Longer Remission Duration Research Articles

Better Cardiorespiratory Fitness Defined as VO2max Increases the Chance of Partial Clinical Remission and Prolongs Remission Duration in People with Newly Diagnosed Type 1 Diabetes.

An essential process affecting the course of type 1 diabetes (DM1) is the appearance and duration of clinical remission. One of the most important factors promoting the occurrence of remission is physical activity, due to increased activity of antioxidants, reduces insulin resistance and improves glucose transport. Maximal oxygen capacity (VO2max) is an objective measure of the body's aerobic capacity. To assess VO2max, oxygen uptake should be measured directly during the exercise test. The aim of the study was to evaluate the physical capacity in adults with DM1 and its relationship with the occurrence of partial clinical remission (pCR) during 2 years follow-up. The pCR was assessed by the following mathematical formula: A1c (%) + [4 × insulin dose (U/kg/d)]. The result ⩽9 indicates pCR. VO2max was assessed between 6th and 24th month of diabetes duration using an ergospirometer (COSMED K5 System), during an exercise test carried out on a cycloergometer (RAMP incremental exercise test). The study group consisted of 32 adults with DM1. People with pCR were proved to have higher VO2max level [36.0 (33.0-41.5) vs 30.9 (26.5-34.4) ml/min/kg, P = .009. Univariate and multivariate regression confirmed a significant association between VO2max and presence of pCR [AOR 1.26 (1.05-1.52), P = .015]. Duration of remission was longer among group with higher VO2max results [15 (9-24) vs 9 (0-12) months, P = .043]. The positive relationship was observed between diabetes duration and VO2max (rs = 0.484, P = .005). Multivariate linear regression confirms a significant association between remission duration and VO2max (ml/min/kg) (β = 0.595, P = .002). The higher VO2max, the better chance of partial clinical remission at 2 years of DM1 and longer duration of remission.

Health Care Resource Utilization and Total Costs of Care for Adult Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia in the United States: A Retrospective Claims Analysis

PurposeAlthough immunotherapies such as blinatumomab and inotuzumab have led to improved outcomes, financial burden and health resource utilization (HRU) have increased for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). This study assessed real-world HRU and costs of care among adult patients with R/R B-ALL by line of therapy (LoT) in the United States. MethodsWe selected patients from the MarketScanⓇ Database (January 1, 2016 through December 31, 2020) as follows: ≥1 claims of ALL-indicated first-line (1L) therapies, ≥1 diagnosis of ALL before the index date (1L initiation date), 6-month continuous enrollment before the index date, second-line (2L) therapy initiation, ≥18 years old at 2L, no clinical trial enrollment, no diagnosis of other forms of non-Hodgkin's lymphoma, and no claim for daratumumab or nelarabine during the study period. Outcome measures included claim-based time to next treatment (TTNT), all-cause and adverse event (AE)–related HRU, and all-cause and AE-related costs. FindingsThe R/R B-ALL cohort (N = 203) was 60% male, median age of 41 years, and median Charlson Comorbidity Index score of 3.0. Mean (SD) follow-up was 17.8 (11.8) months. Of those who received 2L, 55.7% (113/203) required 3L, and 15% (30/203) initiated 4L+. Patients relapsed quickly, with a median TTNT of 170 days, 169 days, and 205 days for 2L, 3L, and 4L+, respectively. Hospitalization rates were high across each LoT (2L, 88%; 3L, 73%; 4L+, 73%), and the mean (SD) inpatient length of stay increased by LoT as follows: 8.6 (6.8) days for 2L, 10.6 (13.3) for 3L, and 11.6 (13.6) for 4L+. Mean (SD) overall costs were substantial within each LoT at $513,279 ($599,209), $340,419 ($333,555), and $390,327 ($332,068) for 2L, 3L, and 4L+, respectively. The mean (SD) overall/per-patient-per-month AE-related costs were $358,676 ($497,998) for 2L, $202,621 ($272,788) for 3L, and $210,539 ($267,814) for 4L+. Among those receiving blinatumomab or inotuzumab within each LoT, the mean (SD) total costs were $566,373 ($621,179), $498,070 ($376,260), and $512,908 ($159,525) for 2L, 3L, and 4L+, respectively. ImplicationsThese findings suggest that adult patients with R/R B-ALL relapse frequently with standard of care and incur a substantial HRU and cost burden with each LoT. Those treated with blinatumomab or inotuzumab incurred higher total costs within each LoT compared with the overall R/R B-ALL cohort. Alternative therapies with longer duration of remission are urgently needed, and HRU should be considered for future studies examining the optimal sequencing of therapy.

