Stem Cell Support Research Articles

Eltrombopag restores proliferative capacity and adipose-osteogenic balance of mesenchymal stromal cells in low-risk myelodysplastic syndromes

In low-risk myelodysplastic syndromes (MDS), the proinflammatory signaling is excessive, and the proliferation and differentiation potentials of mesenchymal stromal cells (MSCs) are strongly impaired. Eltrombopag (ELT) has been demonstrated recently effective and relatively safe in low-risk MDS with severe thrombocytopenia. However, its impact on the MDS-MSCs has not been investigated in any detail. Here, for the first time, we investigated the changes induced by ELT in MSCs’ viability, proliferation, apoptosis, senescence, multilineage differentiation properties, and stem cell support capacity in low-risk MDS patients. We demonstrated that ELT may act on improving the impaired inflammatory profile and reactivating the downregulated canonical WNT signaling pathway in low-risk MDS, and also restoring the self-renewal capacity and the balance in adipose-osteogenic differentiation of MDS-MSCs.

Development of Bone Marrow Transplantation Strategies

The use of alternative stem cell sources, the growth of supportive healthcare facilities, and the expansion of indications for bone marrow transplantation (BMT) as well as partially matched donors from the same family are all continuing evolutionary trends as the use of BMT has been developed and expanded to include donors who are not related by blood but have Partial histocompatibility antigen compatibility. Although the outcomes of these transplants are not as good as those performed with first-degree siblings, patients with leukemia, aplastic anemia, and immunodeficiency disorders who cannot receive treatment otherwise they can receive it now. Patients suffering from diseases such as acute myeloid leukemia, acute lymphoblastic leukemia, and Hodgkin lymphoma also show success with autologous bone marrow transplants. Furthermore, bone marrow or blood stem cell support is used after intensive chemotherapy. Patients with stage II, III, and IV breast cancer can benefit from treatment with bone marrow cells found in peripheral blood. In this review, the most important developments in autologous and allogeneic bone marrow transplantation, the control of infectious diseases, and the use of gene therapy to alter genetic disorders that are transmitted from parents to their offspring through bone marrow or peripheral blood infusions are outlined.

Mosaic chromosomal alterations in hematopoietic cells and clinical outcomes in patients with multiple myeloma.

Mosaic chromosomal alterations (mCAs) in hematopoietic cells increase mortality and risk of hematological cancers and infections. We investigated the landscape of mCAs and their clinical consequences in 976 patients with multiple myeloma undergoing high-dose chemotherapy and autologous stem cell support (ASCT) with median 6.4 years of follow-up. mCAs were detected in the stem cell harvest product of 158 patients (16.2%). Autosomal aberrations were found in 60 patients (6.1%) and affected all chromosomes. Loss of chromosome X was found in 51 females (12.7%) and loss of chromosome Y in 55 males (9.6%). Overall survival and progression were similar between carriers of autosomal mCAs and non-carriers. In contrast, female patients with loss of the X chromosome had longer overall survival (age-adjusted[a.a.] HR 0.54, 95% CI 0.32-0.93, p = 0.02), lower risk of progression (a.a. HR 0.55, 95% CI 0.35-0.87; p = 0.01), and better post-transplant response (higher degree of complete response (CR) or very good partial response (VGPR)). The reason for this substantial effect is unknown. Additionally, myeloma clones in the stem cell product was confirmed by mCA analysis in the few patients with multiple mCAs (n = 12 patients). Multiple mCAs conferred inferior overall survival (a.a. HR 2.0, 95% CI 1.02-3.84; p = 0.04) and higher risk of myeloma progression (a.a. HR 3.36, 95% CI 1.67-6.81; p < 0.001), which is presumed to be driven by suspected myeloma contaminants.

The Effect of Age on High-Dose Therapy with Autologous Stem Cell Support in Multiple Myeloma: A Single-Center Experience.

