Consultancy; Sanofi: Consultancy, Other: Speaker; EUSA Pharma: Consultancy; Cellworks: Consultancy.

Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients

ObjectiveTo describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy.MethodsRetrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies.ResultsA total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment.ConclusionWhile corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.

Retrospective investigation of tacrolimus combined with an anti-tumor necrosis factorα antibody as remission induction therapy for refractory ulcerative colitis: Efficacy, safety, and relapse rate.

Background and AimCombined therapy with tacrolimus (TAC) and an anti‐tumor necrosis factorα (TNFα) antibody is used to induce remission in ulcerative colitis (UC) patients who have not responded to monotherapy with either drug. We evaluated the efficacy and safety of combined therapy, as well as the relapse rate.MethodsCombined therapy was performed to induce remission in UC patients showing an inadequate response to monotherapy with TAC or an anti‐TNFα antibody. The following items were assessed retrospectively: (i) clinical characteristics, (ii) the remission induction rate, (iii) the relapse rate, and (iv) adverse events.ResultsCombined therapy induced remission in 7 of the 12 patients (58.3%). There were no significant differences in clinical characteristics between the patients with and without the successful induction of remission. However, the number of female patients tended to be higher in the remission group than in the nonremission group. The remission group also showed trends of a lower clinical activity index (Lichtiger index; CAI) on admission and before combined therapy and a lower total dose of prednisolone during hospitalization. The 1‐year relapse rate was 33.3%. Adverse events due to combined therapy included renal impairment (n = 2), tremors (n = 2), influenza (n = 1), and a positive cytomegalovirus antibody test (n = 3). None of these events were serious.ConclusionsCombined therapy was effective in more than half of the patients with refractory UC who had not responded to monotherapy. Our findings suggest that combination therapy may be a new, third option for the treatment of refractory UC.

Loss of the GPI-anchor in B-lymphoblastic leukemia by epigenetic downregulation of PIGH expression.

Adult B‐lymphoblastic leukemia (B‐ALL) is a hematological malignancy characterized by genetic heterogeneity. Despite successful remission induction with classical chemotherapeutics and novel targeted agents, enduring remission is often hampered by disease relapse due to outgrowth of a pre‐existing subclone resistant against the treatment. In this study, we show that small glycophosphatidylinositol (GPI)‐anchor deficient CD52‐negative B‐cell populations are frequently present already at diagnosis in B‐ALL patients, but not in patients suffering from other B‐cell malignancies. We demonstrate that the GPI‐anchor negative phenotype results from loss of mRNA expression of the PIGH gene, which is involved in the first step of GPI‐anchor synthesis. Loss of PIGH mRNA expression within these B‐ALL cells follows epigenetic silencing rather than gene mutation or deletion. The coinciding loss of CD52 membrane expression may contribute to the development of resistance to alemtuzumab (ALM) treatment in B‐ALL patients resulting in the outgrowth of CD52‐negative escape variants. Additional treatment with 5‐aza‐2′‐deoxycytidine may restore expression of CD52 and revert ALM resistance.

Identification of Chemotherapy-Induced Leukemic-Regenerating Cells Reveals a Transient Vulnerability of Human AML Recurrence

Despite successful remission induction, recurrence of acute myeloid leukemia (AML) remains a clinical obstacle thought to be caused by the retention of dormant leukemic stem cells (LSCs). Using chemotherapy-treated AML xenografts and patient samples, we have modeled patient remission and relapse kinetics to reveal that LSCs are effectively depleted via cell-cycle recruitment, leaving the origins of relapse unclear. Post-chemotherapy, invivo characterization at the onset of disease relapse revealed a unique molecular state of leukemic-regenerating cells (LRCs) responsible for disease re-growth. LRCs are transient, can only be detected invivo, and are molecularly distinct from therapy-naive LSCs. We demonstrate that LRC features can be used as markers of relapse and are therapeutically targetable to prevent disease recurrence.