#3191 RISK OF CKD IN LUPUS NEPHRITIS: CORRELATION WITH DURATION OF REMISSION AND DEVELOPMENT OF RENAL AND EXTRARENAL FLARES

Abstract Background and Aims Achievement of remission and prevention of SLE flares are important therapy targets in patients with SLE in order to avoid the development of systemic chronic damage. In patients with lupus nephritis, the correlation between the duration of remission, the occurrence of SLE flares and the development of CKD is unclear. The aims of this study are to investigate a) the risk of CKD in patients with lupus nephritis b) the correlation between the risk of CKD and the development of renal and extrarenal SLE flares c) the correlation between the risk of CKD and the achievement and duration of remission d) the probability and predictors of renal and extrarenal remission. Method This is a retrospective multicentric study of prospectively collected data. Patients were included if they were >18 years old, they had a histological diagnosis of lupus nephritis and they had at least 5 years of follow up after the diagnosis. CKD was defined as eGFR <60 ml/min/1.73m2 without active urinary sediment for at least 3 months. Remission was defined as normal renal function (serum creatinine <1.0 mg/dl, eGFR >60 ml/min/1.73m2), proteinuria <0.5 g/24h and cSLEDAI = 0 for at least 1 year. The probability of developing flares and achieving remission was estimated using Cox regression analysis. Results CKD developed in 57 patients out of the 303 included in the study (18.8%) during a median follow-up of 14.8 years. During the observation 257 patients achieved remission in a median time of 1.4 (0.7-3.6) years, while 46 patients never achieved it. 115 patients maintained remission until the end of follow-up (9.5 (5.8-14.5) years), while 142 developed a flare after a median time of 3.6 (2.3-5.9) years from the beginning of remission. Altogether, in these 142 patients, 174 SLE flares developed during a median follow-up of 17.8 (13.3-24.2) years: 132 renal flares (20 with serum creatinine increase, 112 with proteinuria) and 42 extra-renal flares. CKD developed in 11 patients with creatinine flares (55%), 19 patients with proteinuric flares (16.9%) and 1 patient with extra-renal flares (2.4%) (p<0.0001). The longer was the duration of remission, the lower the probability that remission was interrupted (Figure 1A) by the development of a SLE flare: the risk of flare reduced from 10% when the remission lasted less than 5 years, to 5% if the remission lasted 5-10 years and to 2% if the remission lasted more than 10 years (Figure 1B). CKD developed in 26 out of the 46 patients who never achieved remission (56%), in 31 patients among those who achieved remission but developed SLE flares (21.8%) and in none among those who maintained remission until the end of the observation (p<0.0001). We found that 3 years of persistent remission significantly reduced the risk of CKD development (Figure 2). At multivariate Cox regression analysis, age >40 years (OR: 1.017; 95% CI: 1.005-1.028; p = 0.004), therapy with hydroxychloroquine (OR: 1.384; 95% CI: 1.109-1.661; p = 0.021) and absence of arterial hypertension (OR: 0.699; 95% CI: 0.425-0.975; p = 0.011) were independent predictors of remission. Conclusion in patients with lupus nephritis, the risk of CKD is significantly higher if renal-extrarenal remission is not achieved or if it is interrupted by SLE flares. In particular, the risk of CKD is very high in patients who develop renal flares with creatinine increase. A longer duration of remission is related to a lower risk of SLE flares and of CKD: in particular, 3 years of remission protect from the development of CKD. Age older than 40 years, therapy with hydroxychloroquine and absence of arterial hypertension are associated with the achievement of remission.

Anti-apoptotic genes and non-coding RNAs are potential outcome predictors for ulcerative colitis

Due to the lack of clinical, immunologic, genetic, and laboratory markers to predict remission in ulcerative colitis (UC) without relapse, there is no clear recommendation regarding withdrawal of therapy. Therefore, this study was to investigate if transcriptional analysis together with Cox survival analysis might be able to reveal molecular markers that are specific for remission duration and outcome. Mucosal biopsies from patients in remission with active treatment-naïve UC and healthy control subjects underwent whole-transcriptome RNA-seq. Principal component analysis (PCA) and Cox proportional hazards regression analysis were applied to the remission data concerning duration and status of patients. A randomly chosen remission sample set was used for validation of the applied methods and results. The analyses distinguished two different UC remission patient groups with respect to remission duration and outcome (relapse). Both groups showed that altered states of UC with quiescent microscopic disease activity are still present. The patient group with the longest remission duration and no relapse revealed specific and increased expression of antiapoptotic factors belonging to the MTRNR2-like gene family and non-coding RNAs. In summary, the expression of anti-apoptotic factors and non-coding RNAs may contribute to personalized medicine approaches in UC by improving patient stratification for different treatment regimens.

Effects of pulsed dye laser treatment in psoriasis: A nerve-wrecking process?

