Primary Disease Relapse Research Articles

Defining primary refractory large B-cell lymphoma

AbstractPatients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have “primary refractory disease.” However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological Resource cohort (MER; N = 949) or the Lymphoma Epidemiology of Outcomes cohort (LEO; N = 2755) from September 2002 to May 2021. Primary refractory LBCL was defined as no response (stable disease [SD]) or progressive disease (PD) during, or by the end of, frontline (1L) IC (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving CR at EOT to 1L IC (early relapse). In the MER cohort, patients with PPD had inferior overall survival (OS; 2-year OS rate: 15% MER, 31% LEO) when compared with other subgroups considered in defining primary refractory disease, EOT PR (2-year OS rate: 38% MER, 50% LEO) and early relapse (2-year OS rate: 44% MER, 58% LEO). Among patients receiving 1L IC with curative intent, we identified that patients with PPD are the key subgroup with poor outcomes. We propose a definition of primary refractory LBCL as SD or PD during, or by the end of, 1L treatment.

Successful clinical approach to the metastatic uterine leiomyosarcoma to the epicardium—a case report

BackgroundUterine leiomyosarcoma is a rare and aggressive tumour with a poor prognosis. Its metastases to the heart are even rarer, especially to the epicardium. The majority of reported cardiac metastases of uterine leiomyosarcoma were in the cardiac chambers or intramyocardial. Surgical resection of the uterine leiomyosarcoma in the early stages is the only definitive treatment for this disease. However, in the cases of cardiac metastasis, surgery is recommended only in emergencies and patients with expected beneficial outcomes.Case presentationOur patient was a 49-year-old female referred to the Department of Cardiac Surgery for scheduled surgery of pericardial neoplasia. The patient underwent a hysterectomy and adnexectomy three years prior owing to the uterine leiomyosarcoma. A regular follow-up magnetic resonance imaging of the abdomen and pelvis discovered neoplasia in the diaphragmic portion of the pericardium. No other signs of primary disease relapse or metastases were found. The patient was asymptomatic. The multidisciplinary team concluded that the patient is a candidate for surgery. Surgery included diastolic cardiac arrest achievement and resection of the tumour. Macroscopically, a parietal layer of the pericardium was completely free from the tumour that invaded only the apical myocardium of the left ventricle. Completed histopathology confirmed the diagnosis of leiomyosarcoma of the uterine origin. Three months after surgery, the patient received adjuvant chemotherapy with doxorubicin and dacarbazine. One year after surgery, there are no signs of new metastases.ConclusionsStrict surveillance of patients with uterine leiomyosarcoma after successful treatment of the early stage of the disease is of utmost importance to reveal metastatic disease to the heart in a timely manner and to treat it with beneficial outcomes. Surgery with adjuvant chemotherapy might be a good approach in patients with a beneficial prognosis. From a surgical point of view, it is challenging to assess the appropriate width of the resection edges to be radical enough and, at the same time, sufficiently conservative to ensure the satisfactory postoperative function of the remaining myocardium and avoid repetitive tumour growth. Therefore, intraoperative histopathology should always be performed.

A New Machine Learning-Based Prognostic Prediction Strategy for Patients with Diffuse-Large B-Cell Lymphoma

Introduction - Diffuse large B-cell lymphoma (DLBCL) is a frequent and aggressive lymphoma. First line of treatment associates an anti-CD20 immunotherapy with an anthracycline-based chemotherapy (R-CHOP). After this treatment, 30% of patients present primary refractory disease or early relapse within two years (R/R DLBCL). At date, CAR-T cells improve the prognosis of patients with R/R DLBCL compared with high-dose chemotherapy followed by autologous stem-cell transplant. However, predicting this failure remains a challenge at time of diagnosis. Current standard tools as the R-IPI score have many weaknesses, particularly for patients most at risk. A multitude of clinical, biological and PET data are available and could help to precise R/R DLBCL probability. In this study, we propose a new strategy based on machine learning and exploitation of a large dataset to early detect patients with high risk of R/R DLBCL at diagnosis. Material and methods - Between August 2012 and November 2021, we retrospectively collected a cohort of 218 patients with DLBCL receiving first-line treatment R-CHOP. Twenty-two parameters were evaluated for each patient, including well-known predictive factors such as R-IPI components, but also advanced metabolic parameters (SUVmax, total metabolic tumor volume (TMTV), total lesion glycolysis (TLG) and Dmax), as well as pathological and biological features. We used supervised machine learning (ML) to build a multidimensional model to predict POD24, which is defined by primary refractory disease or relapse within two years. Conventional binomial logistic regression was also performed to create a conventional predictive model. In parallel, a group of three hematologists was asked to generate a consensus about POD24 occurrence using Delphi method. Results - Median age was 70 years. With a median follow up of 46 months, complete response rate was 87% and overall response rate was 89%. Overall survival and progression-free survival were respectively 81.6 % (95%CI 76.6 - 86.9) and 70.6 % (95%CI 64.8 - 76.9) at 24 months. POD24 event occurred in 23,5 % of patients. Performance status, Ann-Arbor staging, number of extranodal sites, medullar infiltration, TMTV, TLG, Dmax, lymphocytes and LDH showed significant predictability of POD24 when considered in univariate analysis. We used forward selection of variables to build a conventional predictive model including LDH, lymphocytes and Dmax. Area under the ROC curve was 0,72. Secondly, a ML model was trained on 147 patients and was applied on a test cohort with 49 remaining patients. Prediction accuracy was 89.7% and area under the ROC curve was 0,91. Decision threshold was raised to 0.75 cut-off, allowing to predict 60% of POD24 with 100% specificity. The four predominant variables in the model were Dmax, hepatic SUV, LDH and monocytes. Additionally, experts were confronted to 55 patients randomly sampled from the cohort, 14 (25%) of whom showed POD24. Prediction accuracy was 71% and area under the ROC curve was 0,73. Seventy-nine percents of POD24 was predicted by experts, with 68% specificity. Conclusion - We present a ML model that was built to predict POD24 and then R/R situations in DLBCL patients. It showed great accuracy with high specificity rate. In new immunotherapies and CAR-T cells era, this proof-of-concept study highlights the fact that ML models could be a helpful to decide on first-line strategies for DLBCL patients. Larger multicentric study is necessary to confirm and validate this model for clinical use.