Background: This retrospective one-center study demonstrates the complications related to high-dose therapy with autologous stem cell support (HDT) and the survival of multiple myeloma (MM) patients according to age groups. Methods: We categorized the patients into two groups: those who were ≤65 years old (group 1) (N = 115) and those who were >65 years old (group 2) (N = 26). The mean duration of follow-up was 48 (1-125) months. Results: In group 2 patients, the use of a reduced dosage of melphalan (12 [46%] versus 30 [26%]) was more frequent in comparison to group 1 (p = 0.046). There was a statistically significant difference between the two groups regarding the neutrophil engraftment days (p = 0.001) and the median progression-free survival (PFS) (p = 0.02). The PFS was 44 months for group 1 and 30 months for group 2. There was no statistically significant difference between the groups in relation to the median duration of hospitalization, presence of bacteremia, intravenous antibiotic administration, and overall survival (OS). Conclusions: The study's results indicate that HDT is a reliable method of treatment for older patients with MM, provided that they obtain a suitable conditioning regimen and, furthermore, these patients achieved a comparable OS rate to that of younger patients.

GCT-29. MULTI-INSTITUTIONAL ANALYSIS OF PEDIATRIC RELAPSED/REFRACTORY CENTRAL NERVOUS SYSTEM GERMINOMAS

Abstract BACKGROUND Relapsed central nervous system germinomas are rare with no universal agreement regarding management. We explored the prognostic factors that may impact the treatment of patients with relapsed CNS germinoma. METHODS We collected data on relapsed/progressive germinomas from nine large international sites. Data was summarized using descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fischer’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS Twenty-seven patients with relapsed (24) and progressive (3) germinomas were included (3.7% metastatic). Median age at diagnosis was 15.8 years (interquartile range (IQR): 11.9-18.5). Complete remission (CR) after initial treatment (chemotherapy 63.9% and radiotherapy 88.9%) was achieved in 15 patients (55.6%). The median time from diagnosis to relapse/progression was 20.0 months (range: 10.8-65.1 months) with 55.6% occurring within 24 months. Twenty-five patients (92.6%) underwent chemotherapy, 15 (55.6%) received high-dose chemotherapy with stem cell support (HDCx), and 16 received (59.3%) radiotherapy. At last follow-up, 86.6% of HDCx and 87.5% of radiotherapy recipients were alive. Median time to last follow-up was 41.8 months (IQR: 19.6-132.1). Fifteen children (55.6%) achieved CR after therapy and 21 (77.8%) were alive at last follow-up. Of patients receiving irradiation, 12.5% received whole ventricular irradiation, 81.3% craniospinal irradiation, and 6.3% focal irradiation. Chemotherapy at relapse was associated with improved 5-year OS (OR=1.32 95%CI: 1.06-1.64) Re-irradiation at relapse (OR=2.6, 95%CI: 0.36-19.2) and HDCx at relapse (OR=2.17, 95%CI: 0.30-15.71) did not reach statistically significant difference. CR after initial therapy (OR=1.25, 95%CI: 0.97-1.61) was not associated with improved 5-year OS, CR after relapse therapy was associated with increased 5-year OS (OR=3.50, 95%CI: 1.08-11.24) CONCLUSIONS Relapsed CNS germinomas are salvageable at relapse. This ongoing multi-institutional study will contribute to existing knowledge about relapsed/progressive CNS germinomas and inform prospective clinical trials to improve outcomes for children with relapsed/progressive disease.

Intensive salvage chemotherapy with VDTPACE or mCBAD followed by hematopoietic stem-cell support for refractory/relapsed multiple myeloma.

