Safety profile and low risk of disease relapse after BNT162b2 mRNA SARS-COV-2 vaccination in patients with rare rheumatic diseases

Vaccination today represents the first defence against the effects of the Coronavirus disease 2019, mainly in rheumatic patients, where an increased risk for hospitalization and death has been reported (1,2). The previous studies on the safety and tolerability of BNT162b2 mRNA-SARS-CoV-2 (3) vaccine in patients affected with rheumatic diseases(RDs) included predominantly patients with inflammatory arthritis (4-6). This study was focused on patients affected with rare RDs and systemic lupus erythematosus (SLE) to assess the safety of the BNT162b2 mRNA SARS-CoV-2 vaccine and possible disease flares after vaccination.

Delivering on the promise of early detection with liquid biopsies

Liquid biopsy approaches are relatively well developed for cancer therapy monitoring and disease relapse, but they also have incredible potential in the cancer early detection and screening field. There are, however, several challenges to overcome before this potential can be met. Research in this area needs to be cohesive and, as a driver of research, Cancer Research UK is in an ideal position to enable this.

Thyroid Cancer In Children: A Multicenter International Study Highlighting Clinical Features And Surgical Outcomes Of Primary And Secondary Tumors

Background: Thyroid gland malignancy is rare in pediatrics (0.7% of tumors); only 1.8% are observed in patients < 20 yrs with a higher prevalence recorded in females and adolescents. Risk factors include genetic syndromes - MEN disorders, autoimmune disease and ionizing radiation exposure. Radiotherapy is also linked with increased risk of secondary thyroid cancers. The present study describes the clinical features and surgical outcomes of primary and secondary thyroid tumors. Methods: Institutional data was collected on pediatric patients with thyroid cancer during 2000 - 2020 from 8 International Surgical Oncology centers. Statistical analysis was performed using GraphPad Prism. Results: Of 255 cases of thyroid cancer, only 13 (5.1%) were secondary tumors. Primary thyroid malignancies were more likely to be multifocal in origin (odds ratio [OR] 1.993, 95% confidence interval [CI] 0.7466-5.132, p 0.2323), had bilateral glandular location (OR 2.847, 95% CI 0.6835-12.68, p 0.2648) and proved metastatic at 1st diagnosis (OR 1.259, 95% CI 0.3267-5.696 p>0.999). Secondary tumors showed a higher incidence of disease relapse (OR 1.556, 95% CI 0.4579-5.57, p 0.4525) and surgical morbidity (OR 2.042, 95% CI 0.7917-5.221, p 0.1614) including hypoparathyroidism and recurrent laryngeal nerve injury. Overall survival (OS) was 99% at 1 year and 97% after 10 years. No EFS differences were evident with primary vs. secondary tumors (Chi square 0.7307, p 0.39026). Conclusions: This multicenter study demonstrates excellent survival for pediatric thyroid malignancy. Secondary tumors exhibit greater disease relapse (15.8% vs 10.5%) and a higher incidence of surgical related complications (36.8% vs 22.2%).

Prognostic value of minimal residual disease before allogeneic hematopoietic stem cell transplantation in patients with acute leukemia

Introduction. One of the main causes of treatment failure after allogeneic hematopoietic stem cells transplantation (alloHSCT) for acute leukemia (AL) is disease relapse. In recent years, multiparameter fl ow cytometry (MPC) has been widely used to detect minimal residual disease (MRD) because of its capacity to identify patients with a high risk of relapse due to availability and the ability to obtain results in a timely manner.Aim — to evaluate the prognostic value of MRD status before allo-HSCT and the effect of donor type and conditioning intensity on long-term results of allo-HSCT of MOB-positive patients.Patients and methods. The analysis included 107 patients with acute myeloid leukemia (AML) and 63 patients with acute lymphoblastic leukemia (ALL) who underwent allo-HSCT between September 2015 and June 2020. All patients were in complete morphological remission before allo-HSCT. At the time of allo-HSCT 91 patients with AML and 37 patients with ALL were in the first complete remission (CR), in their second and more than two CRs were 16 and 26 patients, respectively. The median follow-up was 18 (1.5–48) months for AML and 14 (1.8–60.1) months for ALL. Immunophenotypic study was performed before allo-HSCT. MRD was detected using a combination of the “different from normal” method and the search for cells with a leukemia-associated immunophenotype.Results. The disease status at the time of transplantation and the presence of MRD before allo-HSCT were independent factors infl uencing the probability of relapse (disease status: HR = 2.911, 95% CI: 1.328–6.379; MRD before allo-HSCT: HR = 7.667, 95% CI: 3.606–16.304) and post-transplant mortality (disease status: HR = 2.911, 95% CI: 1.328–6.379; MRD before allo-HSCT: HR = 7.667, 95% CI: 3.606–16.304). In univariate analysis, the relapse-free survival of MRD+ patients with AL in the first CR was significantly worse than in MRD– (AML: 23 % versus 57 %, p < 0.0001, ALL: 34 % versus 61.7 %, p = 0.0484), and the probability of relapse in MRD+ patients was significantly higher (AML: 75 % versus 12 %, p < 0.0001, ALL: 57 % versus 7 %, p = 0.0072). Pre-transplant MRD status was not prognostically significant for AL-patients in the second and third remission. The development of chronic GVHD reduces post-transplant mortality if it does not require systemic therapy with glucocorticosteroids (HR = 0.006, 95% CI: 0.008–0.446).Conclusion. Testing for MRD of patients with AL in the first CR before allo-HSCT is necessary for risk stratification and identification of patients who will need preventive post-transplant therapy in order to prevent disease relapse.