Autologous Stem Cell Transplantation Remains a Curative Option As Second Line Treatment for Patients with Relapsed/Refractory Large B Cell Lymphoma: Spanish Multicenter Geth-TC/Geltamo Study

Introduction: High dose therapy and Autologous Stem Cell Transplantation (ASCT) has remained the treatment of choice for transplant-eligible patients with relapsed/refractory (R/R) large B cell lymphoma (LBCL) and chemosensitive disease. Recently, CART therapy has been approved in second line for patients with primary refractory disease or early relapse (<1 year of first-line therapy) and the current role of ASCT has been questioned. However, several studies have shown that despite early failure of first line, patients with chemosensitive disease after salvage therapy can be cured with ASCT consolidation. Our objective was to analyze the efficacy of ASCT in patients with R/R LBCL after a long-term follow up and try to define the optimal role of ASCT. Patients and methods: We performed a retrospective multicenter study based on GETH-TC database of ASCT. We included patients from centers of GETH-TC/GELTAMO with R/R LBCL who underwent ASCT from January 2010 to December 2021. All the patients received rituximab and anthracycline-based frontline therapy. Diffuse LBCL NOS, high-grade B-cell lymphoma double/triple hit and NOS, primary mediastinal, transformed follicular lymphoma (tFL) and other less frequent LBCL subtypes were included. Plasmablastic and primary central nervous system lymphoma were excluded. Patients who underwent ASCT in first CR were also excluded except patients with tFL who had received previous anthracycline-based frontline therapy for the indolent lymphoma. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in the overall series and according to different prognostic factors, including disease status at ASCT. Disease status was defined as complete remission (CR), partial response (PR) and refractory disease (stable disease or progression) assessed by PET/CT. Results: Seven-hundred and ninety-one patients fulfilled the inclusion criteria. Patients characteristics are summarized in Table 1. After a median follow-up of 74 months (95%CI 68-81), 65% of the patients were alive and 84% of them free of disease. Six-year-PFS and OS were 51% (95%CI 47-54) and 63% (95%CI 60-67), respectively. Non-relapse mortality at 1 year was 9% (95%CI 7-11). The main causes of death were progression in 161 (58%), ASCT-related toxicity in 18 (6%) and other causes in 98 (35%). PFS was significantly influenced by age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p<0.01). OS was influenced by age at diagnosis, R-IPI at diagnosis, age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p<0.01). In the multivariate analysis, age >60 years at ASCT [HR 1.31 (95%IC: 1.06-1.62), p=0.011], ASCT as ≥3 th line [HR 1.81 (95%IC: 1.42-2.31), p<0.001] and PR versus CR at ASCT [HR 1.46 (95%IC: 1.18-1.81), p<0.001] were the only independent variables influencing PFS, Figure 1. Age >60 years at ASCT [HR 1.62 (95%IC: 1.24-2.12), p<0.001], ASCT as ≥3 th line [HR 1.77 (95%IC: 1.32-2.37), p<0.001] and PR versus CR at ASCT [HR 1.58 (95%IC: 1.22-2.05), p<0.001] were the only independent variables for OS. From 307 (39%) patients who relapsed after ASCT, 59 received CART therapy (median PFS 8.9 months) and 69 allo-SCT (median PFS 10.8 months). Refractory disease or early relapse did not significantly influenced survival. Analyzing this population separately (n=477), disease status at ASCT (PR versus CR) and ASCT as ≥3 th line were the only independent variables for both PFS [HR 1.46 (95%IC: 1.11-1.92), p=0.007; HR 1.79 (95%IC: 1.32-2.43), p<0.001, respectively] and OS [HR 1.92 (95%IC: 1.38-2.67), p<0.001; HR 1.91 (95%IC: 1.35-2.69), p<0.001, respectively]. Conclusions: To our knowledge, this is the largest series analyzing the efficacy of ASCT in patients with R/R LBCL after rituximab-containing frontline therapy. Our results indicate that ASCT is a curative option for patients with chemosensitive disease (especially in CR after salvage), regardless of the timing of relapse after frontline treatment. These data support that ASCT could be considered in patients with primary refractory or early relapse, provided the disease is sensitive to salvage therapy.