Triple- and quad-refractory multiple myeloma patients usually have an aggressive course and a poor prognosis. Available therapeutic options are scarce. The objective of the current study was to evaluate responses and toxicities of VDTPACE or mCBAD with hematopoietic stem-cell support as a bridge to subsequent therapies in patients with refractory/relapsed multiple myeloma. Thirteen patients were included (11 mCBAD, 2 VDTPACE), and 21 cycles of chemotherapy with hematopoietic stem-cell support were delivered. Mean number of previous therapies was 4.8. Stem cells were infused on a median day 9.9 after chemotherapy. Mean time to neutrophil recovery was 18.2 days in patients receiving the first cycle and 15.9 following subsequent cycles. Before therapy, most patients were in PD (77%), PR (15%), or VGPR (8%). Following treatment, the best responses achieved were PR (46%), VGPR (46%), and CR (8%). Median overall and progression-free survivals were 17 and 9 months. There has been no case of non-relapse mortality. In the 21 cycles, the main complications were infectious. Intensive chemotherapy can decrease disease burden in patients with relapsed/refractory MM, and stem-cell support can successfully decrease toxicities and treatment-related mortality associated with these regimens and may be a good bridging option.

Carfilzomib plus rituximab, ifosfamide, carboplatin and etoposide (C-RICE) led to higher response, OS, and PFS in patients with transplant-eligible relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

7042 Background: The CORAL study highlighted the need to develop novel salvage regimens for R/Rr/r DLBCL previously treated with R+CHOP. Overall response rate (ORR) to second line immuno-chemotherapy was 51% with a 3-year progression free survival (PFS) of 30% following high-dose chemotherapy and autologous stem cell support (HDC-ASCS). Optimal disease control (complete remission [CR] or partial remission [PR]) prior to HDC-ADCS and more recently to chimeric antigen receptor T-cell therapy (CAR T), correlates with improved outcomes. Dysregulation of Bcl-2 family members has been associated with acquired resistance to rituximab and chemotherapy which we have previously shown may be mitigated by co-treatment with proteasome inhibition in pre-clinical model. Subsequently, we conducted a Phase I/II clinical trial evaluating the safety and efficacy of CRICE as salvage therapy for R/R DLBCL (Blood Adv. 2023 7:1146-1155). Methods: Here we retrospectively compared the clinical outcomes of R/R DLBCL patients treated with CRICE (N=28) versus RICE (N=38) on our prior clinical trial (NCT01959698). Demographic, clinical, and pathological characteristics were collected for both groups (Table). Study endpoints consisted of differences in overall response rate (ORR), CR/PR rates, median progression free survival (PFS) and overall survival (OS) between the two cohorts. Results: The addition of Carfilzomib to RICE resulted in improved clinical outcomes. A higher ORR (92.9 vs 76.3, P=0.073) and CR rates (82.1 vs. 44.7, P=0.002) were observed in CRICE vs. RICE treated patients. Multivariate analysis confirmed the higher CR rates in CRICE vs. RICE when adjusted by DLBCL subtype (GCB vs. nNon-GCB, P=0.003). More CRICE patients proceeded to HDC-ASCS (52.6% vs. 47.4%, P=0.618). The 3yr PFS rate was higher in CRICE (54%, 32-72%) vs. RICE treated patients (35%, 19-51%). While the median PFS was longer in CRICE treated patients 36.8m (0.8, 73.2) vs. 3.2m (0.5, 54.2) (RICE), it did not reach statistical significance (P=0.714). No differences in OS were observed between CRICE &amp; RICE patients, median OS 67.3m vs. 71.8m. Conclusions: The CRICE outcomes were more striking in patients with non-GCB r/r DLBCL (ORR 85%, mPFS and OS not reached). CRICE led to high CR rates and longer PFS among r/r DLBCL patients, especially in non-GCB DLBCL patients. CRICE could be an attractive regimen to achieve disease control in r/r DLBCL patients undergoing consolidation therapy with HDC-ASCT or CAR T-cell therapy. [Table: see text]

Steady-State Versus Chemotherapy-Based Stem Cell Mobilization in Multiple Myeloma: A Single-Center Study to Analyze Efficacy and Safety.