Case reports of invasive mucormycosis associated neutropenic enterocolitis in leukemic children: diagnostic and treatment challenges and review of literature

Background Bacterial enterocolitis is one of the most common neutropenic fever complications during intensive chemotherapy. Despite aggressive antibacterial treatments, this complication usually imposes high morbidity and mortality in cancer patients. Management of bacterial neutropenic enterocolitis are well known; however, management of fungal neutropenic enterocolitis may be more challenging and needs to be investigated. Prompt diagnosis and treatment may be life-saving, especially in patients at risk of mucormycosis-associated neutropenic enterocolitis. Case presentation We report two mucormycosis-associated neutropenic enterocolitis cases in pediatric leukemic patients receiving salvage chemotherapy for disease relapse. Both patients' clinical signs and symptoms differ from classical bacterial neutropenic enterocolitis. They were empirically treated as bacterial neutropenic enterocolitis with anti-gram-negative combination therapy. Despite broad-spectrum antimicrobial treatment, no clinical improvement was achieved, and both of them were complicated with severe abdominal pain necessitating surgical intervention. Mucormycosis is diagnosed by immunohistopathologic examination in multiple intraoperative intestinal tissue biopsies. Both patients died despite antifungal treatment with liposomal amphotericin-B and surgical intervention. Conclusion Mucormycosis-associated neutropenic enterocolitis is one of the most unfavorable and untreatable side effects of salvage chemotherapy in leukemic children with disease relapse. This report could be of considerable insight to the clinicians and scientists who counter the enigma of fungal infections during febrile neutropenia and help to understand better diagnosis and management.

Clinical Significance of Plasma Epstein-Barr Virus DNA in Peripheral T-Cell Lymphomas

<b><i>Introduction:</i></b> The clinical implications of plasma Epstein-Barr virus (EBV) DNA in patients with peripheral T-cell lymphoma (PTCL) remain unclear. <b><i>Objective:</i></b> This study aimed to explore the clinical correlations of pre- and post-treatment plasma EBV-DNA concentrations with treatment outcomes and prognosis in patients with PTCL. <b><i>Methods:</i></b> We retrospectively reviewed 128 patients diagnosed with PTCL with available data on pre-treatment plasma EBV-DNA, including 63 patients for whom post-treatment plasma EBV-DNA data were also available. Patients with extra-nodal NK/T-<X00_Del_TrennDivis></X00_Del_TrennDivis>cell lymphoma were excluded from this study. <b><i>Results:</i></b> Pre-treatment plasma EBV-DNA was elevated (e.g., ≥500 copies/mL) in 35.2% of PTCL patients, with significant differences in positive rates between different subtypes of PTCL (<i>p</i> &#x3c; 0.001). High pre-treatment EBV-DNA concentrations were associated with advanced age (&#x3e;60 years), elevated lactate dehydrogenase levels, high International Prognostic Index (IPI), and positive EBV-encoded RNAs-ISH in tumor specimens. In multivariate analyses, pre-treatment EBV-DNA ≥500 copies/mL was an independent prognostic factor after adjusting for IPI and pathological subtypes (hazard ratio = 2.14, <i>p</i> = 0.032). For patients with elevated pre-treatment EBV-DNA, normalization of EBV-DNA concentrations after first-line chemotherapy was significantly associated with better overall response rate (81.3% vs. 22.2%, <i>p</i> = 0.014), progression-free survival (12.0 months vs. 3.7 months, <i>p</i> = 0.011), and overall survival (37.9 months vs. 7.8 months, <i>p</i> = 0.012). For patients achieving remission to first-line therapy, rebound of EBV-DNA levels during follow-up was associated with disease relapse or progression. <b><i>Conclusions:</i></b> These results suggest that pre-treatment plasma EBV-DNA concentration is a strong prognostic factor for PTCL. For patients with elevated pre-treatment EBV-DNA, dynamic monitoring of EBV-DNA changes after initiation of therapy is useful for predicting treatment outcome and disease relapse.

