Long-term Complete Remission Research Articles

Long-term complete remission in a patient with high-risk primary mediastinal B-cell lymphoma and iatrogenic symptomatic bradycardia after only two courses of DA-EPOCH-R followed by chemo-free treatment.

Most patients with Primary Mediastinal B-Cell Lymphoma (PMBCL) are cured by rituximab and doxorubicin-based immunochemotherapy, with or without radiotherapy. In cases with relapsed and refractory (RR) disease the prognosis was historically poor. Recently, immune checkpoint-based strategies have been shown to be highly effective in patients with RR-PMBCL. We report the case of a 23-year-old woman who, due to recurring episodes of symptomatic chemotherapy-induced sinus bradycardia, was unable to receive the planned six courses of immunochemotherapy, mediastinal radiotherapy, and autologous transplantation, leading to the early initiation of a chemo-free strategy. The patient maintains a continuous complete remission at a four-year follow-up after only two cycles of immunochemotherapy followed by nivolumab plus brentuximab vedotin (BV) and pembrolizumab consolidation. Beyond describing an underreported complication of anticancer treatments, the favorable clinical outcome suggests that in PMBCL, a minimal load of chemotherapy, integrated by early PD-1 blockade, with or without BV, may be sufficient to achieve long-term disease control and cure at least in some patients.

Effect of AVM0703 treatment on the limitations of R-CHOP and survival in a model applicable to ABC subtype DLBCL.

e19060 Background: The current treatment regimen for DLBCL consisting of rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (RCHOP), is challenged by molecular and prognostic characterization of DLBCL. Activated B-cell (ABC) lymphoma has a significantly worse prognosis (5 yr OS rate: 45% - 56%) than germinal center B-cell (GCB) lymphoma (78% - 80%) after RCHOP treatment. Around 40% of patients ultimately relapse and/or develop primary refractory disease, cardiotoxicity and long-term secondary malignancies. Efforts are being made to improve the RCHOP backbone by including dose intensification and by the addition of new agents to increase the efficacy and reduced toxicity of RCHOP (McKelvey EM Cancer 1976; Wilson WH Blood 2002; Molina TJ JCO 2014; Coiffier B Hematology 2016). AVM0703, an immunomodulatory drug, mobilizes bispecific γδ and inv-TCR double-positive novel T and NKT cells. In a previous study employing an aggressive, immune resistant A20 mouse lymphoma model (Bascuas T J Transl Med. 2016), neoadjuvant AVM0703 was additive/synergistic, when cyclophosphamide/fludarabine (CyFlu) was dosed 3 and 24 hr later, with no additional toxicities. In the present study we combined AVM0703 with RCHOP to evaluate the efficacy in A20 mice model. Methods: 10 week old Balb/c mice were injected with 2x106 murine A20 B-cells in the flank and were randomized (1:1 male: female) into 1) Placebo 2) 3 cycles RCHOP 3) 3 cycles AVM0703 (18mg/kg HED) 4) 3 cycles AVM0703+RCHOP, when tumor size reached ~100 mm3. Mice who achieved complete remission (CR) were re-challenged at 21-25 wks later. Pre and post re-challenge, presence of memory cells was analyzed using flow cytometer. All mice were monitored continuously as per the IACUC protocol. Results: Mice treated with the combination of AVM0703+RCHOP achieved superior CR compared to RCHOP alone, which was not curative in any mice. In first phase of the study, 3 out of 11 AVM0703 +RCHOP treated mice showed CR after only 1-cycle. In second phase, 2 of 12 mice survived in CR for >150 days after 3 cycles, whereas no RCHOP mice survived beyond 2 cycles. AVM0703+RCHOP treated mice in long-term CR, had memory cells (CD44hi-Cd62low) pre- and post re-challenge, and no A20 engraftment, suggesting strong immunological memory induced by AVM0703+RCHOP. Conclusions: AVM+RCHOP demonstrated anti-tumor activity in A20 lymphoma mice, with reduced toxicity, compared to RCHOP. Larger preclinical studies are underway to confirm the activity of AVM0703+RCHOP against RCHOP resistant ABC DLBCL, and the potential to reduce total RCHOP exposure to only 3 cycles while maintaining or improving efficacy. [Table: see text]