High-dose chemotherapy followed by autologous hematopoietic stem cell support is recommended in the treatment of eligible multiple myeloma (MM) patients. The aim of this study was to compare the efficacy and safety of steady-state versus chemotherapy-based stem cell mobilization in our Hungarian patient population. The subjects were 210 MM patients who underwent stem cell mobilization procedure between 2018 and 2022. Solo granulocyte colony-stimulating factor (G-CSF) was administered in 104 cases, while 106 patients received chemotherapy which was followed by G-CSF administration. We evaluated the ratio of successful mobilizations, the amount of collected stem cells, the incidence of infections and cost-effectivity in the two groups. In the steady-state group, there was a significantly higher need for plerixafor (45% vs. 13%, P < 0.001), unsuccessful stem cell mobilization was more frequent (11% vs. 3%, P = 0.024) and the mean amount of collected stem cells was lower (6.9 vs. 9.8 × 106, P < 0.001) than in the chemotherapy group. However, infections were less frequent (4% vs. 27%, P < 0.001) and the number of days spent in hospital was significantly lower (6 vs. 14 days, P < 0.001). Plerixafor was more frequently administered in those who had received lenalidomide or daratumumab than in those who had been treated with other regimens (41% vs. 23%, P = 0.007 and 78% vs. 23%, P < 0.001, respectively). Steady-state mobilization is a safe method; however, the higher rate of plerixafor administration and unsuccessful attempts may question its superiority to chemomobilization.

Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support.

Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support.

Evaluation of the Efficacy of Stem Cells Therapy in the Periodontal Regeneration: A Meta-Analysis and Mendelian Randomization Study.

Stem cell therapy for periodontal defects has shown good promise in preclinical studies. The purpose of this study was to evaluate the impact of stem cell support on the regeneration of both soft and hard tissues in periodontal treatment. PubMed, Cochrane Library, Embase, and Web of Science were searched and patients with periodontal defects who received stem cell therapy were included in this study. The quality of the included articles was assessed using Cochrane's tool for evaluating bias, and heterogeneity was analyzed using the I2 method. An Mendelian randomizationinvestigation was conducted using abstract data from the IEU public databases obtained through GWAS. Nine articles were included for the meta-analysis. Stem cell therapy effectively rebuilds periodontal tissues in patients with periodontal defects, as evidenced by a reduction in probing depth, clinical attachment level andbone defect depth . And delta-like homolog 1 is a protective factor against periodontal defects alternative indicator of tooth loosening. The findings of this research endorse the utilization of stem cell treatment for repairing periodontal defects in individuals suffering from periodontitis. It is recommended that additional extensive clinical investigations be carried out to validate the efficacy of stem cell therapy and encourage its widespread adoption.

Plasma Proteome Analyses Identify Predictors of Graft Rejection Prior to Stem Cell Infusion and Support Interferon-Mediated Ferroptosis As a Novel Mechanism of Graft Rejection

Plasma Proteome Analyses Identify Predictors of Graft Rejection Prior to Stem Cell Infusion and Support Interferon-Mediated Ferroptosis As a Novel Mechanism of Graft Rejection