How to integrate CD19 specific chimeric antigen receptor T cells with other CD19 targeting agents in diffuse large B-cell lymphoma?

About one third of patients with diffuse large B-cell lymphoma (DLBCL) have a relapsing/refractory (R/R) disease after first line chemo-immunotherapy, with particularly poor outcomes observed in patients with primary refractory disease and early relapse. CD19 specific chimeric antigen receptor (CAR) T cell therapy is a game changer that results in durable and complete response rates in almost half of the patients with R/R DLBCL. Other emerging CD19-targeting therapies include monoclonal antibodies, bispecific antibodies and targeting antibody-drug conjugates, which also show encouraging results. However, the timing and sequencing of different anti-CD19-targeting agents and how they might interfere with subsequent CAR T cell treatment is still unclear. In this review, we summarize the results of the pivotal clinical trials as well as evidence from real-world series of the use of different CD19-targeting approved agents. We discuss the effect of various therapies on CD19 expression and its implications for treatment sequencing.

Early Identification of Refractory/Relapsed Diffuse Large B Cell Lymphoma with Serial Ctdna Sampling

Background: Diffuse Large B Cell Lymphoma (DLBCL) is an aggressive lymphoma that is curable in 60% of patients with chemoimmunotherapy. Outcomes are poor for those experiencing relapsed or refractory disease (rrDLBCL), particularly for patients with primary refractory disease (REFR, < 9 months from diagnosis) and early relapse (ER, 9 months to 2 years from diagnosis). Some of these patients would be candidates for chimeric antigen receptor T cell therapy (CART) in second line, where outcomes are superior when the disease burden is low. Therefore, exploring strategies to identify these high-risk patients early is important. Plasma circulating tumor DNA has been shown to be prognostic in various DLBCL cohorts. Method: We developed a custom panel of 170 genes to identify early treatment failure in a cohort of 171 patients that had profiling performed on 323 plasma samples. Plasma samples were taken serially starting at diagnosis and as patients progressed through frontline treatment. All plasma samples underwent DNA extraction, library preparation and subsequent sequencing using a panel of DLBCL related genes at high read depth (~1000x). Single nucleotide variant (SNV) calling was carried out using a custom pipeline including paired normal DNA for improved somatic variant detection. ctDNA fraction was estimated based on the highest variant allele fraction detected, using a loss of heterozygosity somatic model. Our ctDNA analysis focused on samples at diagnosis, cycle 2 of therapy, and end of treatment in order to identify early determinants of refractory disease. Changes in ctDNA levels between time points were represented as log2 ratio of ctDNA fraction. Results: rrDLBCL cases were separated into 3 categories based on the time between diagnosis and progressive disease (PD): 47 REFR, 34 ER, and 31 late relapse (LR, >24 months). The remaining patients were disease free after frontline therapy for over 24 months (CR, n=59), resulting in a cohort enriched for rrDLBCL (65% of cases). The average international prognostic index (IPI) of each group at diagnosis was REFR=3.38, ER=2.87, LR=2.81, and CR=2.41. Cell of Origin, as determined by Hans algorithm, showed a higher number of non-GCB samples in ER and LR groups (53% and 60%, respectively) while REFR and CR displayed increased GCB cases (63% and 66%, respectively). The REFR patients were significantly more likely to be of a 4/5 IPI score at diagnosis than other groups (p=0.0203). Progression-free survival (PFS2) at relapse therapy for REFR (median=0.29 years) was shorter when compared to both ER (p=0.0104, median=0.44 years) and LR (p=0.0012, median=0.80 years). Using the diagnostic plasma sample, there was no significant difference in ctDNA fraction in any of the three groups. When the sample with the highest ctDNA fraction was compared between patients, REFR had significantly higher levels than LR and CR, consistent with a higher overall tumor burden (p=0.001 and 0.026, respectively). There was a trend towards higher ctDNA fraction at the end of treatment in both REFR and ER groups. As ctDNA dynamics are known to be informative of molecular response, we compared patients using the change in ctDNA fraction at cycle 2 of therapy (log2 ratio). This value was significantly different in REFR patients (p=0.0073 vs ER), consistent with a lower rate of molecular response to treatment. Conclusions: While refractory and later relapsed DLBCL have similar ctDNA features at diagnosis, we find they have distinct ctDNA dynamics during treatment. REFR had higher maximal ctDNA levels across time points and both REFR and ER patients exhibited higher levels of ctDNA at end of treatment. Moreover, patients with minimal change in ctDNA levels at cycle 2 of therapy are at a high risk of treatment failure and refractory disease. Further exploration of the specific mutational patterns is ongoing. These results could enable the earlier identification of rrDLBCL and facilitate the prioritization of approaches for therapeutic intervention in rrDLBCL.