#509 Idiopathic nephrotic syndrome in children in Chad

Abstract Background and Aims The objective of our study was to describe the characteristics and outcomes of Nephrotic Syndrome (SN) in children from three major hospitals in one of the world's poorest countries, Chad. Method This observational, cross-sectional, descriptive, and multicenter study took place over a period of 36 months (1 January 2019–31 December 2021) and was carried out in three hospitals in N'Djamena, Chad. Children aged 1–15 years presenting with NS were included in the study. Results Out of 16,776 children hospitalized or followed up with in outpatient clinics, 24 cases of NS were identified, yielding a prevalence of 0.14%. The median age at presentation was 6.16 years (1–10). Nineteen children were male (sex ratio 3.8). Eight cases were classified as impure NS (33.3%). Edema was present in all patients, while oliguria was present in 29.16% (n = 7), and arterial hypertension was present in 20.83% (n = 5) of cases. Mean proteinuria, albuminemia, and total proteins were 2.86 g/L, 19.13 g/L and 30.41 g/L, respectively. The median serum creatinine was 87.3 µmol/L (75–1375 µmol/L). Three patients experienced acute renal failure upon admission. Four patients had secondary NS. All idiopathic NS patients (n = 20) who had received corticosteroid therapy had a 90% response rate to steroids. Non-responsive or relapsed patients underwent kidney biopsy (n = 7), revealing focal segmental glomerulosclerosis (FSGS; n = 4) as the most common histological lesion, followed by minimal change disease (n = 2) and membranoproliferative glomerulonephritis (n = 1). The median length of hospitalization stay was 10.67 (5–27) days. None of the patients with idiopathic NS died. At the last follow-up, sixteen patients (80%) achieved long-term complete remission with normal renal function; however, four of those had subsequent relapses. One patient with secondary NS died. Conclusion In Chad, childhood idiopathic nephrotic syndrome predominantly affects young males; steroid sensitivity is as high as 95%, and in the long-term, 80% of patients achieve remission with normal renal function.

Recent Advances in Material Technology for Leukemia Treatments.

Leukemia is a widespread hematological malignancy characterized by an elevated white blood cell count in both the blood and the bone marrow. Despite notable advancements in leukemia intervention in the clinic, a large proportion of patients, especially acute leukemia patients, fail to achieve long-term remission or complete remission following treatment. Therefore, leukemia therapy necessitates optimization to meet the treatment requirements. In recent years, a multitude of materials have undergone rigorous study to serve as delivery vectors or direct intervention agents to bolster the effectiveness of leukemia therapy. These materials include liposomes, protein-based materials, polymeric materials, cell-derived materials, and inorganic materials. They possess unique characteristics and are applied in a broad array of therapeutic modalities, including chemotherapy, gene therapy, immunotherapy, radiotherapy, hematopoietic stem cell transplantation, and other evolving treatments. Here, an overview of these materials is presented, describing their physicochemical properties, their role in leukemia treatment, and the challenges they face in the context of clinical translation. This review inspires researchers to further develop various materials that can be used to augment the efficacy of multiple therapeutic modalities for novel applications in leukemia treatment.

Sustained Remission Without Corticosteroids Among Patients With Pemphigus Who Had Rituximab as First-Line Therapy