A 5-Stage System for ASCT Multiple Myeloma

652. Multiple Myeloma: Clinical and Epidemiological INTRODUCTION: In the last three decades, significant advancements in multiple myeloma (MM) treatment, including immunomodulators, targeted therapies, chemotherapy combinations, autologous stem cell transplantation (ASCT), and CAR-T therapy, have emerged. ASCT offers hope for MM patients by using high-dose chemotherapy with stem cell support. However, it carries risks of severe toxicity. Despite evaluating factors like age, performance status, and co-morbidities for ASCT eligibility, outcomes for MM patients still vary greatly. Various models, such as the ISS-series systems, have been developed to assess risk factors for progression-free and overall survival We conducted a study on 5,259 ASCT patients since 1989, identifying 7 easy variables (ISS stage, diagnosis-transplant interval, ferritin, transferrin, LDH, age, and gender) and creating a 5-stage system. This system helps evaluate the risk of MM patients before ASCT. METHODS: In this retrospective study, data from 5,259 MM patients receiving ASCT (1989-2022) were collected (median follow-up: 57 months). We assessed 30 clinical variables pre-ASCT. Multiple imputation was used to deal with the missing values. Patients were split into a 70% training set and a 30% validation set. Univariate/multivariate Cox regression analysis identified 7 clinical and demographic signatures. Signatures were scored based on hazard ratios normalized to ISS III vs. ISS I&amp;II. K-adaptive partitioning generated a 5-stage system, ATM5S, evenly distributed and validated in the training set. Harrel's c-index was used to compare ATM5S with the current myeloma systems. RESULTS: 3683 patients (70%) in the test cohort had a median age of 59.6, median PFS 38.8 month and median OS 56.1 month. IgG was the most common isotype (55%). Univariate Cox analysis showed that 27 variables were significant predictors for both PFS and OS. Multivariate Cox analysis showed that time from diagnosis to transplant, ferritin, transferrin, LDH, ISS stage, lymphocytes, platelets, calcium, gender and age were independent prognostic factors for both OS and PFS. We selected the most easy, understandable and well-distributed (with high-risk group&amp;gt;20%) 7 variables: ISS, time from diagnosis to transplant, ferritin, transferrin, LDH, age and gender and developed a score system, which resulted into a 5-stage system (ATM5S) by k-adaptive partitioning. This staging system also demonstrated a significant discriminatory effect in the validation set (30%, 1576 patients). CONCLUSIONS: The Arkansas Transplant-Myeloma 5-Stage System (ATM5S) showed a promising performance in both training and validation cohorts.

The Effect of Stem Cell Infusion on Immune Effector Cell Associated Hematotoxicity with BCMA CAR T in Multiple Myeloma

Introduction: In recent pivotal clinical trials and real-world studies of patients undergoing BCMA CAR-therapy for multiple myeloma (MM), a significant percentage have exhibited persistent Immune Effector Cell Associated Hematotoxicity (ICAHT). The resulting, sometimes profound and long lasting cytopenias, are associated with increased morbidity, such as high rates of infections and bleeding and complicate further anti-MM therapy once the patient relapses post CAR-T cell therapy. While growth factor support is widely applied in patients with ICAHT, the effects are usually short lived. Consequently, the use of CD34 selected stem cell boost in ICAHT as a more permanent solution has been described, however studies have been limited by small patient numbers and short follow up. Herein, we report on our multi-institutional experience at ICAHT in patients who received autologous BCMA CAR T therapy both in commercial and clinical trial settings. Methods: We included recipients of autologous BCMA CAR T therapy at 2 large academic centers between 2020 and 2023. For this study, neutropenia was defined as an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia as platelet counts ≤ 70,000 and anemia as hemoglobin ≤9 g/dL. ICAHT was characterized by the presence of any of these hematological abnormalities. The variables were assessed at 21 days, 3 months, and 6 months post CAR-T infusion. Median follow up time was 23 months. Results : A total of 108 patients received BCMA CAR T therapy, 42 (39%) were treated on a clinical trial, 52 (48%) received commercial Idecabtagene vicleucel and 14/108 (13%) commercial Ciltacabtagene autoleucel. Baseline characteristics of the whole patient cohort are shown in table 1. The median age was 68 (range 57-69) years, with 63/107 (60%) being male. About 11% (n=12) patients were Black. 97/108 (90%) received at least one prior ASCT and the median prior lines of therapy was 5 (range 4-6). At D+21, ICAHT was observed in 68% (n=69/102) of patients, which reduced to 35% (n=30/86) and 27% (n=21/78) at the 3-month and 6-month assessments, respectively. Risk factors for ICAHT were the following: history of a prior ASCT, higher number of prior lines of therapy, a decreased platelet count prior to lymphodepletion and history of ICANS, which interestingly occurred in 11/69 (16%) patients who developed ICAHT but was not seen in those without ICAHT. About 97%(n=67/69) of patients with ICAHT had stem cells in storage and 26% (n=17/69) received a stem cell boost. The median time to stem cell boost following CAR T infusion was 116 (range 49-166) days. The median dose of stem cell infused was 3.91 (range 2.11-5.12) x10 6 CD34/kg cells. Unsurprisingly, patients with ICAHT who received a stem cell boost had significantly worse cytopenias prior to stem cell boost compared to those ICAHT patients without stem cell infusions at 120 days. Hgb was 8.4g/dL vs 10.2g/dL, p=0.02, and mean platelet levels were 30x10 9/L vs 54x10 9/L, p=0.01, compared to ICAHT patients without stem cell support. ANC levels were not significantly different between those two ICAHT groups (1700/mL vs 1500/mL), likely due to a higher use G-CSF support in ICAHT patients who received stem cell support (75% vs 55%, NS). Stem cell infusion significantly improved Hgb levels at 3 and 6 months follow up with an increase to 10.6g/dL, p=0.002, and 10.5g/dl, p=0.02, respectively. Similarly, platelet counts at 3- and 6-months post stem cell boost improved significantly to 131x10 9/L, p=&amp;lt;0.001, and 150x10 9/L, p=&amp;lt;0.001, respectively. ANC levels showed a nonsignificant increase to 2.8/mL and 3.9/mL at 3 and 6 months, yet, G-CSF support was no longer required. We further investigated whether the occurrence of secondary AML/MDS was associated with ICAHT, however these events were rare and developed in only 2 patients, one who had no ICAHT and the other one who had ICAHT without stem cell boost. Conclusion: Nearly one-third of the patients who underwent BCMA CAR T therapy continued to experience ICAHT even at the 6-month post-infusion period. The utilization of a stem cell boost for managing ICAHT lead to significantly improved Hgb and platelet counts at 3 and 6 months follow up with also substantial improvement in ANC without further G-CSF requirements. These results suggest that the use of stem cell infusions in CAR-T cell induced ICAHT can improve cytopenia associated morbidities and facilitate further anti MM therapy post CAR-T relapse.

PSORIASIS COMBINED WITH SYSTEMIC AMYLOIDOSIS: CLINICAL OBSERVATION

Secondary amyloidosis is a frequent complication of chronic inflammatory processes. That is why comorbid conditions are possible in which the underlying disease is combined with systemic amyloidosis. Once started, secondary amyloidosis becomes an independent process that complicates the course of the underlying disease that caused it and often becomes the main cause of death of the patient. The aim is to present a case report of psoriasis combined with systemic amyloidosis. Material and methods. The material was a clinical case of psoriasis combined with AL-amyloidosis in a 36-year-old patient who was in a state of persistent clinical remission for 12 years after treatment with melphalan in combination with the introduction of autologous stem cells. From the biopsy material of a psoriatic plaque, we made paraffin sections with a thickness of 5 microns, which were stained with hematoxylin and eosin, or hematoxylin and Congo Red, or thioflavin and subjected to light, polarization and luminescence microscopy. Results. Amyloid deposits were found in the dermis of the patient's psoriatic plaque, which were detected by examining sections stained with Congo Red in polarized light and thioflavin under luminescent microscopy. Conclusions. Despite a persistent clinical remission of systemic AL-amyloidosis, comorbid to preceding psoriasis, obtained as a result of the use of a modern pathogenetic method for treating such conditions – a course of melphalan in combination with autologous stem cell support – amyloid deposits in the psoriatic duty plaque were found in the examined patient.

Assessment of Effectiveness and Adverse Effect of New Combination Chemotherapy (irinotecan, cisplatin, and dexamethasone) in Relapse and Refractory Hodgkin Lymphoma.