Pulsed dye laser (PDL) therapy can be effective in treating psoriasis, with a long duration of remission. Although PDL therapy, albeit on a modest scale, is being used for decades now, the underlying mechanisms responsible for the long-term remission of psoriasis remain poorly understood. The selective and rapid absorption of energy by the blood causes heating of the vascular wall and surrounding structures, like perivascular nerves. Several studies indicate the importance of nerves in psoriatic inflammation. Interestingly, denervation leads to a spontaneous remission of the psoriatic lesion. Among all dermal nerves, the perivascular nerves are the most likely to be affected during PDL treatment, possibly impairing the neuro-inflammatory processes that promote T-cell activation, expression of adhesion molecules, leukocyte infiltration and cytokine production. Repeated PDL therapy could cause a prolonged loss of innervation through nerve damage, or result in a 'reset' of neurogenic inflammation after temporary denervation. The current hypothesis provides strong arguments that PDL treatment affects nerve fibres in the skin and thereby abrogates the persistent and exaggerated inflammatory process underlying psoriasis, causing a long-term remission of psoriasis.

Haploidentical versus Double-Cord Blood Stem Cells as a Second Transplantation for Relapsed Acute Myeloid Leukemia.

There are limited data on second stem cell transplantation (SCT2) outcomes with alternative donors for relapsed AML after the first stem cell transplantation (SCT1). We analyzed the outcomes of 52 adult AML patients who received SCT2 from haploidentical donors (HIT, N = 32) and double-cord blood (dCBT, N = 20) between 2008 and 2021. The HIT group received T-cell-replete peripheral blood stem cells after reduced-toxicity conditioning with anti-thymocyte globulin (ATG), while the dCBT group received myeloablative conditioning. For a median follow-up of 64.9 months, the HIT group, compared to the dCBT group, had earlier engraftment, superior 2-year overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) with similar relapse. Multivariate analysis demonstrated that HIT was significantly associated with better OS, DFS, and lower NRM than dCBT. Both longer remission duration after SCT1 and complete remission at SCT2 were significantly associated with a lower relapse rate. In addition, bone marrow WT1 measurable residual disease (MRD) positivity was significantly associated with inferior OS and higher relapse. This study suggests that T-cell-replete HIT with ATG-based GVHD prophylaxis may be preferred over dCBT as SCT2 for relapsed AML and that WT1-MRD negativity may be warranted for better SCT2 outcomes.

Continuously Improving Outcome over Time after Second Allogeneic Stem Cell Transplantation in Relapsed Acute Myeloid Leukemia - a Retrospective Analysis of 1540 Patients on Behalf of the Acute Leukemia Working Party of EBMT

Second allogeneic stem cell transplantation (alloSCT2) is an increasingly used treatment for acute myeloid leukemia relapsing after first alloSCT. The scope of this study was to analyze trends in patient characteristics, transplant settings and outcome over time to identify factors associated with improved results after alloSCT2. In this retrospective registry-based analysis, 1540 patients receiving a second alloSCT after hematologic relapse between 2000 and 2019 were included, excluding alloSCT2 given for graft failure. Patients were grouped by period of transplant in 5-year intervals, median follow-up from alloSCT2 was 4.9 years. Over time, the number of patients reported to have received an alloSCT2 in EBMT centers increased from 144 in the period 2000-2004 to 619 in 2015-2019, with remarkable changes with respect to patient characteristic and transplant setting: In recent time periods, patients were of older age (median age 43.4 years between 2000-2004 and 48.6 years between 2015-2019, p=0.012) and had a better performance status before alloSCT2 (2000-2004: Karnofsky index ≥90% in 25.5% patients, 2015-2019: increase to 58.5%, p<0.001). Beyond, the interval between relapse after alloSCT1 and alloSCT2 increased from 2.5 to 3.5 months (p<0.001). In the more recent time periods, a different donor for second alloSCT and especially unrelated [increase from 30.6% (2000-2004) to 61.7% (2015-2019)] and haploidentical [increase from 0.7% (2000-2004) to 22.9% (2015-2019)] donors were used more frequently (p<0.0001 each). Finally, over time more myeloablative conditioning (MAC) (p=0.045), more in vivo T cell depletion (p<0.001), post-transplant cyclophosphamide (p<0.001) and ciclosporin A/MMF for graft versus host disease (GVHD) prophylaxis (p<0.001) were used in alloSCT2. Concerning clinical results after alloSCT2, cumulative relapse incidence (RI) after alloSCT2 decreased over time, whereas outcome improved (Figure 1). Between 2000 and 2019, two-year overall survival (OS) increased from 22.5% to 35%, leukemia free survival (LFS) increased from 14.5% to 24.5%. Whereas no clear trend was observed for incidence of GVHD and non-relapse mortality (NRM), RI decreased from 64% to 50.7%. In multivariate analysis, a later period of alloSCT2 was closely associated with improved OS and LFS (2015-2019: HR 0.47, p<0.001 for OS, HR 0.53, p=0.01 for LFS). Beyond, disease status at alloSCT2 had significant effects on OS, LFS, RI and NRM (HR for active disease at alloSCT2 1.59, p<0.001 for OS; HR 1.63, p<0.001 for LFS; HR 1.91, p<0.001 for RI; HR 1.35, p=0.04 for NRM). Similarly, longer remission duration after alloSCT1 was associated with better OS and LFS, lower RI and higher rates of NRM and acute GVHD (HR for lower remission duration 1.83, p<0.001 for OS; HR 1.72, p<0.001 for LFS; HR 1.86, p<0.001 for RI; HR 1.46, p=0.01 for NRM, HR 1.32, p=0.02 for acute GVHD). AlloSCT2 from haploidentical or unrelated donor, and older patient age were associated with higher NRM (HR 1.88, p=0.01 for haploidentical donor, HR 2.14, p<0.001 for unrelated donor, HR 1.1, p<0.001 for increasing age by 5-year intervals) and therefore inferior OS (HR 1.34, p=0.02 for haploidentical donor, HR 1.32, p=0.02 for unrelated donor, HR 1.05, p=0.002 for age). Further, MAC was associated with decreased RI without increase in NRM, leading to increased OS and LFS (HR 0.7, p<0.001 for RI, HR 1.1, p=0.47 for NRM, HR 0.82, p=0.02 for OS, HR 0.79, p=0.002 for LFS). LFS and OS were positively affected by a better Karnofsky index (HR 0.84, p=0.02 for LFS, HR 0.74, p<0.001 for OS). In vivo T-cell depletion was associated with lower NRM and lower rates of GVHD (HR 0.7, p=0.02 for NRM, HR 0.52, p<0.001 for acute GVHD II-IV, HR 0.64, p=0.003 for chronic GVHD). In conclusion, according to this large registry analysis on >1500 patients, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. In particular, decreased relapse incidence that did not come at cost of increased toxicity could be observed. This might be a result of better disease control and improved performance score at time of alloSCT2, as well as an increasing use of MAC, in vivo T-cell depletion and eventually post-transplant cyclophosphamide in alloSCT2 over time. These data encourage to perform alloSCT2 in relapsed AML and may help to define future strategies. Figure Legend Figure 1: Outcome after alloSCT2 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine.