ImportanceThe Ritux 3 trial demonstrated the short-term efficacy and safety of first-line treatment with rituximab compared with a standard corticosteroid regimen in pemphigus. No data on the long-term follow-up of patients who received rituximab as first line are available.ObjectiveTo assess the long-term efficacy and safety of the Ritux 3 treatment regimen.Design, Setting, and ParticipantsThis 7-year follow-up study of the Ritux 3 trial included patients with pemphigus from 25 dermatology departments in France from January 1, 2010, to December 31, 2015.ExposurePatients were initially randomized in the rituximab plus prednisone group or prednisone-alone group.Main outcomes and measuresThe primary outcome was the 5- and 7-year disease-free survival (DFS) without corticosteroids, assessed by Kaplan-Meier curves. Secondary outcomes were occurrence of relapse, occurrence of severe adverse events (SAEs), and evolution of antidesmoglein (Dsg) antibody enzyme-linked immunosorbent assay values to predict long-term relapse.ResultsOf the 90 patients in the Ritux 3 trial, 83 were evaluated at the end of follow-up study visit (44 in the rituximab plus prednisone group; 39 in the prednisone-alone group) with a median (IQR) follow-up of 87.3 (79.1-97.5) months. Forty-three patients (93%) from the rituximab plus prednisone and 17 patients (39%) from the prednisone-alone group had achieved complete remission without corticosteroids at any time during the follow-up. Patients from the rituximab group had much longer 5- and 7-year DFS without corticosteroids than patients from the prednisone-alone group (76.7% and 72.1% vs 35.3% and 35.3%, respectively; P < .001), and had about half the relapses (42.2% vs 83.7%; P < .001). Patients who received rituximab as second-line treatment had shorter DFS than patients treated as first line (P = .007). Fewer SAEs were reported in the rituximab plus prednisone group compared with the prednisone-alone group, 31 vs 58 respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). The combination of anti-Dsg1 values of 20 or more IU/mL and/or anti-Dsg3 values of 48 or more IU/mL yielded 0.83 positive predictive value and 0.94 negative predictive value to predict long-term relapse.Conclusions and RelevanceIn this secondary analysis of the Ritux 3 trail, first-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term sustained complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.

Delayed complete remission of hemifacial spasms following microvascular decompression and the implications for optimal time of revision surgery.

Microvascular decompression (MVD) is an effective method for directly treating hemifacial spasms (HFS). The timing for the consideration of failed MVD and reoperation has been paradoxical. This study aimed to investigate the delayed complete remission of HFS in terms of prevalence rate, duration between surgery and delayed complete remission, and predictive factors. A hundred patients with HFS who underwent MVD from 2012-2021 were enrolled in the study. All HFS occurred as a result of compression of the facial nerve by adjacent blood vessels. Clinical information, intraoperative findings, and surgical outcomes were incorporated for data analysis. In the first week after MVD, 67 of 100 patients achieved complete remission of HFS, while the remaining 33 had incomplete remission. In long-term follow-up, 26 individuals gradually developed delayed complete remission with a median duration of 9.1months. Finally, 86 of 100 patients achieved complete long-term remission. Recurrent HFS and incomplete remission were found in 7 and 7 patients, respectively. Factors associated with postoperative complete remission in the first week were a severe degree of facial nerve compression (p = 0.047, OR 2.75, 95% CI 1.01-7.40), with long-term complete remission was left-sided HFS (p = 0.012, OR 5.73, 95% CI 1.47-22.36), and with the appearance of delayed complete remission was the prolonged duration of HFS at least 3years before MVD (p = 0.046, OR 3.75, 95% CI 1.03-13.76). Transient facial paresis was found in 11% of the patients. Of them, facial nerve function recovered completely in all cases. A delayed complete remission of HFS could be expected in long-term follow-up after MVD and is probably related to a longer duration of HFS before surgery. Unnecessary reoperation should be avoided in the early years following the first surgery.

Idiopathic Nephrotic Syndrome in Children in Chad: Epidemiology and Clinical Outcomes.