Current and Future Treatment Options for Eosinophilic Granulomatosis With Polyangiitis

Purpose of review This review aims to give an overview of efficacy and safety of the therapeutic options for eosinophilic granulomatosis with polyangiitis (EGPA). Recent findings There are few current treatments beyond glucocorticoids for the successful induction and maintenance of remission in EGPA, and glucocorticoids remain the cornerstone of treatment. Life-threatening manifestations likely benefit from the addition of cytotoxic agents, although results of studies investigating cyclophosphamide or azathioprine have shown mixed efficacy results and high adverse event rates. More recently, targeted therapies including rituximab and mepolizumab have shown encouraging results. Since bronchial asthma often persists beyond the control of vasculitis disease manifestations, inhaled respiratory therapy and a multispecialty management approach are advocated. Summary EGPA has been the subject of very few randomized controlled trials. Glucocorticoids remain the cornerstone of treatment. Among others, evidence of efficacy for mepolizumab and rituximab is accumulating. The optimization of asthma control is recommended.

Pro: Cyclophosphamide in lupus nephritis.

Based on efficacy and toxicity considerations, both low-dose pulse cyclophosphamide as part of the Euro-Lupus Nephritis protocol and mycophenolate mofetil (MMF) with corticosteroids may be considered for induction of remission in patients with proliferative lupus nephritis. The long-term follow-up data available for low-dose pulse cyclophosphamide, the fact that compliance is guaranteed with this regimen and economic issues all favour the Euro-Lupus regimen in this author's opinion. For maintenance treatment, either azathioprine (AZA) or MMF may be used; AZA is preferred in case pregnancy is planned, while MMF is preferred when the disease relapses during use of AZA and, possibly, after successful induction of remission with MMF.

Identifying Subclonal Epigenetic Changes Driving Chemoresistance in Infant MLL-r Acute Lymphoblastic Leukemias

IntroductionThis study addresses the unsolved clinical problem of relapse in MLL-rearranged infant (<1 year old) acute lymphoblastic leukemia (ALL): 80% of infants with ALL harbor MLL rearrangements (MLL-r) and 66% of these will relapse and die with current treatment [5-year event free survival is 34%]. The typical pattern of failure in MLL-r ALL is successful remission induction (>90%) followed by early relapse (60-80%), suggesting rapid emergence of one or more chemoresistant subclones. Recently, whole genome sequencing of 47 MLL-r infant ALL cases showed a mean of only 1.3 non-silent mutations in the predominant leukemic clone (Andersson Nat. Gen. 2015;47:330-7). The critical barrier to progress in identifying novel, more effective therapies is this striking paucity of genomic changes that are found in addition to the MLL rearrangement. Therefore we hypothesized that epigenetic changes drive evolution of chemoresistant subclones and cause relapse.MethodsWe tested this hypothesis on two MLL-r infant ALL cases that had paired diagnosis-relapse (DX-RL) leukemic specimens using whole genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq). We prepared WGBS and RNA-seq libraries and performed paired-end sequencing (2x100bp) using Illumina HiSeq 2500. Paired-end reads received a methylated (1) or unmethylated (0) calls at each contiguous CpG they cover producing a data set of four 0/1-state-long "epialleles" with 16 possible methylation state patterns ("0-0-0-0" to "1-1-1-1"). For each epiallele, we calculated the frequency of each of the 16 patterns at DX and RL. We developed analysis methods to align bisulfite-converted reads to the genome, call methylation states at CpGs within reads, assess subclonal "epiallele" frequency changes between DX and RL, map the genomic locations of epialleles to promoter regions of their corresponding gene isoforms, and quantify differential gene isoform expression between DX and RL.ResultsWGBS generated ~400 million paired-end reads per sample with 25X average coverage. After removing duplicates and repeats, we obtained methylation calls at ~15 million CpGs per case. RNA-seq generated RNA transcript quantification for ~47,000 isoforms from ~30,000 genes per sample. We extracted from the WGBS data paired-end reads that map uniquely to gene promoter regions and that cover at least 4 contiguous CpGs to a depth of at least 4X. In all, case A had 237,040 epialleles annotated to 11,484 gene promoters, and case B had 853,678 epialleles annotated to 14,717 gene promoters. By plotting the change in epiallele frequency between DX and RL, we were able to identify epiallele-defined subclones that were: not detectable at DX but present at RL ("emergent" at RL), present at DX but undetectable at RL ("driven extinct" at RL), and unchanged significantly between DX and RL ("founder") (Fig. 1). For example, in case A, we found 145 "1-1-1-1" epialleles that were at 0% frequency at DX and 66±17% (mean±st.dev.) frequency at RL (corresponding to 76±11% methylation increase at RL) that were associated with 29±77-fold decrease in expression of their associated gene isoform. 18 of these epialleles were: mapped to the promoter of IKZF1 (a known tumor-suppressor gene in ALL), present at 0% frequency at DX and 40±0.04% at RL, and associated with 8.5±10-fold decrease in IKZF1 isoforms expression. These results support the hypothesis that subclonal methylation changes associated with corresponding expression changes may drive chemoresistance and relapse.ConclusionsWe have developed analytic techniques to integrate WGBS and RNA-seq data for discovery of subclonal epigenetic changes that either emerge or are driven extinct under the selective pressure of chemotherapy treatment. Such data provide support for the hypothesis that chemoresistance in this disease may be driven by epigenetic mechanisms. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clopidogrel-induced refractory thrombotic thrombocytopenic purpura successfully treated with rituximab

Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by microvascular aggregation of platelets and fibrin strands causing thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction. TTP can develop as a result of a deficiency in ADAMTS13 enzyme activity due to either a genetic defect or, more commonly, the development of anti-ADAMTS13 autoantibodies. TTP can also be associated with pregnancy, organ transplant, lupus, infections, and drugs. Here, we present a case of TTP that developed shortly after the start of clopidogrel treatment for acute ischemic stroke and acute myocardial infarction, and describe the clinical presentation, refractory course of the disease, and successful induction of remission through the use of rituximab in a setting of pre-existing autoimmune diseases.

Unusual Acute Sequelae of α1-Antitrypsin Deficiency: A Myriad of Symptoms With One Common Cure

Panniculitis associated with α1-antitrypsin deficiency (AATD) is well documented but rare. We report the first case, to our knowledge, of successful induction of clinical remission of AATD-related panniculitis following a single 120-mg/kg dose administration of plasma-purified α1-antitrypsin (AAT). A 23-year-old man with known PiZZ AATD presented to the hospital with a diffusely swollen and tender right upper limb. This was associated with subcutaneous induration, and a discrepancy of 5 cm in upper limb circumference at the mid arm was noted. There was no convincing precipitant for cellulitis or an infectious cause, and inflammatory markers were raised, with a C-reactive protein (CRP) level of 93.9 mg/L and erythrocyte sedimentation rate (ESR) of 71 mm/h. Doppler ultrasonography ruled out DVT. No antimicrobials or antiinflammatory medications were administered during or prior to admission. Biopsy specimens of the right upper limb revealed extensive panniculitis with neutrophils, foamy macrophages, and fat necrosis. A diagnosis of AATD-associated panniculitis was made. Following this, a single IV dose of 120 mg/kg of plasma-purified AAT was administered. By day 7 post AAT infusion, CRP level had normalized to 4.6 mg/L and ESR had dropped to 22 mm/h. Limb circumference discrepancy on day 7 was 1 cm. There was no tenderness to palpation or induration, and a clinical remission of panniculitis was observed. We report the first case, to our knowledge, of clinical remission following a single treatment with IV AAT at a dose of 120 mg/kg. This opens avenues to more timely and effective treatment of the more severe presentations of AAT-associated panniculitis.

Approach to patients with primary refractory acute myeloid leukemia.

Despite successful remission induction in 60-80% of patients with newly diagnosed acute myeloid leukemia, there remain a significant number of patients who exhibit primary refractory disease. Here we examine the data for predicting likelihood of having refractory disease, available therapeutic options, and how to decide the appropriate treatment option for a patient. Recently identified recurrent molecular mutations and early response to chemotherapy as determined by kinetics of peripheral blast clearance or nadir bone marrow biopsy assist in determining the likelihood of primary refractory disease. Newer cytotoxic agents, used as salvage chemotherapy, or in novel conditioning regimens for hematopoietic stem cell transplant may represent improvement over prior regimens. FMS-like tyrosine kinase 3 gene inhibitors and other targeted therapies currently in clinical trials show promise for select patients. Hypomethylating agents provide benefit to patients who are not candidates for other therapies. Recent advances in understanding the pathogenesis of acute myeloid leukemia have not yet translated to a significantly improved outlook for patients with refractory disease. While there are several therapeutic options, outcomes remain poor and further studies are needed to identify and validate novel approaches.