Flares of Acute Graft-Versus-Host Disease: Mount Sinai Acute Gvhd International Consortium (MAGIC) Study

[Background] The current standard first-line treatment for acute graft-versus-host disease (GVHD), systemic high-dose steroids, induces clinical responses in a majority of patients. Flares of GVHD after initial improvement often occur during tapering or discontinuation of immunosuppression. There is no consensus regarding the definition of GVHD flare and little has been published regarding its natural history. [Methods] We retrospectively evaluated clinical data and blood samples from 968 allogeneic hematopoietic cell transplantation (HCT) recipients from 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of acute GVHD treatment between 2014 and 2021. VGPR was defined as the complete resolution of acute GVHD manifestations except residual stage 1 skin disease. Flares were defined as a recurrence of acute GVHD after achievement of CR/VGPR if (1) patients had an increased symptom severity of at least 1 organ stage; (2) received intensified treatment (increase in steroid dose ≥ 0.25 mg/kg or initiation of additional systemic immunosuppression); and (3) had no prior history of primary disease relapse or donor lymphocyte infusion preceding the flare. Serum samples obtained at the time of CR/VGPR and at the time of flares were analyzed for ST2 and REG3α concentrations that generated MAGIC algorithm probabilities (MAPs) resulting in previously validated Ann Arbor (AA) scores (1, 2, and 3). [Results] The median recipient age at HCT was 55 years (range: 0 to 79); 18.6% of patients had grades III-IV acute GVHD before CR/VGPR. The median maximum daily dose of corticosteroids before CR/VGPR was 1 mg/kg methylprednisolone equivalent (range, 0.1 to 3.2 mg/kg). Flares developed within 6 months following CR/VGPR in 210/968 (21.7%) patients with a median onset of 28 days (range: 2 to 448). Symptom severity at the onset of flare symptoms varied widely (grade I: 22%; grade II: 38%; grade III-IV: 41%) and the development of a flare was associated with a five-fold increase in NRM (hazard ratio [HR], 4.84 [95% CI, 3.19-7.36], P < 0.001) when considered as a time-dependent covariate in a multivariate regression model. The large majority of non-relapse deaths after flares (54/71, 76%) were due to acute GVHD or complications from its treatment. The AA scores at the time of first CR/VGPR successfully stratified patients for risk of six-month NRM (AA1: 5%, AA2: 11%, AA3: 34%, P < 0.001) (Figure A). Increasing AA score at CR/VGPR was also associated with significantly increased risk of GVHD flares (Figure B). Not only did the risk of flare increase with each rising AA score, but the number of patients with severe (grade III/IV) symptoms at flare onset also increased (AA1: 34%, AA2: 43%, AA3: 54%). We next generated a multivariate regression model of risk factors for the development of flares. High AA scores at the time of CR/VGPR (AA2: HR, 1.81 [95% CI, 1.32-2.48], P = 0.001; AA3: HR, 3.14 [95% CI, 1.98-4.98], P < 0.001), HCT from HLA mismatched unrelated donor (HR, 1.74 [95% CI, 1.00-3.02], P = 0.049), and interestingly, rapid achievement of CR/VGPR from the time of initial treatment (≤14 days) (HR, 1.84 [95% CI, 1.21-2.80], P = 0.004) were all identified as significant risk factors. Meanwhile, no other transplant, GVHD, or treatment characteristics associated with the development of flares including maximum GVHD severity, maximum steroid dose, and use of additional immunosuppressive agents other than steroids before CR/VGPR. AA scores measured at the onset of flare symptoms in 98 patients also predicted six-month NRM (AA1, 6%; AA2, 19%; AA3 42%, P = 0.01). [Conclusion] Despite advances in treatment, flares of GVHD symptoms following excellent (CR/VGPR) responses still occur in over one fifth of patients in current practice and are associated with a five-fold increase in six-month NRM. AA scores from serum biomarkers predict outcomes despite the absence of symptoms, suggesting that MAGIC biomarkers detect subclinical damage to GI crypts that can drive later recrudescence of clinical GVHD. Measurement of the MAP at the time of response to GVHD treatment may thus help to risk-stratify tapering strategies of immunosuppressive therapy.

Azathioprine monotherapy withdrawal in inflammatory bowel diseases: A retrospective mono-centric study.

There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation. To describe the events following AZA cessation. Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups. A total of 133 ulcerative colitis patients and 141 Crohn's disease patients were included. Therapy with AZA was stopped in the 1st year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years. AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.