Cell Competition between Wild-Type and JAK2V617F Mutant Cells Prevents Disease Relapse after Stem Cell Transplantation in a Murine Model of Myeloproliferative Neoplasm

Introduction Disease relapse after allogeneic stem cell transplantation is a major cause of treatment-related morbidity and mortality in patients with myeloproliferative neoplasms (MPNs). The cellular and molecular mechanisms for MPN relapse are not well understood. In this study, we investigated the role of cell competition between wild-type and JAK2V617F mutant cells in MPN disease relapse after stem cell transplantation. Methods JAK2V617F Flip-Flop (FF1) mice (which carry a Cre-inducible human JAK2V617F gene driven by the human JAK2 promoter) were crossed with Tie2-cre mice to express JAK2V617F specifically in all hematopoietic cells and vascular endothelial cells (Tie2FF1), so as to model the human diseases in which both the hematopoietic stem cells and endothelial cells harbor the mutation. Results To investigate the underlying mechanisms for MPN disease relapse, we transplanted wild-type CD45.1 marrow directly into lethally irradiated Tie2FF1 mice or age-matched control mice(CD45.2). During a 6-7mo follow up, while all wild-type control recipients displayed full donor engraftment, ~60% Tie2FF1 recipient mice displayed recovery of the JAK2V617Fmutant hematopoiesis (mixed donor/recipient chimerism) 10 weeks after transplantation and developed a MPN phenotype with neutrophilia and thrombocytosis, results consistent with our previous report. Using CD45.1 as a marker for wild-type donor and CD45.2 for JAK2V617F mutant recipient cells, we found that the wild-type HSCs (Lin -cKit +Sca1 +CD150 +CD48 -) were severely suppressed and the JAK2V617F mutant HSCs were significantly expanded in the relapsed mice; in contrast, there was no significant difference between the wild-type and mutant HSC numbers in the remission mice. (Figure 1) Cell competition is an evolutionarily conserved mechanism in which "fitter" cells out-compete their "less-fit" neighbors. We hypothesize that competition between the wild-type donor cells and JAK2V617F mutant recipient cells dictates the outcome of disease relapse versus remission after stem cell transplantation. To support this hypothesis, we found that there was no significant difference in cell proliferation, apoptosis, or senescence between wild-type and JAK2V617F mutant HSPCs in recipient mice who achieved disease remission; in contrast, in recipient mice who relapsed after the transplantation, wild-type HSPC functions were significantly impaired (i.e., decreased proliferation, increased apoptosis, and increased senescence), which could alter the competition between co-existing wild-type and mutant cells and lead to the outgrowth of the JAK2V617F mutant HSPCs and disease relapse. (Figure 2) To understand how wild-type cells prevent the expansion of JAK2V617F mutant HSPCs, we established a murine model of wild-type and JAK2V617F mutant cell competition. In this model, when 100% JAK2V617F mutant marrow cells (from the Tie2FF1 mice) are transplanted alone into lethally irradiated wild-type recipients, the recipient mice develop a MPN phenotype ~4wks after transplantation; in contrast, when a 50-50 mix of mutant and wild-type marrow cells are transplanted together into the wild-type recipient mice, the JAK2V617F mutant donor cells engraft to a similar level as the wild-type donor cells and the recipient mice displayed normal blood counts during more than 4-months of follow up. In this model, compared to wild-type HSPCs, JAK2V617F mutant HSPCs generated significantly more T cells and less B cells in the spleen, and more myeloid-derived suppressor cells (MDSCs) in the marrow; in contrast, there was no difference in T, B, or MDSC numbers between recipients of wild-type HSPCs and recipients of mixed wild-type and JAK2V617F mutant HSPCs. We also found that program death ligand 1 (PD-L1) expression was significantly upregulated on JAK2V617F mutant HSPCs compared to wild-type cells, while PD-L1 expression on mutant HSPCs was significantly decreased when there was co-existing wild-type cell competition. These results indicate that competition between wild-type and JAK2V617F mutant cells can modulate the immune cell composition and PD-L1 expression induced by the JAK2V617F oncogene. (Figure 3) Conclusion Our study provides the important observations and mechanistic insights that cell competition between wild-type donor cells and JAK2V617F mutant recipient cells can prevent MPN disease relapse after stem cell transplantation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