To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt. We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally. Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18).For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt.For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively.For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients. In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235.

A 3-decade multicenter European experience with cladribine as upfront treatment in 384 patients with hairy cell leukemia

Cladribine is regarded as the first treatment of choice of symptomatic hairy cell leukemia (HCL): it provides high rates of response and very long duration of remission in some cases. Disease-specific patients records have been reviewed at four European centers of excellence; all patients with HCL requiring treatment who received frontline cladribine have been extrapolated. Responses have been classified according to Consensus Resolution Criteria. Three hundred and eighty-four patients have been diagnosed and followed between 1969 and 2018; all received frontline cladribine (subcutaneously or intravenously). A complete response was obtained in 72% of cases and a partial response in 22%. A continuous complete response was documented in 20% of patients at a median follow-up period of 8.5 years (range, 1-22 years). Median overall survival was reached at 25 years. Median progression-free survival was 13 years and median disease-free survival was 11 years. Cladribine is effective as frontline treatment of HCL and may determine deep disease control in a significant proportion of cases, given that more than 50% of treated patients require no further therapy. Good quality responses may be maintained for more than 20 years in up to 35% of patients.

Impact of Consolidative Unrelated Cord Blood Transplantation on Clinical Outcomes of Patients With Relapsed/Refractory Acute B Lymphoblastic Leukemia Entering Remission Following CD19 Chimeric Antigen Receptor T Cells.

BackgroundWhile chimeric antigen receptor (CAR)-T cell therapy is becoming widely used in hematological malignancies with remarkable remission rate, their high recurrence remains an obstacle to overcome. The role of consolidative transplantation following CAR-T cell-mediated remission remains controversial. We conducted a retrospective study to explore whether bridging to unrelated cord blood transplantation (UCBT) could improve the prognosis of patients entering remission after CAR-T therapy with different characteristics through subgroup analyses.MethodsWe reviewed 53 patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) successfully infused with CD19 CAR-T cells and achieved complete remission (CR). In this study, 25 patients received consolidative UCBT (UCBT group) and 28 patients did not accept any intervention until relapse (non-UCBT group). Subgroup analysis on prognosis was then performed according to gender, age, number of previous relapses, tumor burden, presence of poor prognostic markers, and structure of CAR.ResultsCompared with the non-UCBT group, patients who underwent consolidative UCBT had better median event-free survival (EFS; 12.3 months vs. 6.2 months; P = 0.035) and relapse-free survival (RFS; 22.3 months vs. 7.2 months; P = 0.046), while no significant difference was found in overall survival (OS; 30.8 months vs. 15.3 months; P = 0.118). Subsequent multivariate analysis revealed that bridging to UCBT was a protective factor for RFS (P = 0.048) but had no significant effect on EFS (P = 0.205) or OS (P = 0.541). In the subgroup analysis, UCBT has an added benefit in patients with specific characteristics. Patients who experienced ≥2 relapses or with sustained non-remission (NR) showed better RFS (P = 0.025) after UCBT. Better EFS was seen in patients with poor prognostic markers (P = 0.027). In the subgroup with pre-infusion minimal residual disease (MRD) ≥5% or with extramedullary disease (EMD), UCBT significantly prolonged EFS (P = 0.009), RFS (P = 0.017), and OS (P = 0.026). Patients with occurrence of acute graft-versus-host disease (aGVHD) appeared to have a longer duration of remission (P = 0.007).ConclusionConsolidative UCBT can, to some extent, improve clinical outcomes of patients with R/R B-ALL entering remission following CD19 CAR-T therapy, especially in patients with more recurrences before treatment, patients with poor prognostic markers, and patients with a higher tumor burden. The occurrence of aGVHD after UCBT was associated with better RFS.