Correlation Analysis between Cerebrospinal Fluid Status and Prognosis in Childhood with Acute Lymphoblastic Leukemia by Flow Cytometry

To study the cerebrospinal fluid (CSF) status and prognosis value in patients with newly diagnosed acute lymphoblastic leukemia (ALL) by flow cytometry (FCM). The clinical features of the 75 newly diagnosed ALL patients from September 2020 to December 2021 in our centre were retrospective analyzed, as well as the bone marrow (BM) and CSF minimal residual disease (MRD) data, and the CSF conventional cytology data. Central nervous system infiltration(CNSI) positive was as CSF MRD positive by FCM or leukemia cells detected by conventional cytology. The status of CSF were compared and analyzed by FCM and conventional cytology, the clinical features and the prognosis value of different CNSI status in these patients were analyzed. Among 75 newly diagnosed ALL, 16 cases (21%) with CNSI positive (CNSI+) were detected by FCM, while only 2 positive cases (3%) were detected by conventional cytology. The CNSI+ rate detected by FCM was significantly higher than conventional cytology(P<0.05). Compared with CNSI- ALL patients, the median age of CNSI+ ALL patients was significantly younger, and the median platelet count was significantly lower, the difference was statistically significant (P<0.05). Up to follow-up time (August 31, 2022), four ALL patients were died, including 3 patients were CNSI- and 1 patient was CNSI+. Furthermore, three cases were primary disease relapse, including 1 case was CNSI+. There was no significant difference in overall survival (OS) rate and relapse-free survival (RFS) rate of the patients with different CNSI status. Compared with conventional cytology, FCM is a more sensitive assay to evaluate the central nervous system status in ALL patients. After active treatment, there was no significant difference in OS and RFS between patients with different CNSI status at diagnosis.

A coordinated strategy for a simple, pragmatic approach to the early identification of the ultra-high-risk patient with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma seen in clinical practice. Despite huge strides in understanding its biology, front-line therapy has remained unchanged for decades. Roughly one-third of patients are primary refractory or relapse following the end of conventional first-line therapy. The outcome of patients with primary refractory disease and those with early relapse (defined as relapse less than one year from end of therapy) is markedly inferior to those with later relapse and is exemplified by dismal overall survival. In this article, we term patients with features that identify them as being at particularly high-risk for either primary refractory disease or early relapse, as 'ultra-high-risk'. As new treatment options become established (e.g., bispecific T-cell engagers, chimeric antigen receptor 'CAR' T-cells and antibody-drug conjugates), it is likely that there will be a push to incorporate some of these agents into the first-line setting for patients identified as ultra-high-risk. In this review, we will outline advances in positron emission tomography, widely available laboratory assays and clinical prognosticators, that can detect a high proportion of patients with ultra-high-risk disease. Since these approaches are pragmatic and able to be adopted widely, they could be incorporated into routine clinical practice. This article is protected by copyright. All rights reserved.

Different recovery patterns of CMV-specific and WT1-specific T cells in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: Impact of CMV infection and leukemia relapse.

In allogeneic hematopoietic cell transplantation (allo-HSCT), both virus-specific T cells and leukemia-specific T cells need to be reconstituted to protect patients from virus infections and primary disease relapse. Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality after allo-HSCT. Emerging data indicate that CMV reactivation is associated with reduced risk of leukemia relapse in patients with acute myeloid leukemia (AML) undergoing allo-HSCT. In a cohort of 24 WT1+ AML patients during the first year following HSCT, CMV specific CD8+ T cells (CMV-CTL) reconstituted much faster than WT1-specific CD8+ T cell (WT1-CTL) after allo-SCT. Moreover, CMV-CTL expressed lower levels of exhaustion markers and were more functional as identified by production of IFN-γ/TNF-α and expression of Eomes/T-bet. Interestingly, our patients with CMV reactivation presented higher frequency of CMV-CTL, lower levels of Eomes+T-bet- and higher levels of Eomes+T-bet+ expression in response to WT1 and CMV pp65 antigen during the first year after transplantation as compared to patients without CMV reactivation. Kinetics of CMV-CTL and WT1-CTL after transplantation might be associated with measurable residual disease and later leukemia relapse. Our results support that CMV reactivation, aside from the CMV-CTL reconstitution, could influence WT1-CTL reconstitution after allo-HSCT, thus potentially contributing to the remission/relapse of AML.

Allogeneic hematopoietic stem cell transplantation with the modified myeloablative conditioning regimen for children with chronic active Epstein-Barr virus infection.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only effective treatment for chronic active Epstein-Barr virus infection (CAEBV). The clinical efficacy and safety of allo-HSCT with different conditioning regimens in children with CAEBV remain unclear. To evaluate the effectiveness and safety of allo-HSCT with the modified myeloablative conditioning (MAC) regimen for children with CAEBV and also the factors affecting the outcomes. We retrospectively analyzed children with CAEBV who underwent allo-HSCT with the modified MAC regimen at Beijing Children's Hospital, Capital Medical University from October 2016 to June 2021. Data related to the clinical manifestations, engraftment, and outcome were extracted from the medical records. The cohort comprised 41 patients (24 males, 17 females) with a median transplantation age of 92.6 (60.4, 120.7) months and a median follow-up time of 28.2 (15.3, 40.2) months. Four patients (9.8%) died, among which three died from primary disease relapse, and one died from grade IV acute graft-versus-host diseases (aGVHD) after stopping treatment. The 3-year overall survival (OS) and 3-year event-free survival (EFS) rates were 88.8% ± 5.4% and 85.0% ± 5.7%, respectively. The 3-year OS and EFS did not significantly differ between the patients with hemophagocytic lymphohistiocytosis (HLH) and the patient without HLH (87.7% ± 6.8% vs. 91.7% ± 8.0%, P = 0.790; 85.0% ± 6.9% vs. 84.6% ± 10.0%, P = 0.921), or among the patients with complete remission, partial remission, and activity disease before HSCT (all P > 0.05). Multivariate analysis showed that grade III-IV aGVHD was a risk factor for mortality (Hazards ratio: 11.65, 95% confidence interval: 1.00, 136.06; P = 0.050). Allo-HSCT with the modified MAC regimen is safe and effective for pediatric CAEBV. This treatment benefits patients with HLH or active disease. Patients with Grade III-IV aGVHD may be associated with worse outcomes.