Background: Chemotherapy with Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD regimen) cannot cure all patients with Hodgkin lymphoma. In this study, we evaluated the efficacy and adverse effect of a new regimen consist Irinotecan, Cisplatin, and Dexamethasone (ICD) in relapsed and refractory Hodgkin lymphoma as the second to fifth line of treatment. Materials and Methods: We performed a retrospective study in 26 relapsed or refractory patients with Hodgkin lymphoma receiving at least the first-line chemotherapy regimen (ABVD) and (ICD) as salvage therapy in Thaleghany Hospital from 2012 to 2018. This regimen consisted of Irinotecan 65mg/m2 D1, D8, Cisplatin 30mg/m2 D1, D8, and dexamethasone 40mg D1, 2, 8, and 9 was administered every 3 weeks for 6 cycles. Treatment was discontinued in cases of disease progression or severe toxicity. Response to treatment was evaluated after two cycles. Patients with complete and partial remission were candidates for high-dose chemotherapy and autologous stem cell transplantation. Twenty-four patients were enrolled in the study. The mean age of 22 patients was 31.5 (19-67) years. Seven patients (29.1%) were in the first recurrence, and 17 (70.8%) were in the second or subsequent recurrence. Results: According to this study, three patients (12.5%) had complete response, 13 (45%) had partial response, four (16.6%) had stable disease, and four (16.6%) had progressive disease. Nine patients (37.5%) received high-dose chemotherapy and autologous stem cell support after ICD regimen. None of the cycles of chemotherapy were delayed due to treatment-related adverse event. Overall survival after six months in all patients was 91%, and mortality rate was 8.3% at the end of the study. Conclusion: The goal of salvage chemotherapy in relapsed or refractory Hodgkin Lymphoma is achieving CR or PR preparation patients for stabilization with BMT. Thus, we recommend ICD as one of the most effective protocols with overall response rate of 66% in this population.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T cell lymphomas (PTCLs) are a rare, heterogeneous group of hematological malignancies with too often poor prognosis for almost all subtypes. The T-Cell Project (TCP; registered at clinicaltrials.gov identifier: 01142674) was a prospective cohort study aimed at better understanding clinical characteristics and outcome of patients with PTCL. Here we report the results of 10-year follow up, focused on late relapses and long term survival. Methods: The TCP started in September 2006 as a prospective registry of patients with mature PTCLs. Between December 2006 and March 2018, 1669 patients were registered and 1,553 patients were eligible in the study. Recently, a survey was launched asking for the willingness of the centers to provide long term follow up data. So far, out of 1,553 eligible patients, 713 were referred by Centers that provided information on long-term follow-up and have been included in the present analysis; 840 cases, referred by centers that did not participate to this long term survival analysis were excluded. However, both groups showed similar baseline characteristics and 5y OS (44% vs. 44%) and PFS (37% vs. 35%), thus minimizing selection biases Result: Out of these 713 patients, 255 patients (36%) had a diagnosis of PTCL NOS, 133 (19%) of AITL, 124 (17%) of ALCL ALK-, 62 (8%) of ACL ALK- and 13 (2%) of NKTCL. The median age at diagnosis was 56 years (range, 18–88 years), with a slight male predominance (55%). B symptoms were present in 44% and extranodal involvement in 56% of patients. Patients receiving chemotherapy alone and radiotherapy alone comprises 58% and 3% respectively; while the 18% received CHT+RT. Of evaluable patients, 60% received anthracycline-based chemotherapy, 24% anthracycline/etoposide and 12% etoposide alone. A minority (16%) of the total cohort underwent high-dose chemotherapy with autologous stem cell support as first-line consolidation. After a median follow-up of 82 months, 35 (12%) of patients had an event of progression or death beyond 5 years. The 5- and 10-year rates of both overall survival and progression-free have decreased from 44% and 40%, to 31% and 27%, respectively (Figure 1). For those patients alive at 5 years, the chance of surviving the subsequent 5 years was 83% (95% CI: 61–99). Furthermore, for patients progression free at 5 years the probability of being disease alive and free in the subsequent 5 years was 78% (95% CI: 60–96). Ten year OS and PFS rates for patients alive at 5 years were: 77% and 73% for PTCL NOS, 85% and 76% for AITL, 88% and 87% for ALCL ALK-, 100% and 100% for ALCL ALK+), and 78% and 80% (for NKTCL). Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib.