DNMT3A Mutations Should be Considered in the Risk Stratification for Pediatric and Adolescent and Young Adult Patients with Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is rare but accounts for 20% of leukemia in the pediatric, adolescent and young adult (AYA) population. Five-year survival ranges widely from 22-90% based on subtype and cytogenetic abnormalities. The risk stratification of AML continues to evolve with increased recognition of inferior prognostic factors in the adult population; however, there has been a lack of similar progress in pediatrics. The DNA methyltransferase 3A (DNMT3A) mutation, most frequently at arginine 882 (DNMT3A mut) is observed in 14-34% of adult AML patients and is associated with inferior outcomes. This mutation shows evidence of anthracycline resistance, which may contribute to its poor prognosis as standard induction therapy for AML consists of a backbone of anthracyclines and purine analogs. Overall survival (OS) and disease-free survival (DFS) are improved in adult patients with DNMT3A mutation who receive consolidative allogeneic hematopoietic stem cell transplant (allo-HSCT). DNMT3A mutation has also been reported in the pediatric and AYA AML in 0-1.5% of cases with unclear prognostic implications. In case its presence in this patient population confers inferior outcomes similar to those seen in adults, these patients may also benefit from allo-HSCT Objective: Describe the outcome of pediatric and AYA AML patients with DNMT3A mutations Methods: This study was approved by the institutional review board at the University of Texas at MD Anderson Cancer Center. All patients aged ≤25 years, diagnosed with AML who underwent treatment at our institution between May 1st, 2014 and November 30 th 2020 were screened. Patients who did not undergo testing for DNMT3A mutation were excluded. Outcomes for patients with and without the DNMT3A mutation who underwent allo-HSCT were compared. Results: One hundred and five patients were diagnosed with AML during the study period. Forty-five patients were not tested for the DNMT3A mutation and were excluded. Sixty patients were tested for the DNMT3A mutation and were included in the analysis. Seven patients (11.7%) (4 males, 3 females) were found to be DNMT3A mutation positive (+ve). Four of them had the R882 missense mutation. Thirty-three patients (33/60; 55%) (16 males, 17 females) underwent allo-HSCT, with 6 of those being DNMT3A+ve. The median age of DNMT3A+ve and DNMT3A negative(-ve) patients undergoing allo-HSCT was 18.5 years (12.6-22.7) and 20 years (11.1-24) respectively (Figure1). Five patients who were DNMT3A+ve underwent allo-HSCT due to disease relapse and 1 patient due to associated FLT3 mutation. Median overall survival was similar in patients with and without DNMT3A mutations who received allo-HSCT at 744 (515-2473) days and 729(48-2492) days respectively (p value =0.77) (Figure 1). Median OS was significantly lower in the one DNMT3A +ve patient who did not undergo allo-HSCT at 430 days compared to those who underwent allo-HSCT (p value=0.01). Two of the six (33.3%) DNMT3A +ve patients who underwent allo HSCT died due to disease relapse (DR). The one DNMT3A patient who did not undergo allo HSCT died due to refractory disease. In the 27 patients who were DNMT3A -ve and received allo-HSCT, 13 died (13/27;48.1%), 6 from disease relapse (6/27; 22.2%), 2 due to multiorgan failure (2/27; 7.4%) and 5 unknown (5/27;18.5%). Relapse-free survival (RFS) was not significantly different between DNMT3A+ve and DNMT3A -ve patients who underwent allo-HSCT at 422 (31-1948) days and 271 (65-2048) days respectively (p value = 0.7).Of the four patients with the R882 missense mutation, 2 died due to DR (one patient at 192 days post allo-HSCT, one patient who did not undergo allo-HSCT at 352 days after achieving clinical remission one(CR1). Of the 3 patients with non R882 mutations, one died due to DR at 98 days post allo-HSCT. Conclusion: DNMT3A mutations, although rare in AML, may be associated with poor prognosis and impact risk stratification. This study suggest that consolidative allogeneic HSCT is a reasonable management consideration for this subgroup of patients. DNMT3A is not included in the current AML risk stratification of pediatric and young adult patients and further research is needed to determine the clinical significance of DNMT3A mutations in pediatric and AYA patients with AML and the impact of upfront allo-HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Descriptive Analysis of Immune Thrombotic Thrombocytopenic Purpura (iTTP) Patients with Fatal Outcomes in the U.S. Thrombotic Microangiopathy (USTMA) TTP Registry