Decisional Role of Interim PET in Relapsed/Refractory Classical Hodgkin Lymphoma Treated with Begev Chemotherapy As First Salvage

Achievement of complete response (CR) before autologous stem cell transplantation (ASCT) is one of the main predictive factors of outcome in patients (pts) affected by relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) eligible to high-dose chemotherapy. The predictive role of interim PET during salvage treatment is well established in pts treated with IGEV or ICE but has not been investigated in pts receiving BEGEV (Bendamustine, Gemcitabine and Vinorelbine) as first salvage treatment. With the aim to investigate the predictive value of PET after 2 cycles of BEGEV (PET2) in terms of CR rate and survival, we retrospectively collected data of consecutive R/R cHL pts eligible to ASCT treated from 2011 to 2021 in 3 Italian centres. PET scans were locally evaluated using Deauville Score (DS), considering a score 1-3 negative and consistent with CR. Early relapse was defined as a relapse occurring ≤12 months from the end of first-line therapy. Survival functions were calculated from the date of initiation of BEGEV chemotherapy. Ninety-four cHL R/R pts receiving BEGEV as first salvage therapy were included. Fifty-one (54.3%) pts were male. First-line therapy consisted in 2 to 6 ABVD chemotherapy cycles accordingly to clinical stage followed by consolidation radiotherapy (RT) in 24 (25.5%) pts. At relapse, median age was 37 years (range: 18-71 years), 51 (54.3%) pts were in stage III-IV, 16 (17%) pts had B symptoms and 34 (36.2%) pts had extranodal involvement (EI). Fifty-one (54.3%) pts were primary refractory, 23 (24.5%) pts had an early and 20 pts (21.3%) a late relapse. PET2 was performed in 86 (91.5%) pts, and resulted negative in 61 (70.9%) and positive in 25 (29.1%) pts (DS 4 in 17 and DS 5 in 8 pts). PET after 4 BEGEV cycles (PET4) was performed in 82 (87.2%) pts and resulted negative in 63 (67%) and positive in 19 (20.2%) pts (DS 4 in 10 and DS 5 in 9 pts). Complete response after 4 BEGEV was achieved in 55/61 (90.2%) PET2 negative pts and 7/25 (28%) PET2 positive pts. Considering pts evaluable for both PET2 and PET4, PET2 positive pts had a statistically lower probability to achieve CR at PET4 when compared to PET2 negative pts (Odds ratio: 0.07, CI 95%: 0.02-0.29; p<0.00001). Autologous SCT was performed in 81 (86.2%) pts, following BEGEV in 56 pts (69.1%) and after further salvage treatments in 25 (30.9%). A post-ASCT consolidation strategy was performed in 24 (29.6%) pts, and consisted in RT in 18 pts and brentuximab-vedotin in 6 pts. Ten pts received an allotransplant: in 3 cases allotransplant was planned in a tandem modality, while in 7 cases was performed after further salvage treatments for post-ASCT relapse or progression. With a median follow-up of 36.4 months (interquartile range: 20.1-50.0), 3-years overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) for the whole study population were 91.7%, 61.6% and 53.9%, respectively. No significant differences in OS were detected according to PET2 result. Conversely, both 3-years PFS and EFS were significantly superior in PET2 negative vs PET2 positive pts: 3-years PFS was 61.6% (CI 95%: 52.1-72.9) in PET2 negative and 43.6% (CI 95%: 27.9-68.4) in PET2 positive pts (p=0.0004) (Figure 1), while 3-years EFS was 71% (CI 95%: 59.8-84.3) and 23.3% (CI 95%: 11.3-48.1), (p<0.001). Univariable analysis of PFS was performed using Cox regression model and evaluating adverse risk factors at relapse (primary refractory and early relapse vs late relapse, presence of EN involvement and B-symptoms) and demonstrated a significantly inferior PFS for pts with EI (HR 1.94, CI 95% 1.01-3.74, p=0.47) and primary refractory disease or early relapse (HR 2.02, CI 95%: 1.01-4.04, p=0.047), but not for pts with B symptoms (HR 1.05, CI 95%: 0.43-2.51, p=0.9). Multivariate Cox regression model of PFS evaluating presence of EI at relapse (HR 1.55 , CI 95%: 0.74-3.25, p=0.240), time to relapse (primary refractory and early relapse vs late relapse, HR 0.84 (CI 95%: 0.36-1.96, 0.683) and PET2 result, identified PET2 positivity as the only predictive factor for PFS (HR 3.24, CI 95%: 1.55-6.77, p=0.002). In conclusion, R/R cHL pts with PET2 positive during BEGEV salvage treatment had a lower probability to achieve CR after 2 additional BEGEV cycles and a significantly inferior PFS, and could benefit from early exposure to new therapeutic strategies before ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Naxitamab and granulocyte macrophage colony stimulating factor (GM-CSF) in combination with irinotecan and temozolomide in patients with high-risk neuroblastoma with primary refractory disease or in first relapse: An international, single-arm, multicenter phase 2 trial.