Nephrotic syndrome (NS) remains the most common presentation of glomerular diseases in children. Moreover, NS is primarily idiopathic, accounting for 90% of cases, with an average onset age between 2 and 10 years. The objective of our study was to describe the characteristics and outcomes of NS in children from three major hospitals in one of the world's poorest countries, Chad. This observational, cross-sectional, descriptive, and multicenter study took place over a period of 36 months (1 January 2019-31 December 2021) and was carried out in three hospitals in N'Djamena, Chad. Children aged 1-15 years presenting with NS were included in the study. Out of 16,776 children hospitalized or followed up with in outpatient clinics, 24 cases of NS were identified, yielding a prevalence of 0.14%. The median age at presentation was 6.16 years (1-10). Nineteen children were male (sex ratio 3.8). Eight cases were classified as impure NS (33.3%). Edema was present in all patients, while oliguria was present in 29.16% (n = 7), and arterial hypertension was present in 20.83% (n = 5) of cases. Mean proteinuria, albuminemia, and total proteins were 2.86g/L, 19.13g/L and 30.41g/L, respectively. The median serum creatinine was 87.3 µmol/L (75-1375 µmol/L). Three patients experienced acute renal failure upon admission. Four patients had secondary NS. All idiopathic NS patients (n = 20) who had received corticosteroid therapy had a 90% response rate to steroids. Non-responsive or relapsed patients underwent kidney biopsy (n = 7), revealing focal segmental glomerulosclerosis (FSGS; n = 4) as the most common histological lesion, followed by minimal change disease (n = 2) and membranoproliferative glomerulonephritis (n = 1). The median length of hospitalization stay was 10.67 (5-27) days. None of the patients with idiopathic NS died. At the last follow-up, sixteen patients (80%) achieved long-term complete remission with normal renal function; however, four of those had subsequent relapses. One patient with secondary NS died. In Chad, childhood idiopathic nephrotic syndrome predominantly affects young males; steroid sensitivity is as high as 95%, and in the long-term, 80% of patients achieve remission with normal renal function.

Distinct Subtypes of Chemotherapy-Resistant Systemic ALK-Positive Anaplastic Large Cell Lymphoma Demonstrate Long-Term Complete Remissions to Imatinib

Background Platelet-derived growth factor receptor (PDGFR) is expressed in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) positive anaplastic large cell lymphomas (ALCL ALK+). Our previous preclinical research suggested that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib could be an effective treatment strategy for ALCL ALK+. An indicator patient whose ALCL cells expressed PDGFR and who failed three treatment lines (including autologous stem cell transplantation) achieved complete remission (CR) with imatinib. Methods We treated 6 relapsed/refractory (r/r) ALK+ ALCL patients with imatinib, 4 of which within the prospective clinical trial, EudraCT No.: 2013-003505-26. Median follow-up was 40 months (160 weeks, range 4 - 428). Patients were characterized by whole exome sequencing, bisulfite sequencing, RNA-sequencing and immunological profiling. Whole exome sequencing data were integrated and compared to 32 additional ALK+ ALCL patients (Larose et. al., Haematologica, 2021; Creszenzo et al., Cancer Cell 2015; Mologni et al. (unpublished). Results 5-year progression-free survival (PFS) was 67%. 4 out of 6 patients achieved a CR that was maintained throughout the follow-up of 3.3 - 8.9 years. Lymphoma cells of the non-responding patients did not express PDGFRA/B as confirmed by immunohistochemistry and RNA-scope (panel figure A). Cytoplasmic co-expression of both, ALK and PDGFRA/B, in ALCL tumor cells was associated with complete response to imatinib in ALK+ ALCL patients. Methylation profiling confirmed a differentially activated PDGFR axis between responders and non-responders and identified a specific protein kinase profile that included a significant inflammatory upregulation of HGFAC, VEGFa, and TNFa in serum cytokine profiling. The transcriptional differential gene expression includes an upregulation of genes of GO:0045859 (regulation of protein kinase activity) in non-resonders. Ident pathologic variants resulting in amino-acid changes were detected in non-responders in mutated genes linked to kinase activity ( TBC1D28 E56A), protein processing ( EMC1 S323T: cosmicV64345386 and EMC1S325N: cosmicV100916421; and GOLGA8S) and cytokine signaling ( IFNL2, ZFYVE19). The imatinib-resitance profile involving mutations in EMC1 and GOLGA8S could be detected at a frequency of 6/32 (19%) in an independent reference cohort of r/r ALK+ALCL (panel figure B). Exclusive mutations in PPP1R13B linked to p53-pathway were found in all responders. PDGFRA mutations with low allele frequencies (2-5%) were identified soley in imatinib-responders. Additionally, non-responders were characterized by an exclusive mutational signature linked to vesicular endocytosis and cytokine signaling as a resistance mechanism to pan-kinase inhibitor imatinib. Conclusion PDGFRA/B expression in tumour cells of therapy-resistant ALK-positive ALCL patients can discriminate genetically and functionally distinct lymphoma subgroups that are directly related to long-term treatment response to kinase inhibitor imatinib. Our data suggests that significant imatinib responses may be achieved in more than 80% of chemotherapy-resistant ALK+ ALCL cases.