Several studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-κB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-κB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma. Considering that H929 cells were also directly susceptible to PKC and NF-κB inhibition, we showed that treatment of co-cultures with the HKPS peptide and BAY11-7082, followed by bortezomib, increased H929 cell death. Therefore, targeting simultaneously connected signalling elements of BM-MSC responsible for MM cells support with compounds that also have anti-MM activity can be an improved treatment strategy.

Bad to the Bone: Emerging Approaches to Aggressive Bone Sarcomas.

Bone sarcomas are rare heterogeneous tumors that affect patients of all ages including children, adolescent young adults, and older adults. They include many aggressive subtypes and patient groups with poor outcomes, poor access to clinical trials, and lack of defined standard therapeutic strategies. Conventional chondrosarcoma remains a surgical disease, with no defined role for cytotoxic therapy and no approved targeted systemic therapies. Here, we discuss promising novel targets and strategies undergoing evaluation in clinical trials. Multiagent chemotherapy has greatly improved outcomes for patients with Ewing sarcoma (ES) and osteosarcoma, but management of those with high-risk or recurrent disease remains challenging and controversial. We describe the impact of international collaborative trials, such as the rEECur study, that aim to define optimal treatment strategies for those with recurrent, refractory ES, and evidence for high-dose chemotherapy with stem-cell support. We also discuss current and emerging strategies for other small round cell sarcomas, such as CIC-rearranged, BCOR-rearranged tumors, and the evaluation of emerging novel therapeutics and trial designs that may offer a new paradigm to improve survival in these aggressive tumors with notoriously bad (to the bone) outcomes.

From birth to death: The hardworking life of Paneth cell in the small intestine.

Paneth cells are a group of unique intestinal epithelial cells, and they play an important role in host-microbiota interactions. At the origin of Paneth cell life, several pathways such as Wnt, Notch, and BMP signaling, affect the differentiation of Paneth cells. After lineage commitment, Paneth cells migrate downward and reside in the base of crypts, and they possess abundant granules in their apical cytoplasm. These granules contain some important substances such as antimicrobial peptides and growth factors. Antimicrobial peptides can regulate the composition of microbiota and defend against mucosal penetration by commensal and pathogenic bacteria to protect the intestinal epithelia. The growth factors derived from Paneth cells contribute to the maintenance of the normal functions of intestinal stem cells. The presence of Paneth cells ensures the sterile environment and clearance of apoptotic cells from crypts to maintain the intestinal homeostasis. At the end of their lives, Paneth cells experience different types of programmed cell death such as apoptosis and necroptosis. During intestinal injury, Paneth cells can acquire stem cell features to restore the intestinal epithelial integrity. In view of the crucial roles of Paneth cells in the intestinal homeostasis, research on Paneth cells has rapidly developed in recent years, and the existing reviews on Paneth cells have mainly focused on their functions of antimicrobial peptide secretion and intestinal stem cell support. This review aims to summarize the approaches to studying Paneth cells and introduce the whole life experience of Paneth cells from birth to death.

The emergence of the stem cell niche.

Stem cell niches are composed of dynamic microenvironments that support stem cells over a lifetime. The emerging niche is distinct from the adult because its main role is to support the progenitors that build organ systems in development. Emerging niches mature through distinct stages to form the adult niche and enable proper stem cell support. As a model of emerging niches, this review highlights how differences in the skeletal muscle microenvironment influence emerging versus satellite cell (SC) niche formation in skeletal muscle, which is among the most regenerative tissue systems. We contrast how stem cell niches regulate intrinsic properties between progenitor and stem cells throughout development to adulthood. We describe new applications for generating emerging niches from human pluripotent stem cells (hPSCs)using developmental principles and highlight potential applications for regeneration and therapeutics.