The Expression Changes of CX3CL1 and Interlukin-6 Genes During Remission Induction Therapy in Patients With Acute Myeloid Leukemia

Background: Acute Myeloid Leukemia syndrome (AML) is a hematologic malignancy which is due to clonal extensive proliferation of leukemic precursor cells and is rapidly fatal unless treated or response to chemotherapy. Cytogenetic findings have important role in prognosis and categorization of AML. The aim of this study was to investigate the expression changes in CX3CL1 and Interlukin-6 (IL-6) genes before and after chemotherapy as remission induction therapy in AML patients. Materials and Methods: In this study 69 patients (36 males, 33 female) with AML was selected from tertiary medical heath center. A quantitative polymerase chain reaction (PCR) was done for mRNA expression of CX3CL1 and IL-6genes before and after induction chemotherapy. To obtain expression changes in CX3CL1 and IL-6genes, we used 2-ΔΔCT method. Results: The expression of CX3CL1 and IL-6 was significantly increased after induction chemotherapy. Also, the ΔCt mean of CX3CL1 and IL-6 mRNA was not significant between AML subtype groups. Conclusion: In conclusion, as we showed that chemotherapy significantly increase the expression of CX3CL1 and IL-6 which can be used as a prognostic factor of AML.

Rituximab in Remission Induction and Maintenance Therapy for Microscopic Polyangiitis Associated with Gastric Cancer: A Case Report

We herein report a case of a patient with gastric cancer-associated microscopic polyangiitis (MPA) who was treated with combination glucocorticoids and rituximab (RTX) for remission induction and maintenance, and finally to discontinue glucocorticoids without recurrence of gastric cancer or MPA in a year. A 69-year-old man was suspected of having MPA because of fever, high C-reactive protein levels, neuritis, and a high titer of myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA). Upper gastrointestinal endoscopy indicated early-stage gastric cancer, for which he underwent surgery preceded by immunosuppressive therapy for vasculitis. Histopathological images showed vasculitis in the vicinity of the cancerous tissue, suggesting an association between gastric cancer and vasculitis. Postoperatively, fever and inflammatory response improved, but MPO-ANCA increased further and the patient developed alveolar hemorrhage. He resulted in remission with high-dose glucocorticoids and RTX, and he received maintenance therapy with RTX without additional immunosuppressive agents. After 1 year of treatment, he was able to discontinue glucocorticoids without recurrence of gastric cancer or vasculitis. There is no established treatment for malignancy-associated vasculitis other than glucocorticoids. Although more cases need to be accumulated in the future, RTX is expected to be useful in malignancy-associated vasculitis.

Redefining Remission Induction Chemotherapy Ineligibility by Early Mortality in De Novo Acute Myeloid Leukemia

The therapeutic strategies for acute myeloid leukemia (AML) patients ineligible for remission induction chemotherapy have been improving in the past decade. Therefore, it is important to define ineligibility for remission induction chemotherapy. We retrospectively assessed 153 consecutive adult de novo AML patients undergoing remission induction chemotherapy and defined early mortality as death within the first 60 days of treatment. The 153 patients were stratified into the early mortality group (n = 29) and the non-early mortality group (n = 124). We identified potential factors to which early mortality could be attributed, investigated the cumulative incidence of early mortality for each aspect, and quantified the elements. The early mortality rate in our study cohort was 19.0%. Age ≥ 65 years (odds ratio (OR): 3.15; 95% confidence interval (CI): 1.05–9.44; p = 0.041), Eastern Cooperative Oncology Group performance status ≥ 2 (OR: 4.87; 95% CI: 1.77–13.41; p = 0.002), and lactate dehydrogenase ≥ 1000 IU/L (OR: 4.20; 95% CI: 1.57–11.23; p = 0.004) were the risk factors that substantially increased early mortality in AML patients. Patients with two risk factors had a significantly higher early mortality rate than those with one risk factor (68.8% vs. 20.0%; p < 0.001) or no risk factors (68.8% vs. 9.2%; p < 0.001). In conclusion, older age, poor clinical performance, and a high tumor burden were risks for early mortality in AML patients receiving remission induction chemotherapy. Patients harboring at least two of these three factors should be more carefully assessed for remission induction chemotherapy.

Clinical Features of Behçet’s Disease Patients with Joint Symptoms in Japan: A National Multicenter Study

Objectives Approximately 30%–60% of Behçet’s disease patients exhibit joint symptoms. The aim of this study was to determine the clinical characteristics of such patients in Japan. Methods This study retrospectively analyzed 151 Behçet’s disease patients with joint symptoms who had been treated at seven cooperative medical institutions from 2007 to 2017. We investigated their clinical characteristics and treatments. Results The most commonly affected joints were the knee, ankle, and proximal interphalangeal joints. Of the cases with pain and swelling, 18 of 293 joints (11 cases) displayed narrowing of the cleft or deformity by Xray analysis. Improvement in their arthritis was observed in 80% of the patients who received steroids as initial treatment; however, the rate of improvement was lower in patients who had received prednisolone (PSL) at &lt;10 mg/day. The recurrence of joint symptoms was significantly less common in the colchicine group than in the PSL group. Conclusions These results suggest that PSL is effective for remission induction for the treatment of joint symptoms of Behçet’s disease, though it may not be effective at low doses. Additionally, colchicine is effective in preventing the recurrence of joint symptoms in Behçet’s disease. Furthermore, joint damages like joint space narrowing or with any deformity can often be observed in Behçet’s disease patients in Japan.

Safety and Effectiveness of Mepolizumab Therapy in Remission Induction Therapy for Eosinophilic Granulomatosis with Polyangiitis: A Retrospective Study

Objectives: To investigate the safety and effectiveness of mepolizumab (MPZ), an anti-interleukin-5 antibody, as remission induction therapy for severe eosinophilic granulomatosis with polyangiitis (EGPA).Methods: The clinical courses of patients with severe EGPA over 6 months were retrospectively investigated and compared between patients treated with high-dose corticosteroid (CS) plus MPZ therapy (MPZ group, n=7) and those treated with high-dose CS plus intravenous cyclophosphamide (IVCY) pulse therapy (IVCY group, n=13). The primary endpoints were the MPZ retention rate and the IVCY completion rate. The secondary endpoints were adverse events and changes in the Birmingham Vasculitis Activity Score (BVAS), Vascular Damage Index (VDI), eosinophil counts, and concomitant CS doses, and the extent and rates of these changes were compared between the MPZ and IVCY groups.Results: Regarding the primary endpoints, the MPZ retention rate was 100%, and the IVCY completion rate was 61.5%. Regarding the secondary endpoints, adverse events were detected in 2/7 patients (28.6%) in the MPZ group and 7/13 patients (53.8%) in the IVCY group. BVAS and eosinophil counts significantly decreased in both groups at and after month 1, but there was no significant difference in the magnitude of changes between the two groups. VDI scores did not significantly increase in either group, and the degree of changes did not significantly differ between the two groups. Although concomitant CS doses significantly decreased at and after month 1 in both groups, the rates of decrease in CS doses at and after month 3 were significantly higher in the MPZ group.Conclusions: This study suggested that the use of MPZ as remission induction therapy for severe EGPA might be safe and effective for controlling disease activity and reducing CS doses.

Induction of remission in chronic urticaria by immunotherapy using immunoglobulin/histamine complex (Histobulin™): a case report

Background Symptom control is a major concern in chronic urticaria. Histobulin™ is a histamine/immunoglobulin complex that has been approved for allergic rhinitis, bronchial asthma and chronic urticaria in some countries. Not only has the immunoglobulin/histamine complex been reported to be effective in allergic diseases, including chronic urticaria, but recently, the possibility of remission induction in chronic urticaria by the immunoglobulin/histamine complex has been reported. Case presentation Histobulin™ was administered until remission was induced instead of fixing the number of administrations in four cases of chronic urticaria. Two patients showed an early response and finished treatment with 12 injections of Histobulin™, and the other two patients showed a late response and were injected 43 and 46 times. Remission was induced successfully in all four cases. Conclusions Histobulin™ is not only effective but also induces remission in CSU. The Histobulin™ therapy protocol in CSU may be better if the treatment is continued until remission is achieved. Based on the responses of the patients, early responders and late responders were present. The progression of the disease during treatment consisted of a slow improvement phase and a rapid improvement phase. Uniquely, the appropriate allergy laboratory results, including blood eosinophil fraction, total IgE and eosinophil cationic protein level, were normal in all 4 cases. Further studies concerning the mechanisms of Histobulin™ may be needed.

Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission after 5-Azacitidine and Venetoclax: A Multicenter Retrospective Study

The therapeutic landscape for acute myeloid leukemia (AML) has evolved in recent years with the introduction of hypomethylating agents (HMA) and venetoclax in patients previously deemed unfit for curative - intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT), yet there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study to evaluate outcomes of patients with AML who underwent alloHCT in first CR (CR1) after frontline treatment with 5-azacitidine plus venetoclax (aza-ven group). In addition, we collected a historical control group of patients who achieved CR1 following first line intensive chemotherapy followed by alloHCT (intensive group). 24 patients in the aza-ven group were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years, p &lt;0.001), had higher incidence of therapy related AML and AML with antecedent hematologic disorder (p &lt;0.001) and had more often adverse cytogenetics (p=0.022). They had a higher percentage of allografts from matched unrelated donors, and reduced intensity conditioning was more commonly used (Table 1). Median follow up was 8 (range, 0 to 25) months in the aza-ven group and 23 (range, 4 to 56) months in the intensive group. Estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group (p=0.492). The estimated median relapse free survival (RFS) was not reached in the aza-ven group and was 19.3 months (CI 95% 1-38) in the intensive group. There was no difference between the two groups in 12 months RFS (58% and 54% in the aza-ven group and intensive group, respectively, p = 0.892). The estimated median survival of the aza-ven group was not reached and the 12 months overall survival (OS) rate was 63.2%. The estimated median survival of the intensive group was 50 months (CI 95% 5 - 96) and the 12 months OS rate was 70.8%. There was no statistical differences between the two groups regarding OS (p = 0.58). In a subgroup Cox regression analysis of the aza-ven group, adverse ELN 2017 risk category and HCT-CI score ≥3 were predictive of decreased RFS, both in univariate analysis (UVA) and in multivariate analysis (MVA) (HR 10.56, CI 95%1.64-68.1, p=0.013 and HR 6.43, CR 95% 1.34-30.75, p=0,02, respectively). Graft source (alternative vs. matched donor) and HCT-CI score ≥3 were predictive of decreased OS in UVA (HR 19.45, CI 95% 1.66-228.13, p= 0.018 and HR 5.93, CI 95% 1.13-31.05, p=0.03], yet in MVA neither of these factors retained their predictive value. The cumulative incidence of acute GVHD at 6 months was similar between groups: 58% in the aza-ven group vs. 62% in the intensive group (p=0.39). Likewise, there was no difference in the cumulative incidence of chronic GVHD at 12 months: 40% vs 42%, respectively (p=0.747) In conclusion, our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short term post-transplant outcomes comparable to those expected after traditional intensive chemotherapy. Our results were collected in the real world setting, and patients in the aza-ven group were older and had inherently worse leukemia characteristics, including more secondary AML and more adverse cytogenetic features. Future research is warranted to decipher the true spectrum of AML patients who could benefit from remission induction with this less intensive regimen prior to alloHCT. Figure 1 Figure 1. Disclosures Ram: Gilead: Honoraria; Novartis: Honoraria. Wolach: Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Neopharm: Consultancy. Yeshurun: Astellas: Consultancy; Janssen: Consultancy.

Performance of Next Generation Sequencing for Minimal Residual Disease Detection for Pediatric Patients with Acute Lymphoblastic Leukemia: Results from the Prospective Clinical Trial DFCI 16-001

Introduction: Assessment of minimal residual disease (MRD) in a sensitive and timely manner is an essential component of risk stratification in childhood acute lymphoblastic leukemia (ALL). Next generation sequencing (NGS) assays utilize unique genetic sequences created by VDJ rearrangements in leukemia cells to detect MRD at the level of 1 leukemic cell in 1 million cells (Wood et al., 2018). Here we report our experience using NGS MRD for risk group assignment of children and adolescents with newly diagnosed ALL enrolled on the Dana Farber Cancer Institute (DFCI) ALL Consortium Protocol 16-001. Methods: Patients (pts) ages 1-21 years with B- or T-ALL were eligible for enrollment from 8 centers across the US and Canada. Initial risk status was assigned based on age, presenting leukocyte count, central nervous system (CNS) leukemia status, immunophenotype, and disease biology (Table 1). All patients underwent bone marrow evaluation at diagnosis and again upon completion of remission induction approximately four weeks later (Induction 1a, timepoint 1 (TP1)), with samples evaluated by flow cytometry (FCM) and NGS. NGS was primarily used for MRD-based risk determination, with FCM as a back-up test. Patients with high TP1 MRD (≥10 -4) received intensified therapy and underwent additional MRD assessments at 10 and 20 weeks of therapy. Multiparametric FCM was conducted locally for 7 of 8 sites in accordance with local CLIA certified lab practices. One site used centralized FCM. NGS MRD was assessed at Adaptive Biotechnologies Corporation, Seattle, WA using the commercially available assay ClonoSEQ ®. Clonality was evaluated at the immunoglobulin (Ig) heavy and light chain (IgH and IgL) and T cell receptor beta and gamma (TCR-B and TCR-G) loci with the maximal sequence used for MRD determination. Results: NGS evaluation of MRD is feasible A total of 317 patients enrolled on 16-001 between 2017 and 2020 were included in this analysis. Among this cohort, NGS identified unique trackable sequences in 98% of pts (N=310). Of the 7 pts without trackable sequences, 57% were pts with early T precursor (ETP) T-ALL (36% of all ETP pts tested). NGS detected trackable sequences in all non-ETP T-ALL pts (N=40), and 99% of B-ALL pts (N=263). Locus used for MRD determination Patients with B-ALL had a median of 5 trackable sequences (range 0-14) with 92% having at least one IgH and 64% having at least one TCR-G. For B-ALL, the highest MRD value at TP1 was determined by IGH locus in 44% (N=115) of pts and by TCR-G in 41% (N=109). The IgL or TCR-B locus yielded the highest TP1 MRD value in 15% (N=39). In contrast, pts with T-ALL had fewer trackable sequences with a median of 3 (range 0-8). While 28% (N=13) had at least one Ig sequence, the TCR locus was used for MRD determination in nearly all (98%, N=46) with 94% using TCR-G. Comparison of NGS and FCM MRD results NGS and FCM MRD values for 309 pts with results from both assays at TP1 are displayed in Figures 1a-d. Correlation was high between the two modalities for patients with detectable disease by both NGS and FCM (Pearson r=0.87, p&lt;0.0001). NGS additionally detected MRD in the range of 10 -6 to &lt;10 -4 for 160 patients with FCM undetectable disease at TP1, representing 50% of our cohort. Fifty one pts (17%) had high NGS MRD (≥10 -4) but low (8%) or undetectable (92%) FCM MRD (&lt;10 -4), representing 50% of pts classified as high MRD at TP1. For B-ALL pts with high MRD (N=70), 43% (N=30) were high by NGS (≥10 -4) when FCM was low (&lt;10 -4, N=4) or undetectable (N=26) with 90% of discrepancies at the NGS level of 10 -4 (Figure 1a-b). In contrast, for T-ALL pts with high TP1 MRD (N=28), 75% (N=21) were high by NGS alone, all with undetectable FCM. Sixty seven percent of these pts (N=14) had NGS MRD at the level of 10 -4 and the remaining 33% (N=7) were in the range of 10 -3 to &lt;10 -1 (Figure 1c-d). Eight pts, all with B-ALL, had low NGS MRD when FCM was above the threshold of 10 -4. One patient had undetectable NGS MRD and the remaining 7 had NGS MRD in the range of 10 -6 to &lt;10 -4. Conclusions: Delivery of risk adapted therapy for newly diagnosed pediatric pts with ALL utilizing an NGS MRD assay is feasible with evaluable MRD for 98% of patients in our cohort. Importantly, NGS identified more cases as having high MRD than FCM, with the majority of discrepant cases just above the FCM limit of detection (10 -4). NGS provided improved resolution in the range of 10 -6 to &lt;10 -4 for both B-ALL and T-ALL. The prognostic relevance of these low MRD levels awaits longer follow-up. Figure 1 Figure 1. Disclosures Kirsch: Adaptive Biotechnologies: Current Employment, Current holder of stock options in a privately-held company. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Assessing the Impact of Prophylactic Anidulafungin during Remission Induction of Acute Myeloid Leukemia - a Propensity-Score Matching Analysis

Introduction: Invasive fungal disease (IFD) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole has recently emerged as a drug of choice for this purpose. In our setting, alternative strategies such as no upfront prophylaxis, fluconazole, or echinocandins have been used during the remission induction, as posaconazole is not available. While few reports have pointed to micafungin as an option for this aim, studies addressing the use of anidulafungin in AML are lacking. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction. Methods: This retrospective cohort encompassing newly diagnosed AML adult patients (pts) treated at Instituto do Cancer do Estado de Sao Paulo, Brazil, between June 2011 and June 2020. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). Over these years, local policies regarding AP changed. All patients received the "7+3" regimen and were divided into three groups: pts who did not receive any AP and pts who received fluconazole (15-400 mg/day) or anidulafungin (100 mg/day) as AP. Local recommendations for IFD treatment were followed, and they also changed over time. The primary endpoint was IFD rate during the first 60 days from the beginning of chemotherapy, following the recommendation of EORTC/MSG. Multivariable analysis (MVA) was performed by logistic regression. Aiming to equalize subgroups for IFD risk factors, a propensity-score matching was performed using the nearest neighbor method. Results: Overall, 204 pts were included, with a median age of 54 years (range,17-74). The main baseline features of this cohort are summarized in Table 1. Regarding AP, 108 pts received anidulafungin, 82 pts did not receive AP, and 14 pts received fluconazole. The incidence of IFI was 26.6% (95% CI 20.8-33.3), classified as possible, probable, and proven in 65.5%, 1.8%, and 32.7%, respectively. Regarding the fungus specimen, Aspergillus sp. responded for most cases (60%), followed by Fusarium sp. (23%), Candida sp. (11%), and Zygomycetes (4%). Complete response was documented at the end of induction in 49%, with the remaining patients being either refractory (27%) or not available (24%). The 60-day mortality was 25.8%. MVA showed that lower neutrophil counts at the AML diagnosis are associated with IFD during induction (OR=2.8, 95% CI 1.3-6.2), whereas age, genetic classification, and lymphocyte counts were not. Comparing the three abovementioned groups (AP: none, anidulafungin, or fluconazole), significant differences could be seen in AGR and anthracycline doses (Table 2). To analyze the impact of anidulafungin in comparison with 'no AP', a post-matched cohort with 164 subjects was created, matching for neutrophil and lymphocyte counts and AGR. The use of anidulafungin was not significantly related to less IFD during induction (OR=0.7, 95% CI 0.3-1.6), while neutrophil counts remained significant. Few subjects received fluconazole as AP, and it also was not related to less IFD (p=0.35). At the end of induction, complete response status did not relate to IFD during this period (p=1). Treatment for IFD with amphotericin B and voriconazole was given for 60.2% and 13.1% during induction, respectively. Patients under prophylactic anidulafungin received less amphotericin B (p&lt;0.001) but not voriconazole (p=0.49). Fusarium sp. cases that occurred during induction (n=12) received mostly prophylactic fluconazole (42%), which was statistically relevant in comparison to other AP (p&lt;0.001). Among these 12 cases, no favorable genetic risk was found. The occurrence of IFD during induction did not correlate with early mortality (HR=0.97, 95% CI 0.5-1.8) in our cohort. Conclusion: To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the use of AP did not decrease IFD incidence within this phase. Our results point to the fact that the fungistatic activity of echinocandins in molds might be suboptimal for immunocompromised pts. Furthermore, these results strengthen the role of posaconazole in this setting, especially for baseline neutropenic patients or higher risk subsets, such as primary refractory cases. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.