Long-term complete remission and peripheral biomarkers in Hodgkin lymphoma patients after decitabine-plus-camrelizumab epi-immunotherapy and treatment cessation.

Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4weeks can achieve long-term remission after treatment discontinuation.

Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma

Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.

Very Long-Term Complete Remission Can Be Achieved in Men With High-Risk Localized Prostate Cancer and a Very High PSA Value: An Analysis of the GETUG 12 Phase 3 Trial.

Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established. Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions. The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n=328; ≥50ng/mL, n=85) was associated with improved RFS (P=.0005), cRFS (P=.0024), and MFS (P=.0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n=328), 50-100 ng/mL (n=68), and ≥100 ng/mL (n=17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events. Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

Influenza A (H1N1) virus induced long-term remission in a refractory acute myeloid leukaemia.

You et al. present an extraordinary case of a refractory acute myeloid leukaemia (AML) patient who achieved long-term complete remission after infection with Influenza A. Using mouse models, the researchers examined the underlying immunological mechanisms and discovered a decrease in leukaemia proliferation and improved survival in Influenza-A virus-infected mice. These results indicate the potential therapeutic relevance of Influenza A in the treatment of haematological cancers. Commentary on: You et al. Influenza A (H1N1) virus induced long-term remission in a refractory acute myeloid leukemia. Br J Haematol 2023;202:745-748.

EZH2 INHIBITION ENHANCES CAR T ANTITUMOR EFFECT BY INDUCING LYMPHOMA IMMUNOGENICITY AND ENHANCING T CELL FUNCTION

Introduction: Despite recent successes with CAR T-cell therapy against CD19 in patients with B-celllymphomas, only ∼30%–40% of DLBCL and FL patients maintain a durable complete long-term remission, and over half of the patients will ultimately relapse. Several factors contribute to the lack of response or relapse, including tumor cell-intrinsic factors, an immunosuppressive tumor microenvironment (TME), and CAR T-cell dysfunction. DLBCL and FL depend on EZH2 for their proliferation and survival. Somatic gain-of-function mutations of EZH2 (EZH2Y641X, found in 20%–30% FL and GCB-DLBCL) drive lymphomagenesis at least in part through generating immune evasive phenotypes. Of note, EZH2 inhibitors have potent activity against both wild type and mutated EZH2 FL and DLBCL patients. EZH2 also modulates the TME by increasing Tregs and repressing memory-related transcription factors in CD8 T-cells. Methods: To explore the effects of EZH2 inhibition and immunotherapy in a relevant physiological context, we developed and exhaustively characterized a genetically engineered mouse model (GEMM)—designed for conditional expression of EZH2Y641F and overexpression of BCL2 (“EZB”) in germinal center (GC) B-cells—, that recapitulates low-grade human FL with their immune microenvironment. We further generated murine GC B lymphoma cell lines from these GEMM, which develop immune-depleted aggressive DLBCL when adoptively transferred into immunocompetent mice. To investigate CAR T-cell-mediated tumor killing in human cells in combination with EZH2i tazemetostat, we used the GCB-DLBCL cell lines SUDHL4 (EZH2Y641F), OCI-Ly18 and Toledo (WT EZH2). Results: In vivo tazemetostat treatment of EZB GEMM significantly reduced EZB lymphoma B-cells (p < 0.05) and increased of CD4+ and CD8+ cells (p < 0.05), while reducing Tregs (p < 0.01). We found that EZH2i not only directly affected T-cells, but also increased the immunogenicity of EZB lymphoma cells. Pre-treatment of GEMM-derived EZB murine cell line with tazemetostat significantly increased murine CD19 CAR T-cells ability to kill lymphoma B-cells both in vitro and in vivo. Furthermore, tazemetostat pre-treatment of human GCB-DLBCL cell lines increased CAR T tumor killing and avidity, reflecting a superior CAR T-cell efficiency in binding to cancer cells. Strikingly, exposure of murine CAR T-cells to EZH2i enhanced in vivo CAR T tumor killing by increasing memory CAR T and inhibiting exhaustion. In summary, we show that EZH2i enhances CAR T antitumor effect by inhibiting lymphoma cells growth, inducing lymphoma immunogenicity and ability to synapse with T-cells, modulating the TME and enhancing T-cell function. Conclusions: We have elucidated a novel strategy to improve CAR T immunotherapy by combining with epigenetic therapy to modulate lymphoma B-cells, CAR T and the TME, that can significantly improve the clinical outcomes of DLBCL and FL patients. The research was funded by: NIH, Leukemia & Lymphoma Society, The Follicular Lymphoma Foundation, Lymphoma Research Foundation Keywords: genomics, epigenomics, and other -omics, immunotherapy, microenvironment Conflicts of interests pertinent to the abstract M. Ruella Employment or leadership position: Dr. Ruella has patents related to CART that are managed by the University of Pennsylvania