Primary cutaneous indolent B-cell lymphomas – a retrospective multicenter analysis and a review of literature

Introduction: Primary cutaneous indolent B-cell lymphomas (PCBCLs) are not well characterized due to their rarity and indolent character. Methods: We retrospectively reviewed the data from 52 patients with primary cutaneous follicular lymphoma (PCFL) (n = 26), marginal zone lymphoma (PCMZL) (n = 25) or undefined PCBCL (n = 1) treated in 10 hematology centers in 1999–2019. Results: Patients characteristics and diagnostic approach: In almost half of the patients, pruritus or pain were present at diagnosis. The lesions were predominantly located on the head and trunk. The disease was present in a form of solitary infiltration or disseminated lesions with a similar frequency. Treatment details and outcomes: Surgery, radiotherapy, rituximab alone or combined with chemotherapy were applied as first-line treatment in 33%, 25%, 21% and 21% of patients, with complete response (CR) achieved by 94%, 83%, 50% and 70% of patients, respectively (p = 0.28). The median duration of response (DoR) was 65 months (95%CI 35–155). Survival: After the median follow-up time of 46 months (range: 3–225), the estimated 5-year overall survival (OS) and progression-free survival (PFS) were 93% and 54%, respectively. Discussion: Clinical presentation was largely consistent with the literature data, however, we observed some differences, including higher predilection to affect upper extremities (25%) and more frequent multifocal appearance in PCFCL (64%) and unifocal in PCMZL (70%). A high proportion of patients with indolent PCBCL achieved CR after the first-line therapy (77%), regardless of treatment mode. We did not find any impact of clinical features on treatment outcomes. Conclusions: All treatment modalities resulted in a high overall response rate. Surgery and/or radiotherapy are the optimal therapeutic options for patients with localized disease. The decision to treat systemically should rather be limited to the generalized form of the disease. High response rate, long duration of remission and excellent long-term survival confirm the truly indolent character of PCFCL and PCMZL.

Efficacy of Different Doses of Daunorubicin Induced Chemotherapy in Patients with Newly Diagnosed Primary Acute Myeloid Leukemia Under 65 Years Old

To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients. The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group ［75 mg/(m2·d)］ and 51 cases in the standard-dose group ［60 mg/(m2·d)］. And then the effects of different doses of daunorubicin on complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events were analyzed. Median follow-up time of all the patients was 15 months. The CR rate and MRD- CR rate of the escalated-dose group was 88.5% and 71.4%, respectively, which were higher than 64.7% and 41.2% of the standard-dose group (P=0.029, P=0.008). The estimated 2-year RFS of the escalated-dose group was 68.4%, which was higher than 38.5% of the standard-dose group (P=0.015), but estimated 2-year OS showed no statistically significant difference (77.1% vs 66.7%, P=0.059), as well as grade 3－4 adverse events. The escalated dose of daunorubicin had prolonged RFS (13 months vs not reached, P=0.022) and OS (23 months vs not reached, P=0.029) in the FLT3-ITD－ AML patients. The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Incidence, Treatment Patterns, and Outcomes of Histiocytic Disorders in the United States: A Forty-Year Population Study