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy (TMA) occurring due to an acquired deficiency in ADAMTS13. Mortality due to iTTP is estimated at 10% with current standard treatment that consists of plasma exchange (PLEX) and corticosteroids. The United States TMA (USTMA) registry incorporates 15 large US referral centers across the nation, and includes patients diagnosed with iTTP between 1985 and 2019. We sought to perform a descriptive analysis on the patients with fatal outcomes attributable to acute iTTP episodes in the registry. Methods: We utilized the USTMA registry (n=771) and analyzed twenty-two baseline patient demographics, presenting symptoms, and laboratory findings. The study cohort included participants with iTTP diagnosis based on the presence of thrombocytopenia (platelet count &lt;100 /µL), microangiopathic hemolyic anemia (hemoglobin less than the lower limit of normal with schistocytes on the peripheral blood smear), and either ADAMTS13 activity &lt;10% or ADAMTS13 activity &lt;20% with an anti-ADAMTS13 inhibitor or antibody. For participants diagnosed before the ADAMTS13 assay was developed (2006), the iTTP diagnosis was based on the clinical course and absence of alternative causes. iTTP exacerbation was defined as clinical disease recurrence within 30 days of PLEX discontinuation, and clinical relapse was defined as disease recurrence after 30 days of last PLEX, as per the international working group definitions 1. Results: A total of 33 patients (4.28%) in the USTMA cohort died during acute iTTP episodes. The patient demographics and initial presenting lab values are summarized in Table 1. Time of death (Figure 1): 22 patients (66.7%) died during the initial iTTP episode, and within 30 days of presentation. 3 patients (9.0%) died during disease exacerbation of the initial episode. 8 patients (24.2%) died due to disease relapse. Median time to death at initial presentation/exacerbation (n=25) = 8 days [IQR: 4-19] Median time to death due to relapse = 1.6 years [IQR: 1.1-5.7] Patient demographics and presenting features (Table 1): Median age = 51 years [IQR: 27.8-60] Sex = 54.5% female, 45.5% male Presence of neurologic symptoms on presentation: 22 (66.7%) Presence of any symptoms on presentation: 32 (97%) Conclusion: Patients with fatal outcomes due to acute iTTP episodes presented with variable symptoms and baseline characteristics. While the vast majority of deaths occurred during the initial acute episode, death also occurred during exacerbation of the initial episode or subsequent disease relapse. Vigilant laboratory and clinical monitoring both after achieving initial remission and during long-term follow-up are necessary, to allow detection of disease exacerbation and relapse, and potentially prevent iTTP-related deaths. 1. Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood. 2021;137(14):1855-1861. Figure 1 Figure 1. Disclosures Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria.

Optimizing Treatment Approaches for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The choice of therapy for chronic lymphocytic leukemia (newly diagnosed as well as relapsed/refractory disease) depends on the disease (presence or absence of del(17p) or TP53 mutation) and patient characteristics (age, comorbidities, functional status and patient preference). Many patients can choose between continuous treatment with a Bruton’s tyrosine kinase (BTK) inhibitor or time-limited therapy with venetoclax/obinutuzumab. For patients with 17p deletions, the data support the use of continuous treatment with a BTK inhibitor, although these patients should also be referred to clinical trials evaluating novel combination therapy options with minimal residual disease monitoring. The choice of therapy for relapsed disease also depends on prior therapy and duration of response to prior therapy in addition to the disease and patient characteristics (as mentioned earlier). BTK inhibitor– or venetoclax-based regimens are recommended for patients experiencing relapse following chemoimmunotherapy. In the case of disease relapse following BTK inhibitor therapy, prospective data are available only for venetoclax-based regimens, whereas disease relapse (after a period of durable remission) following time-limited therapy with venetoclax-based regimens can be managed through re-treatment with venetoclax or a BTK inhibitor.