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy.

Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%-50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

Pancreatoblastoma in previously pancreatic pseudocysts in a 14-year-old female: a case report

Pancreatoblastoma is a rare tumor characterized by uncontrolled growth of pancreatic epithelial cells with a mix of squamous nests and acinar differentiation. Diagnostic modalities include abnormal liver enzyme, pancreatic enzyme, and imaging findings. Treatment options include surgical resection, sometimes combined with chemotherapy, depending on the tumor’s size and grade. We reported a pancreatoblastoma in a 14-year-old female with prior pancreatic pseudocysts. The transformation from pseudocysts to pancreatoblastoma is believed to be caused by the heterozygosity molecular loss on the 11p chromosome and several genetic mutations. Magnetic resonance cholangiopancreatography showed a well-defined, heterogeneous mass in the pancreatic head, with 70% of the mass composed of cysts. A partial pancreatectomy was performed because a complete pancreatectomy may harm the adjacent structures. However, a complete resection combined with chemoradiation may be the best option for long-term survival and complete remission. In this case, she was disease-free until 30 months after the chemotherapy protocol.

The Efficacy and Safety of Rituximab in Children with Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome: A Meta-Analysis of Randomized Controlled Trials

IntroductionTo explore the efficacy and safety of Rituximab (RTX) in children with steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing nephrotic syndrome (FRNS) through meta-analysis.Material and methodsMeta-analysis searches were performed before November 30th, 2021, using the PubMed, Embase, Web of Science, and Cochrane Library databases to collect randomised controlled trials (RCTs). FRNS or SDNS children younger than 18 years of age were included. The RTX group was treated with RTX combined with conventional therapy, whereas the control group was given conventional therapy. Review Manager 5.3 and STATA 15.0 were used to perform the statistical analyses.ResultsOf 1450 screened articles, a total of eight studies eligible for inclusion involving 476 patients were included. As compared to the control group, the RTX group had a significantly higher rate of long-term complete remission [RR (95% CI), 1.91 (1.16, 3.14), p&lt;0.05]. RTX did not show significant improvement in the short term [RR (95% CI), 2.48 (0.85, 7.25), p=0.10]. However, the RTX group achieved a higher short-term complete remission rate when two studies with heterogeneity were excluded [RR (95% CI), 2.17 (1.65, 2.84), p&lt;0.001]. Proteinuria levels were reduced more effectively in the RTX group [MD (95% CI), −1.84 (−2.42, −1.26), p &lt;0.001)]. The RTX group and the control group had no significant differences in adverse events.ConclusionsRTX can be considered as an effective and safe treatment option for children with SDNS or FRNS. However, it is necessary to conduct further studies via RCTs to evaluate the persistent long-term effects.