TPS10061 Background: Neuroblastoma (NB) is the commonest extracranial solid tumor in children. At diagnosis, &gt; 50% have high-risk (HR) disease with poor prognosis despite intensive therapy; thus, there is a high unmet medical need. Naxitamab is an anti-GD2 monoclonal antibody indicated under accelerated approval in the US with GM-CSF for the treatment of relapsed/refractory HR NB in the bone and/or bone marrow in patients (pts) ≥1 year of age with a partial response, minor response, or stable disease to prior therapy. Irinotecan and temozolomide (IT) are commonly used salvage chemotherapies following failure of frontline therapy. The objective of this study is to investigate the efficacy and safety of naxitamab plus IT in pts with HR NB with primary refractory disease or first relapse. Methods: Trial 203 (NCT04560166) is an international, single-arm, multicenter phase 2 trial for HR NB patients ≥12 mo of age, with either evaluable primary refractory disease or first relapse following induction and consolidation therapy. The primary endpoint of the study is the centrally-assessed overall response rate (ORR) (complete [CR] or partial response) at or before completion of 4 cycles of treatment. Key secondary endpoints include ORR after 2 cycles of treatment, duration of response (DoR), CR rate, time to first subsequent therapy or death, progression-free survival (PFS), and overall survival (OS). 52 pts will be enrolled to provide 82% power to demonstrate that response rate is significantly higher than 20%. Key inclusion criteria are documented HR NB at time of diagnosis; received frontline induction/consolidation therapy; active disease despite previous aggressive chemotherapy; and measurable tumor (CT/MRI) that is either MIBG-avid/PET-positive or have MIBG scan with uptake at ≥1 site. Key exclusion criteria include prior treatment with duration ≤3 wks (chemotherapy), ≤6wks (autologous stem cell transplant or therapeutic 131I-MIBG), ≤4wks (radiation therapy), or progressed while on anti-GD2; residual NB in the bone marrow only; and CNS/leptomeningeal disease in the prior 6 mo. In addition, there should not be &lt; 50% performance status per Lansky or Karnosky scale and life expectancy &lt; 6 mo. Pts will receive irinotecan 50 mg/m2/day IV and temozolomide 100 mg/m2/day orally (both on Days 1-5) in combination with naxitamab 2.25 mg/kg/day IV (Days 2, 4, 8 and 10) and GM-CSF 250 ug/m2/day sc (Days 6-10) in 21 days cycle. Response rates will be assessed using the 2-sided binomial test at the 5% significance level; DoR, PFS, and OS will be estimated using Kaplan-Meier analysis. Adverse events will be graded per CTCAE. Clinical trial information: NCT04560166.

Outcomes of classic Hodgkin lymphoma, relapsed within one year of diagnosis, in the era of novel agents.

7515 Background: Primary refractory disease (PRD) and early relapse (ER) are predictors of poor prognosis in classic Hodgkin lymphoma (cHL). In this multicenter retrospective study, we describe outcomes of PRD and ER in pts with relapsed/refractory (R/R) cHL treated with salvage therapy (ST) and autologous stem cell transplant (ASCT). Methods: Of 14 sites, adult patients with R/R cHL who received ST and underwent ASCT were enrolled. PRD was defined as progression on frontline chemoimmunotherapy or within 6 months of diagnosis. ER was defined as relapse from 6 months-1 yr of diagnosis. Pts who relapsed &gt;1 yr of diagnosis were called late relapses (LR). Study objectives were Overall response rates (ORR), CR rates, PFS, and OS. Results: Of 986 total pts, 160 had PRD, 365 had ER and 461 had LR. Significantly higher number of pts with PRD, but not ER, had bulky disease (41% vs 27%, p&lt;0.01) and B symptoms (53% vs 38%, p&lt;0.001) than LR. Higher proportions of pts with PRD and ER required &gt;1 line of ST (44% vs 30% vs 23%, p&lt;0.001) before ASCT and received BV maintenance (25% vs 24% vs 16%, p&lt;0.05). When adjusted for B symptoms and Bulky disease, PRD and ER had significantly lower ORR (65% vs 76% vs 84%, p&lt;0.001) and CR (37% vs 46% vs 57%, p&lt;0.001) to first ST than LR. Pts with PRD and ER had significantly lower PFS (56.3%, 61.4%, vs 77.6%, p&lt;.0001) and OS (93% vs 89% vs 94%, p=0.01) than LR. In pts with ER, Brentuximab/bendamustine (BBV) and brentuximab vedotin/nivolumab (BV/nivo) had a trend towards higher ORR (92% vs 92% vs 75%) but significantly higher CR (79.2% vs 76% vs 42%, p&lt;0.01) than platinum based chemotherapy (PBC). In pts with PRD, BBV and BV/Nivo had a statistically insignificant trend towards higher ORR and CR than PBC. The table shows 2 yr PFS by type of ST in PRD, ER, LR. There was no difference in PFS by time to relapse in BV/nivo, CPI and miscellaneous agents. BV/Nivo had a significantly higher PFS than PBC in PRD (88% vs 48%, p&lt;0.05) and ER (95% vs 57%, p&lt;0.05). There was no difference in PFS of PBC and other ST in PRD, ER or LR. OS was not significantly associated with type of ST in either group. Conclusions: PRD and ER are associated with lower response to ST and survival after ASCT compared to late relapse. In pts with PRD and ER, BV/Nivo has high ORR and CR and leads to significantly higher PFS comparable to pts with late relapse and may be preferable ST regardless of time to relapse. [Table: see text]

PolyMyalgia Rheumatica treatment with Methotrexate in Optimal Dose in an Early disease phase (PMR MODE): study protocol for a multicenter double-blind placebo controlled trial

BackgroundPolymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting people older than 50, resulting in pain and stiffness of the neck, shoulder, and pelvic girdle. To date, glucocorticoids (GC) remain the cornerstone of treatment, but these have several drawbacks. Firstly, a large proportion of patients do not achieve GC-free remission within either the first (over 70%) or second year of treatment (over 50%). Secondly, GC-related adverse events (AE) occur in up to 65% of patients and can be severe.The current EULAR/ACR guidelines for PMR recommend early introduction of methotrexate (MTX) as a GC sparing agent in patients at risk for worse prognosis. However, earlier trials of low to medium quality only studied MTX dosages of 7.5–10 mg/week with no to modest effect. These doses may be suboptimal as MTX is recommended in higher doses (25 mg/week) for other inflammatory rheumatic diseases. The exact role, timing, and dose of MTX in PMR remain unclear, and therefore, our objective is to study the efficacy of MTX 25 mg/week in recently diagnosed PMR patients.MethodsWe set up a double-blind, randomized, placebo-controlled superiority trial (PMR MODE) to assess the efficacy of MTX 25 mg/week versus placebo in a 1:1 ratio in 100 recently diagnosed PMR patients according to the 2012 EULAR/ACR criteria. All patients will receive prednisolone 15 mg/day, tapered to 0 mg over the course of 24 weeks. In case of primary non-response or disease relapse, prednisolone dose will be temporarily increased. Assessments will take place at baseline, 4, 12, 24, 32, and 52 weeks. The primary outcome is the difference in proportion of patients in GC-free remission at week 52.DiscussionNo relapsing PMR patients were chosen, since the possible benefits of MTX may not outweigh the risks at low doses and effect modification may occur. Accelerated tapering was chosen in order to more easily identify a GC-sparing effect if one exists. A composite endpoint of GC-free remission was chosen as a clinically relevant endpoint for both patients and rheumatologist and may reduce second order (treatment) effects.Trial registrationDutch Trial Registration, NL8366. Registered on 10 February 2020

A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation: A Retrospective Study from the CIBMTR

Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes.Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the “classical” TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption.Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These “core” alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into “core” (N=930) and “non-core” (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B).Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and “core”/“non-core” TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with “core” TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), “non-core” TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, “core” vs. “non-core” HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The “core”/“non-core” TCE3 model was also associated with TRM with alloHCT from “core” TCE3-permissive donors showing lower risks of TRM than “non-core” TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002).Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of “core” TCE3-permissive donors might reduce patient morbidity after transplantation. [Display omitted] DisclosuresPaczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Combination with Corticosteroids, Is Well-Tolerated, with Rapid Pharmacodynamic and Clinical Response in Newly Diagnosed Acute Graft-Versus-Host Disease

Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Combination with Corticosteroids, Is Well-Tolerated, with Rapid Pharmacodynamic and Clinical Response in Newly Diagnosed Acute Graft-Versus-Host Disease

Phenotypic High-Risk Disease in the Context of Carfilzomib and Lenalidomide Combination Induction Therapy for Newly Diagnosed Transplant-Eligible Myeloma Patients

Phenotypic High-Risk Disease in the Context of Carfilzomib and Lenalidomide Combination Induction Therapy for Newly Diagnosed Transplant-Eligible Myeloma Patients

Novel Salvage Regimens Lead to Better Response and Survival in Relapsed Refractory Classic Hodgkin Lymphoma after Autologous Stem Cell Transplant

Novel Salvage Regimens Lead to Better Response and Survival in Relapsed Refractory Classic Hodgkin Lymphoma after Autologous Stem Cell Transplant