BackgroundLangerhans cell histiocytosis (LCH) is an orphan disease of clonal dendritic cells, which can affect any organ of the body. There is paucity of data on treatment patterns and outcomes of adult LCH pts, who are usually treated with pediatric-based therapies. No prospective clinical trial has been conducted to date to identify optimal therapeutic strategies in adult LCH. Uncertainty of the natural history of LCH in adults including its pathogenesis, treatment patterns, and outcomes have limited development of novel treatments. Here, we used the Surveillance Epidemiology and End Results (SEER) to describe the epidemiology of LCH, trends in treatment practices over time, and survival outcomes over a forty-year period.MethodsAll 18 registries of SEER covering a period from 1973 to 2014 was used to assemble LCH cohort. LCH cases included in the study had a diagnosis of malignant histiocytosis or LCH (unifocal, multifocal, disseminated, or not otherwise specified). Descriptive data on incidence, demographics, and treatment were collected. Relative survival (RS) was stratified by 5-year (yr) time increments, four age groups [< 20 years (yrs) - pediatric; 20-39 yrs; 40-59 yrs, and > 60 yrs - elderly], and treatment type was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. As LCH pts tend to live longer, we calculated RS probabilities, which compares survival in the pt cohort with the expected survival of the general population having the same characteristics with respect to age, sex, race, and calendar period. Survival probabilities were calculated using the SEER Survival System (SEER*Stat). RS estimates (proportion of cancer pts surviving for a specified period) were calculated by the life table method. Analysis was performed using SEER*Stat.ResultsA total of 1480 LCH pts were identified who met the inclusion criteria. Of these, 55% were male, 82% Caucasians, and 58% of cases were diagnosed in the pediatric age group (age <18). The incidence rate remained stable from 1973 to 2009 with an average of 17 new cases per year at an age-adjusted incidence rate of 0.3 per 1,000,000. However, introduction in 2010 of a new International Classification of Diseases code resulted in a significant increase in recorded cases from that year going forth. A variety of treatment modalities were used including 47.8% receiving chemotherapy, 26.2% receiving surgery, and 10.3% receiving radiation therapy. Survival analysis of available SEER data on 705 LCH pts showed a median RS of 16.2 years with 52% of pts alive at 25 yrs. Survival rates have steadily improved since 1973 when assessed in 5-yr increments and since 2003, survival rates have remained steady at 90% (Figure 1). When analyzed by age groups, survival rates successively worsened with advancing age groups with 80% of pediatric pts alive two decades from diagnosis compared to no survivors in the elderly group (Figure 2). In treated pts, receipt of chemotherapy or radiation therapy at diagnosis conferred no survival benefit over those not receiving such treatments (Figures 3 and 4). Likewise, pts receiving surgery at diagnosis did not have significant survival benefit over those not treated with surgery (Figure 5). Notably, 34.1% of the 1480 pts died due to a hematologic malignancy, while 13.1% died due to a solid tumor malignancy. In those who later developed second cancers, there was a significant risk of solid tumor (Odds ratio (OR) 1.69, 95% CI 1.08-2.51, P < 0.05) and hematologic malignancies (OR 4.89, 95% CI 1.96-10.07, P < 0.05).ConclusionTo our knowledge, this is the first population based study to examine treatment and survival trends in histiocytic disorders, which remain rare and poorly characterized. Notable observations from this study show no relative survival benefit with chemotherapy, radiation therapy, or surgery indicating these treatments were mainly to control local or systemic disease. As such, novel therapeutic approaches are needed to improve outcomes. Although this study shows consistent survival gains since 1973, this is likely due to improvements in supportive care practices. Unfortunately, outcomes in the elderly are dismal compared to pediatric pts. While pts with histiocytic disorders generally have a long duration of remission, we demonstrate that they are at risk for second cancers, particularly hematologic malignancies. [Display omitted] DisclosuresGerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Advani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Remission of chronic spontaneous urticaria following omalizumab with gradually extended dosing intervals: Real-life data.

Omalizumab is a well-established treatment option in chronic spontaneous urticaria unresponsive to antihistamines at standard or higher doses. However, characteristics of the remission and relapse following the withdrawal of omalizumab remain largely unknown. We aimed to define the characteristics of remission in CSU following omalizumab with gradually lengthened dosing intervals in this retrospective study of 102 patients who were treated with at least 3 doses of omalizumab between 2013 and 2020. Of 102 patients, 70 (68.6%) showed a CR to omalizumab at standard doses. Omalizumab could be discontinued in 47 of 70 patients using gradually lengthened dosing intervals. Following a mean follow-up duration of 12.2months, 25 (58.1%) patients were still in remission while 18 (41.9%) had relapse (Follow-up data were not available in 4 patients). The relapses were unresponsive to antihistamines in 14 patients (77.7%), however, re-treatment with omalizumab led to complete control of symptoms. The patients younger than 40were more likely to relapse. Despite the need for comparison with fixed-dosing intervals in larger, prospective studies, the results of this study imply that omalizumab with gradually extended dosing intervals might provide a long duration of remission in CSU.

OP0182 IN RA PATIENTS IN REMISSION, WHICH BIOMARKERS PREDICT SUCCESSFUL TAPERING OF CSDMARDS?

Background:Recommendations for the management of patients with RA who achieve stable clinical remission ≥6 months with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) are to taper (with the aim of potentially stopping), although there are currently no validated biomarkers permitting prediction of sustained remission.Objectives:To assess the rate of sustained remission over 12 months In RA patients in remission, who received either (i) structured tapering of csDMARDs or (ii) continuation of current therapy, focusing on the value of imaging and immunological biomarkers as well as patient-reported outcome measures (PROs).Methods:RA patients (n=200) prospectively attending a remission clinic, fulfilling DAS28(3v)CRP&lt;2.6 for ≥6 months on stable csDMARD therapy (mono or combination therapy &amp; no corticosteroids) were included. Patients were offered the choice of structured cs-DMARD tapering according to a pre-defined protocol (Table 1) or remaining on stable therapy. Clinical, ultrasound (US), immunological (T-cell subsets) and PRO data were collected at inclusion. Loss of remission was defined as increase of DAS28(3v)CRP &gt;2.6. Mann-Whitney-U and Chi-square tests were used to compare outcomes. After imputing missing data, regressions for predicting sustained remission were performed. AUROCs were used to compare models.Table 1.csDMARD tapering scheduleDrugBaseline DoseTaper 1Taper 2Taper 3Taper 4Taper 5Hydroxychloroquine200mg bd200mg odStop---Hydroxychloroquine200mg odStop----Sulfasalazine1.5g bd1g bd1.5g od500mg bd500mg odStopSulfasalazine1g bd1.5g od500mg bd500mg odStop-Sulfasalazine500mg bd500mg odStop---Sulfasalazine500mg odStop----Methotrexate25mg/week15mg/week7.5mg/weekNo changeStop-Methotrexate15mg/week7.5mg/weekNo changeStop--Methotrexate7.5mg/weekNo changeStop---NB: Patients were seen 3-monthly. If they remained in remission following tapering, they proceeded to the next taper unless there is a significant clinical reason not to taper at the time of assessment (as per standard care). Order of cs-DMARD tapering applies to patients on dual/triple therapy. All but 5 (112) were on methotrexate.Results:The decision to taper treatment was associated with male gender, longer remission duration, normal CRP and lower grey scale scores (p&lt;0.05). Of those who tapered 64% (75/117) remained in clinical remission at 12 months, compared to 80% (66/83, p=0.018) of patients who remained on stable treatment. At 15 months 11/117 (10%) had successfully stopped therapy.In the tapering group, higher CRP, TJC and IRC were consistently associated with inability to sustain remission, as well as higher scores for several PROs (p&lt;0.05) with a trend for total PD (P=0.066). Predicting sustained remission was modelled and retained RAQoL, total PD and a T-cell subset (Figure 1, 85% accuracy, AUROC 0.872).Figure 1.AUROC Analysis of tapering cohort dataIn the non-tapering group, higher CRP/ESR, SJC and shorter disease duration (p&lt;0.05) were associated with flare. No parameter was able to predict sustained remission.Conclusion:In patients who chose to taper, the combination of clinical, PRO, US and T-cell parameters demonstrated added value for predicting sustained remission (85% accuracy) compared to clinical parameters alone. Different biomarkers were associated with sustained remission on continued therapy. These data may assist with informed tapering of csDMARDs.Disclosure of Interests:None declared

Interventions and outcomes of adult patients with B-ALL progressing after CD19 chimeric antigen receptor T-cell therapy

AbstractCD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post–CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post–CAR T progression. Thirty patients (79%) received salvage treatment of post–CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post–CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.

Outcomes of pediatric patients who relapse after first HCT for acute leukemia or MDS.

Disease relapse remains a major cause of treatment failure in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute leukemias or myelodysplastic syndromes (MDS). Comprehensive data on outcomes after post-transplant relapse are lacking, especially in pediatric patients. Our objective was to assess the impact of various transplant-, patient-, and disease-related variables on survival and outcomes in patients who relapse after alloHCT. We describe our institutional experience with 221 pediatric patients who experienced disease relapse after their first alloHCT for acute leukemias or MDS between 1990 and 2018. In a multivariable model, being in first complete remission at first alloHCT, longer duration of remission after alloHCT, experiencing GVHD and receiving a transplant in a more recent time period were significantly associated with a higher likelihood of receiving a second alloHCT after post-transplant relapse. Of these variables, only longer interval from alloHCT to relapse, receiving a second alloHCT or DLI, and receiving a transplant in a more recent time period were associated with improved overall survival. Our data support pursuing second alloHCT for patients who have experienced relapse after their first transplant, as that remains the only salvage modality with a reasonable chance of inducing long-term remission.

Real-world examination of remission patterns in patients (pts) with acute myeloid leukemia (AML).

e19336 Background: For pts with AML, prognosis is poor as long-term remission is elusive and ≥ 60% of pts relapse. The effect of remission status on healthcare resource utilization (HCRU) and costs is unclear. This study assessed administrative claims data from pts with AML to understand the potential benefit of novel, remission-prolonging therapies on HCRU and costs. Methods: Pts with newly diagnosed AML who received frontline therapy and did not undergo hematopoietic stem cell transplantation were identified in the MarketScan Commercial and Medicare Supplemental database from Jan 1, 2012–June 6, 2018. Pts were followed over a fixed 6-month (mos) pre- and variable post-diagnosis period; remission and relapse events were identified by diagnosis codes. Pts were analyzed by duration of remission ( &lt; 3, 3– &lt; 6, 6– &lt; 9, and ≥ 9 mos), based on time from first remission claim to first relapse claim or end of follow up, whichever occurred first. Pt characteristics, relapse, HCRU, and costs were assessed. Results: 459/1003 eligible pts (45.8%) had evidence of remission. Most pts were in remission for &lt; 3 mos (n = 161; 35.1%) or ≥ 9 mos (n = 165; 35.9%); 81 (17.6%) and 52 (11.3%) pts were in remission for 3– &lt; 6 and 6– &lt; 9 mos, respectively. Median follow-up for all pts was 236 days. Across remission cohorts, mean age at diagnosis was 55–59 years and median time to remission (from first AML diagnosis to first remission claim) was 82–90 days. Median time from AML diagnosis to relapse was 265.5 days. Of pts in remission, 30.5% relapsed (41.0%, 28.4%, 40.4%, and 18.2% for &lt; 3, 3– &lt; 6, 6– &lt; 9, and ≥ 9 mos, respectively). From AML diagnosis to the end of follow-up, mean all-cause per pt per mos (PPPM) healthcare costs for all pts were $44,588. Longer durations of remission were associated with reduced mean PPPM costs ($64,188, $53,260, $30,219, and $16,654 for &lt; 3, 3– &lt; 6, 6– &lt; 9, and ≥ 9 mos, respectively); similar trends were observed for AML-related costs. Mean all-cause PPPM costs were also reduced during remission, measured from the first remission claim to the first relapse claim or end of follow-up. A significant decrease was observed for pts in remission for ≥ 6 mos ($35,229, $36,193, $17,486, and $8,933 for &lt; 3, 3– &lt; 6, 6– &lt; 9, and ≥ 9 mos, respectively). Conclusions: In this real-world study, 46% of pts with AML achieved remission after frontline therapy, although durations of remission varied. A longer duration of remission was associated with reduced PPPM costs over the study period indicating a potential economic benefit of remission-prolonging therapies in AML, including maintenance treatments.

Additive effect of leflunomide and glucocorticoids compared with glucocorticoids monotherapy in preventing relapse of IgG4-related disease: A randomized clinical trial

ObjectivesTo evaluate the efficacy and safety of leflunomide (LEF) and glucocorticoids (GCs) combination therapy compared with GCs monotherapy in preventing relapse of IgG4-related disease (IgG4-RD). MethodsA 12-month, randomized, open-label, controlled trial was conducted at a large academic medical center (ClinicalTrials.gov: NCT02703194). Enrolled patients with active IgG4-RD were randomly allocated to the GCs + LEF (20 mg/day) combination therapy or GCs monotherapy group. All patients received GCs with a predefined taper regimen starting from a dosage of 0.5–0.8 mg/kg/d. The primary outcome was the time to relapse. The secondary outcomes included complete response, remission, GCs dosage, and serum IgG4 level. ResultsSixty-six patients with active IgG4-RD were enrolled (33 patients in each group). The demographic and disease characteristics showed no statistically significant differences between groups. Additionally, the initial GCs dosages were similar (50.00 vs. 50.00 mg/day, P = 0.295). Disease relapses occurred in 6 (18.2%) and 14 (42.4%) patients in the combination therapy group and GCs monotherapy group, respectively (P = 0.032). The combination therapy was significantly superior to GCs monotherapy regarding the primary outcome, the time to relapse (HR, 0.35; 95% confidence interval [CI], 0.13–0.90; P = 0.023), as well as the secondary outcome, the time to complete response (HR, 1.75; 95% CI, 1.01–3.02; P = 0.034). A longer duration of remission was observed in the combination therapy group (7.00 vs. 3.00 months, P = 0.002) and less cumulative dosage of GCs was used (5103.13 vs. 5637.50 mg, P = 0.031). Additionally, a higher proportion of patients in the combination therapy group (54.5%) were able to reach a daily GCs dose of ≤5 mg/day compared with the GCs monotherapy group (18.2%) (P = 0.006). The incidences of adverse events were similar in the 2 groups (P = 0.325). ConclusionLEF in combination with GCs therapy is well-tolerated and significantly superior to GCs monotherapy in preventing the relapse of IgG4-RD. LEF can be used as a steroid-sparing agent in the management of IgG4-RD.