Clinical case of pathological complete response of gastric cancer after one cycle of neoadjuvant chemotherapy with fot regimen

Background. Gastric cancer is the 5th most common cancer and the 3rd leading cause of cancer death globally. In Russia, gastric cancer is the 2-nd leading cause of death (10.7 %). Surgery in combination with perioperative/adjuvant chemotherapy is the standard treatment for locally advanced gastric cancer. Four cycles of neoadjuvant chemotherapy and 4 cycles of adjuvant chemotherapy with the FLOT regimen is the most widely used treatment modality. The basis for the widespread use of this chemotherapy regimen was the results of a large randomized FLOT4 trial, according to which the perioperative FLOT regimen showed greater efficacy compared to the ECF regimen.The aim of the study was to demonstrate the feasibility of achieving patholopgical complete response and long-term remission after one course of neoadjuvant chemotherapy with FLOT regimen in a patient with locally advanced gastric cancer.Case description. A 69-year-old patient presented to A. Tsyb Medical Radiological Research Centre with complaints of general weakness, moderate epigastric pain for 2 months. The examination revealed stage T3N0M0 IIA gastric cancer. The patient received one cycle of neoadjuvant chemotherapy with the FLOT regimen. Given the fact, that the patient developed massive bleeding from the tumor, it was decided to stop neoadjuvant treatment. Subtotal gastrectomy with D2 lymph node dissection was performed. Histological examination of the surgical specimen revealed pathological complete response (grade 1a according to the classification of K.Becker et al., 2003). The patient is alive with no signs of disease progression for more than 36 months after starting the treatment.Conclusion. This clinical case demonstrated personalized approach to the treatment of patients with locally advanced gastric cancer. Pathological complete response was achieved after one cycle of neoadjuvant chemotherapy.

A new hope in the management of hematologic malignancy: immunotherapy

In recent years, Hodgkin's and Non-Hodgkin's lymphoma incidence is increasing all over the world. In the United States, lymphomas are the fourth most common malignancies among all. Lymphoid malignancies have a broad spectrum from mild indolent types, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), follicular lymphoma(FL), marginal zone lymphoma, and cutaneous T-cell lymphoma to aggressive types such as diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma, Burkitt's lymphoma, peripheral T-cell lymphoma. With better response rates to chemotherapy, longer disease-free survival and overall survival rates, lymphomas have satisfactory treatment results rather than solid organ tumors for oncologists. Throughout history, conventional chemotherapy agents, radiotherapy and their combinations have been used for the treatment of lymphoma. Especially, in the early stages of Hodgkin's lymphoma, a rate of 85-90% complete remission and high rate long-term remission can be achieved. However, despite this high response rate, 15-30% of patients are resistant to treatment. With current therapiesresponse rate and persistent long-term remission rate in Non-Hodgkin's lymphomas are around 50%. Therefore, new therapeutic approaches such as immunotherapy and the using of cytotoxic properties of T cells against tumor has been developed and used in recent years for the treatment of refractory lymphoma.

Oligometastatic breast cancer and metastasis-directed treatment: an aggressive multimodal approach to reach the cure.

Metastatic breast cancer (BC) is considered an incurable disease and is usually treated with palliative intent. However, about 50% of metastatic BCs present with only a few metastatic lesions and are characterized by longer overall survival. These patients, defined as oligometastatic, could benefit from a multimodal approach, which combines systemic therapy with metastasis-directed treatment (stereotactic ablative therapy or surgery). The current definition of oligometastatic seems incomplete since it is based only on imaging findings and does not include biological features, and the majority of relevant data supporting this strategy comes from retrospective or non-randomized studies. However, the chance of reaching long-term complete remission or even a cure has led to the development of randomized trials investigating the impact of combined treatment in oligometastatic BC (OMBC). The SABR-COMET trial, the first randomized study to include BC patients, showed promising results from a combination of stereotactic ablative radiotherapy and systemic therapy. Considering the randomized trial's results, multidisciplinary teams should be set up to select OMBC patients who could achieve long-term survival with aggressive multimodal treatment.

Long-Term Follow-up of Clinical Outcome Determinants and Correlative Biological Features from the Nordic NLG-T-01 Trial

Introduction The Nordic NLG-T-01 was a large phase II trial evaluating the efficacy of bi-weekly etoposide-containing chemotherapy consolidated by autologous transplant in newly diagnosed patients with systemic peripheral T-cell lymphomas (PTCL) (d'Amore et al, JCO 2012). The final analysis of the trial showed female sex and anaplastic large cell (ALCL) histology to be predictive of a favourable outcome. Here, we present a long-term follow-up evaluating the outcome of NLG-T-01 patients according to clinico-pathological parameters and biological features, in particular rearrangements of the dual specificity phosphatase 22 (DUSP22-IRF4) and the TP63 gene. Methods A cohort of 160 adult PTCL patients aged 18 to 67 years were enrolled. Anaplastic lymphoma kinase (alk)-positive anaplastic large-cell lymphoma (ALCL), primary cutaneous and primary leukemic PTCL were excluded. Considering the high median age of the study population at the time of enrolment (57 yrs) and the length of follow-up, we analyzed, in addition to overall (OS) and progression-free survival (PFS), also disease-specific survival (DSS). Time-to-event end points were calculated by means of Kaplan-Meier estimates. Log-rank tests and Cox regression models were used to analyze prognostic factors. A trial-specific tissue micro-array (TMA) was constructed with those pre-therapeutic biopsies, where sufficient tissue was still available for analysis (n=87). Fluorescent in situ hybridization (FISH) was performed on TMA slides or whole sections using break apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation for rearrangements was performed without knowledge of the specific PTCL diagnosis, clinical course, or outcome. Results At a median FU of 10.7 years (range: 7-14 yrs), 71 of 160 (44,4%) intention-to-treat population patients were still alive and in remission. Causes of death for the 89 deceased patients were: lymphoma (76%), toxicity (10%), second malignancy (6%), other causes (8%). The 10-year OS, PFS and DSS for the whole ITTP were 41%, 38% and 51%, respectively (all CI95% within +/- 10% range). The multivariate analysis for long-term outcome-related parameters confirmed that female patients had a significantly better outcome than their male counterparts (10 yr OS: 68% vs 47%; HR 0.60 - CI95% 0.37-0.97; p=0.039). Elevated International Prognostic Index (IPI) parameters also retained their adverse prognostic impact, in particular age (pr year) (OS: HR 1.03 - CI95% 1.00-1.06; p=0.004 and PFS: HR 1.03 - CI95% 1.01-1.06; p=0.03) and poor performance score (PS ≥2) (OS: HR 1.71 - CI95% 1.08-2.72; p=0.023 and PFS: HR 1.84 - CI95% 1.18-2.86; p=0.009). DUSP22 analysis revealed presence of a classical DUSP22-IRF4 rearrangement in six patients. All of them achieved a complete remission (CR), four stayed in continuous CR for all the follow-up period, one experienced a late relapse approximately 5 years after end of 1st line treatment and responded to 2nd line treatment with a new sustained ongoing CR, and one died of sepsis after high-dose therapy while in CR. TP63 rearrangement was found in one patient, who responded to trial therapy and was in long-term CR at the time of follow-up analysis Fig.1 shows OS according to histological subtypes among the 87 patients analyzed for DUSP22 and TP63 rearrangements. Conclusions Long-term follow up of the Nordic NLG-T-01 trial, confirmed a superior outcome for female patients and an adverse prognosis for elevated IPI parameters, in particular age (per year) and PS ≥ 2. A correlative biological analysis showed a favourable outcome for ALCL patients with DUSP22/IRF4 rearrranged tumours compared to other histological subtypes, including triple negative ALCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal