Relapsed Lymphoma Research Articles

CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias

Background: For patients with relapsed/refractory large B-cell lymphomas (rrLBCL), CD19-directed chimeric antigen receptor T cells (CAR19) improve survival compared to autologous hematopoietic cell transplantation (HCT). However, major toxicities of CAR19 therapy include prolonged cytopenias and associated infections. To better understand the impact of CAR19 on such toxicities, we studied a cohort of LBCL patients achieving durable remissions to assess immune recovery after CAR19 treatment. We (1) compared immune reconstitution in HCT vs CAR19 treated patients, (2) performed molecular analysis of post-CAR19 cytopenic marrow specimens, and (3) profiled emergent mutations in cell free DNA (cfDNA) before and after CAR19. Methods & Results: We first propensity matched rrLBCL patients treated at Stanford with either CAR19 (100% axi-cel) or HCT who achieved durable remissions. Patients were matched based on age, sex, prior systemic lines of therapy, and time from infusion. From 471 eligible cases, propensity score matching was successful in 138 (n=69 per arm). When compared to HCT-treated counterparts, CAR19-treated patients had reduced recovery of absolute lymphocyte counts (ALC) and absolute neutrophil counts (ANC; longitudinal regression day 28-800 ANOVA p<0.005), but similar recovery of hemoglobin and platelets. CAR19-treated patients experienced significantly more Grade ≥3 infections in competing risk analyses (HR 2.61, CI 1.26-5.42), and higher non-relapse mortality (log-rank p=0.027). Next, to characterize mechanisms underlying cytopenias after CAR19, we profiled marrow aspirates from cases requiring biopsy due to prolonged cytopenia or clinical concern for myeloid neoplasms. No patient had evidence of lymphoma relapse at the time of biopsy, and all were >60d from CAR19 infusion (median 377d, range 86-1561d). Among 21 patients profiled by DNA sequencing, 18 (86%) had evidence of ≥1 somatic mutation in genes canonically associated with clonal hematopoiesis (CH) in the marrow ( Fig. 1A), with the most recurrently mutated genes being DNMT3A (38%), TP53 (33%), PPM1D (24%), ASXL1 (14%), and TET2 (14%). Among 6 patients diagnosed with and requiring therapy for a myeloid malignancy, all (100%) had a canonical myeloid karyotypic aberration detected by FISH, as compared with 0 in the 14 other evaluable cases ( Fig. 1A). CAR19 cells were proportionately enriched in the marrow relative to paired peripheral blood by flow cytometry (n = 12, median 2.5-fold enrichment, Wilcoxon p<0.001). Using 10x scRNA-Seq, viable CAR19 was detectable in 7 of 8 marrows (88%) and were predominantly CD4+. We hypothesized that CH clones detectable after CAR19 would also be present in pre-CAR19 blood samples and detectable in cfDNA. To test this, we profiled 786 longitudinal samples from 141 patients using CAPP-seq and serially monitored CH clones in cfDNA. Among 141 eligible cases, 40 (28%) were evaluable for CH, in having both pre- and post-CAR19 infusion specimens, while in durable remission (median follow up 967d). Of 51 CH clones detected in post-infusion cfDNA, 46 (90.1%) were also detectable prior to CAR19, typically expanding post-infusion (median = 1.8-fold, Fig. 1B). We next tested whether expanding CH clones showed evidence for selection after CAR19. Strikingly, among 48 recurrently mutated genes tested, DNMT3A and PPM1D showed significant evidence for clonal selection and expansion after CAR19 (Q-value < 0.05). When compared to patients without emerging CH clones, patients with ≥5-fold clonal expansions of canonical CH genes (23% of cases) had reduced ANC, but not ALC, recovery (median ANC=1.43 vs 2.43 at 6-mo, Wilcoxon p<0.001). This association remained significant in multivariate longitudinal regression that included age, sex, prior lines of therapy, and pre-infusion ANC (ANOVA p = 0.007). Conclusion: CAR19 treated patients experience reduced immune reconstitution and higher infection rates than HCT treated counterparts. Bone marrow findings reveal prolonged CAR19 cytopenia to commonly be associated with clonal cytopenia of undetermined significance (CCUS). Despite durable lymphoma remissions, canonical myeloid clonal expansions are common post-CAR19, and associated with myelosuppression. Non-invasive genotyping could aid in early identification of patients at risk for prolonged cytopenias after CAR19 and inform interventions to decrease associated complications.

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience.

CD19 chimeric antigen receptor (CAR)-T cell therapy has emerged as an effective treatment in those with refractory or relapsed lymphoma. CD19 CAR-T cell therapy can cause direct and indirect toxic adverse effects and increased risk for infection. Infectious complications and optimal antimicrobial prophylaxis strategies are an ongoing area of investigation. A single-center retrospective cohort study was conducted to review recipients of CD19 CAR-T cell therapy between April 2018 and December 2020. Patient characteristics and clinical outcomes were extracted from the electronic health records. Infectious complications were identified in 18/50 (36%) recipients with 31 episodes of infection. The median time to infection was 225 days (range 0-614). Bacterial infections were most common with bloodstream infection followed by sinusitis and skin and soft tissue infection. Eight viral infections were identified, most being respiratory viral illnesses. Two fungal infections were identified: Pneumocystis jirovecii pneumonia (PJP) and disseminated fusariosis. Seventeen infections (54.8%) were classified as severe: leading to death, requiring hospitalization, need for empiric intravenous antibiotics, or significant alteration in hospital course. No characteristics were found to be statistically significant risks for infection, although a trend toward significance was seen in prior autologous stem cell transplant recipients (p = .12) and those with recurrent neutropenia (p = .14). Three patients (6%) died from infection. Infections were common after CD19 CAR-T cell therapy and occurred beyond the first year. Further multicenter studies are needed to define infectious risks and optimize antimicrobial prophylaxis recommendations in recipients of CD19 CAR-T cell therapy.

PTCY-Based Haploidentical Donor Transplantation versus HLA-Matched Related and Unrelated Donor Transplantations in Patients with Refractory or Relapsed Lymphoma-A Matched-Pair Analysis.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has demonstrated its potential as a curative option for patients with r/r lymphoma. With the introduction of post-transplant cyclophosphamide-based (PTCY) graft-versus-host disease (GvHD) prophylaxis, allo-HCT using haploidentical related donors (Haplo-HSCT) has emerged as a valuable alternative for patients without an available HLA-matched donor. In this study, we compared intermediate and long-term outcomes between Haplo-HSCT and HLA-matched related donor (MRD) and unrelated donor (URD) transplantations in 16 matched pairs using age, disease status, lymphoma classification and performance status as matching criteria. Of note, 88% of patients in each group presented with active disease at the time of conditioning. After a median follow-up of >10 years, 10-year overall and progression-free survival and non-relapse mortality incidence after Haplo-HSCT were 31%, 25% and 38%, respectively, and did not differ compared to the values observed in MRD-HSCT and URD-HSCT. A remarkable lower incidence of acute GvHD ≥ II and moderate and severe chronic GvHD was observed after Haplo-HSCT compared to MRD-HSCT (50%/50%, p = 0.03/0.03) and URD-HSCT (44%/38%, p = 0.04/0.08), resulting in slightly higher 10-year GvHD-free and relapse-free survival (25%) and chronic GvHD-free and relapse-free survival (25%) in the Haplo-HSCT group. In conclusion, Haplo-HSCT is an effective treatment in patients with non-remission NHL. Given its advantage of immediate availability, haploidentical donors should be preferably used in patients with progressive disease lacking an HLA-matched related donor.

A case report of relapse of non-Hodgkin lymphoma presented with diabetes insipidus

A case report of relapse of non-Hodgkin lymphoma presented with diabetes insipidus

Intravitreal rituximab for the treatment of intraocular relapse of non-Hodgkin's lymphoma

Clinical caseA 58-year-old woman with intraocular relapse of a diffuse large B cell lymphoma. Weekly intravitreal rituximab (1 mg/0.1 ml) for 4 weeks were administered. 12 months after the last intravitreal rituximab dose, signs and symptoms of lymphomas or adverse reactions associated with intravitreal Rituximab administration were not observed. DiscussionIntravitreal rituximab is an effective and safe treatment of intravitreal lymphoma, by inducing complete remission; it could be a good alternative to other therapeutic options with greater number of serious complications.

Constitutive Interleukin-7 Cytokine Signaling Enhances the Persistence of Epstein-Barr Virus-Specific T-Cells.

The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors (CARs), and C7R-modified GD2.CAR T-cells are currently undergoing clinical trials. To determine if the C7R could also enhance the activity of T-cells recognizing tumors via their native T-cell receptors (TCRs), we evaluated its effects in Epstein-Barr virus (EBV)-specific T-cells (EBVSTs) that have produced clinical benefits in patients with EBV-associated malignancies. EBVSTs were generated by stimulation of peripheral blood T-cells with overlapping peptide libraries spanning the EBV lymphoma antigens, LMP1, LMP2, and EBNA 1, followed by retroviral vector transduction to express the C7R. The C7R increased STAT5 signaling in EBVSTs and enhanced their expansion over 30 days of culture in the presence or absence of exogenous cytokines. C7R-EBVSTs maintained EBV antigen specificity but were dependent on TCR stimulation for continued expansion. C7R-EBVSTs produced more rapid lymphoma control in a murine xenograft model than unmodified EBVSTs and persisted for longer. The findings have led to a clinical trial, evaluating C7R-EBVSTs for the treatment of refractory or relapsed EBV-positive lymphoma (NCT04664179).

Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling.

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

Efficacy and safety of fourth-generation CD19 CAR-T expressing IL7 and CCL19 along with PD-1 monoclonal antibody for relapsed or refractory large B-cell lymphoma

Objective: This study systematically explore the efficacy and safety of fourth-generation chimeric antigen receptor T-cells (CAR-T), which express interleukin 7 (IL7) and chemokine C-C motif ligand 19 (CCL19) and target CD19, in relapsed or refractory large B-cell lymphoma. Methods: Our center applied autologous 7×19 CAR-T combined with tirelizumab to treat 11 patients with relapsed or refractory large B-cell lymphoma. The efficacy and adverse effects were explored. Results: All 11 enrolled patients completed autologous 7×19 CAR-T preparation and infusion. Nine patients completed the scheduled six sessions of tirolizumab treatment, one completed four sessions, and one completed one session. Furthermore, five cases (45.5%) achieved complete remission, and three cases (27.3%) achieved partial remission with an objective remission rate of 72.7%. Two cases were evaluated for disease progression, and one died two months after reinfusion because of uncontrollable disease. The median follow-up time was 31 (2-34) months, with a median overall survival not achieved and a median progression-free survival of 28 (1-34) months. Two patients with partial remission achieved complete remission at the 9th and 12th months of follow-up. Therefore, the best complete remission rate was 63.6%. Cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome were controllable, and no immune-related adverse reactions occurred. Conclusion: Autologous 7×19 CAR-T combined with tirelizumab for treating relapsed or refractory large B-cell lymphoma achieved good efficacy with controllable adverse reactions.

Response Rate After Modified Regime DHAP and Toxicity with Refractory and Relapsed Disease in Lymphoma Patients

Objective: To assess the response rate and toxicity of a modified regimen DHAP (dexamethasone, cytarabine, and cisplatin) and to compare treatment response and toxicity profile with disease status in patients with refractory and relapsed lymphoma who presented to a public hospital in Karachi, Pakistan.Study Design: A cross sectional study.Place and Duration of Study: The study was conducted at the Oncology Department of Jinnah Postgraduate Medical College, Karachi, Pakistan, from December 2021 to October 2022.Methods: Modified DHAP was used to treat all individuals with lymphoma who had refractory disease or had relapse. The modified DHAP treatment includes intravenous infusions of dexamethasone 40 mg every 15 2 minutes on days 1 through 4, cisplatin 25 mg every 3 hours on days 1 through 4, and cytarabine 2x0.5 g/m every hour on days 1 through 4. Cycles were repeated every three weeks. Following each cycle, toxicity was evaluated using WHO criteria. A CT scan and a physical examination were used to assess the therapy response.Results: The median age was 41, ranging from 20 to 74 years. Most of the patients were males (73.9%). Of 92 patients, 32 had refractory disease, and 60 had relapse. Twenty-nine patients had a complete response, 45 patients had a partial response, and the overall response rate of modified DHAP was 80.4%. The most frequent toxicity of modified DHAP was pancytopenia (46.7%), followed by febrile neutropenia (14.1%), respectively. Mortality occurred in 4 patients (13%). Febrile neutropenia was reported more in non-Hodgkin's lymphoma patients than in Hodgkin's lymphoma patients, with a p-value=0.014. Conclusion: Modified DHAP has a better overall response rate and manageable toxicity profile in patients with refractory or relapsed lymphoma.
 How to cite this: Kumari R, Haider G, Abro N, Shah A, Sarim T, Abid K. Response Rate After Modified Regime DHAP and Toxicity with Refractory and Relapsed Disease in Lymphoma Patients. Life and Science. 2023; 4(4): 469-475. doi: http://doi.org/10.37185/LnS.1.1.348

SAT503 Acute Psychosis and Paranoia as an Initial Manifestation of Myxedema Madness

Abstract Disclosure: S. Atam: None. M. Ahmad: None. G.A. McGrath: None. Introduction: Hypothyroidism is a common disease affecting approximately 1 in 300 Americans, with autoimmunity being the most common cause in the United States. Hypothyroidism is known to present with numerous psychiatric manifestations, including depression, cognitive deficits, and rarely psychosis. We present a case of profound hypothyroidism found in a patient who presented with visual hallucinations and paranoia. Case description: The patient was a 64-year-old man with past medical history of follicular Non-Hodgkin's Lymphoma, Type 2 diabetes, hypertension, and sinus bradycardia who presented to the emergency department with three-week history of increasing agitation, insomnia and cold intolerance. He had auditory and visual hallucinations with paranoid ideations, which started a few days prior. His initial vitals were temperature: 98.2°, heart rate: 81 beats per minute, respiratory rate: 20 breaths per minute, and blood pressure: 135/88 mmHg. The patient’s initial lab work was significant for: sodium: 143 mmol/L, potassium: 3.6 mmol/L, creatinine: 1.55 mg/dL (baseline of 1.2 mg/dL), AST: 240 IU/L, ALT: 252 IU/L, INR: 1.1, ammonia: 20 mcmol/L, TSH: 51.7 uIu/ml, free t4: <0.1 ng/dL, free t3: <0.4 ng/dL, and urine drug screen positive for cannabinoids. MRI imaging of the patient’s brain was negative for any acute intracranial process. Although the absence of hypothermia made myxedema coma unlikely, both the acuity and the severity of his psychiatric symptoms in the context of profound hypothyroidism, with no other identifiable cause, collectively suggested “myxedema madness”. The patient was started on intravenous levothyroxine therapy along with quetiapine and haloperidol for agitation. Further lab work demonstrated an anti-tpo antibody of 9.0 IU/mL (< 9) along with a benign lumbar puncture (glucose: 89 mg/dL, protein: 54 mg/dL, WBC: 9/uL, RBC: 1/uL). A review of his recent medical history revealed that last summer, as part of a chemotherapy regimen for relapsed lymphoma, he had been started on Lenalidomide, which is reported to cause primary hypothyroidism in 7% of patients. His overall neurologic function improved over a two-week course, and he was subsequently discharged. Discussion: Hypothyroidism can present with a spectrum of different psychiatric manifestations. However, cases of hypothyroidism-induced psychosis are infrequent. It is reported that only 5-15% of myxedematous patients develop some form of psychosis. Treatment of this altered mental state is centered on thyroid hormone supplementation along with the administration of antipsychotic medications. Improvement in psychotic symptoms is typically seen within weeks to months after initiation of treatment. Through this case, we hope to highlight this rare presentation of hypothyroidism and current proposed treatment strategies. Presentation Date: Saturday, June 17, 2023

Modification of Lugano criteria by pre-infusion tumor kinetics improves early survival prediction for patients with lymphoma under chimeric antigen receptor T-cell therapy

BackgroundChimeric antigen receptor T-cell therapy (CART) is effective for patients with refractory or relapsed lymphoma with prolongation of survival. We aimed to improve the prediction of Lugano criteria for overall...

Isolated Solitary Asymptomatic Skeletal Muscle Relapse of High-Grade Lymphoma Detected on Surveillance 18F- Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography.

While extranodal involvement of diffuse large B-cell lymphoma (DLBCL) is common, skeletal muscle involvement is extremely rare. Isolated skeletal muscle involvement in lymphoma is even rarer. We present here the case of a 26-year-old woman, who was diagnosed to have a solitary isolated skeletal muscle relapse of DLBCL on surveillance 18F-fluorodeoxyglucose positron emission tomography-computed tomography, after completing first-line treatment, that was subsequently confirmed with biopsy.

Outcomes of Bridging and Salvage Radiotherapy in Relapsed or Refractory Mantle Cell Lymphoma Patients Undergoing CD19-Targeted CAR T-Cell Therapy.

We sought to describe our early experience of using bridging and salvage radiation therapy (RT) in patients with relapsed/refractory mantle cell lymphoma (MCL) undergoing CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. A retrospective study was conducted for consecutive MCL patients who were treated with commercially available CD19-targeted CAR T-cell therapy between 2020 and 2022 at a single institution. Patients who received RT pre-and post-CAR T-cell therapy were identified and analyzed using descriptive and statistical analysis. Overall survival (OS) from the date of CAR T infusion was estimated with the Kaplan-Meier method. The duration of local control (LC) was defined as the time between the start date of RT and the date of in-field progression/relapse. Response to RT was analyzed based on the total number of irradiated sites. A total of 21 patients with MCL who received CD19-targeted CAR T-cell therapy were identified (17 brexu cel, 3 tisa-cel, and 1 liso-cel) with a median follow-up of 15.3 months (24 days-36.2 months). The median age was 65 years at time of apheresis (43-83 years). The median OS for the entire cohort following CAR T-cell therapy was 17 months (95% CI: 14.2 months-not reached). Of the 21 patients, 1 patient received bridging RT prior to CAR T infusion, 1 patient received RT pre-and post-CAR T, and 5 patients received salvage RT post-CAR T with a total of 23 irradiated sites. Sites of RT include: extremities (10), central nervous system (3), pelvis/groin (3), head and neck (3), chest (2), abdomen (1), and multiple sites (1). The median dose/fractionation were 16.5 Gy (range, 3.6-45 Gy) and 5.5 fractions (range, 2-16 fractions)- radiation data was incomplete only for 1 patient who received RT at an outside institution. The in-field responses of the 21 evaluable sites were as follows: complete response (CR) (n = 18, 86%) and partial response (PR) (n = 3, 14%), translating into an LC rate of 100%; the remaining 2 sites were not evaluable since the patient died shortly after receiving RT due to progressive lymphoma. Notably, there was no correlation between RT dose and LC; 9 sites received low-dose RT (3.6-6 Gy) with responses as follows: CR (n = 6, 67%) and PR (n = 3, 33%). Only 1 patient experienced grade 3-4 RT-related toxicities. At the time of the last follow-up, 4 patients remained alive, and 3 patients succumbed to progressive lymphoma. As no studies exclusively focusing on CAR T-cell therapy and bridging or salvage RT have been published among relapsed/refractory MCL patients, our early experience underlines that using RT as a bridging and salvage approach is associated with excellent in-field control and limited toxicity in the peri-CAR T setting. Low-dose RT for MCL appears to be very effective in this highly refractory population and warrants further investigation.

Clinical experience of using brentuximab-vedotin as therapy in relapsed/refractory Hodgkin's lymphoma at Hospital Guillermo Grant Benavente, Concepción, Chile

Hodgkin's lymphoma is a B-cell neoplasm with a good prognosis but a poor response to chemotherapy in refractory or relapsed cases. Brentuximab-vedotin is an anti-CD30 monoclonal antibody approved for use in these cases. This study aims to describe the clinical experience of patients treated with brentuximab-vedotin through expanded access modality. A retrospective study on clinical information of patients diagnosed with refractory or relapsed Hodgkin's lymphoma treated with brentuximab-vedotin at the Regional Hospital of Concepción in the period 2015-2021. 7 patients were identified, 5/7 male, with a median age of 35 years (21-50). Five cases were mixed cellularity, and two were nodular sclerosis. Four were in stage II, 1/7 in stage III, and 3/7 in stage IV. The median number of previous treatment lines was 4 (3-5), and the relapse was post-transplantation in two cases. In 6/7 cases, brentuximab-vedotin was used as induction, and in one case, it was used as post-autologous bone marrow transplant maintenance. The administration was outpatient via a peripheral route with a median dose of 150 mg and ten cycles. In one case, dose adjustment was required due to toxicity. Three out of 6 patients achieved complete remission and underwent autologous stem cell transplantation. brentuximab-vedotin is an outpatient medication with low toxicity that can optimize the treatment of patients with relapsed-refractory Hodgkin's lymphoma.

The Role of Radiotherapy in Patients with Refractory Hodgkin Lymphoma after Brentuximab Vedotin and -/or Immune Checkpoint Inhibitors

Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) had important roles in the treatment of relapse or refractory (R/R) Hodgkin lymphoma (HL). Treatment of refractory disease after BV and -/or ICIs remains a challenge. This study was conducted to evaluate the efficacy and safety of radiotherapy for R/R HL after failure to BV or ICIs. We retrospectively analyzed patients in two institutions with R/R HL who had failed after first-line therapy, and were refractory to BV or ICIs, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 19 patients were enrolled. First-line systemic therapy consisted of ABVD (84.2%), AVD + ICIs (10.5%) and BEACOPP (5.3%), respectively. After first-line therapy, 15 patients (78.9%) were refractory, and 4 patients (21.1%) relapsed. After diagnosis of R/R HL, 8 patients (42.1%) received BV, and 17 patients (89.5%) received ICIs. RT was delivered in all 19 patients who failed after BV or ICIs. In 16 efficacy-evaluable patients, the ORR and CR rate were 100% and 100%. The median DOR was 17.2 months (range, 7.9 to 46.7 months). 3 patients progressed at outside of the radiation field. The in-field-response rate was 100%. The 12-month PFS and OS were 84.4% and 100%, respectively. No patients were reported with sever adverse events. This study concluded that radiotherapy was effective and safe for refractory HL after BV or ICIs. Further prospective studies were warranted.

Sulfonamide-Resistant Nocardia Isolated from Alveolar Dental Abscesses in a Child with ALL: A Case Report

Introduction: Nocardia is a catalase-positive and gram-positive bacillus. This organism causes skin, lung, and brain infections more frequently in immunocompromised hosts. Objectives: We report a 10-year-old child with a history of lymphoma relapse undergoing chemotherapy several times. There was no improvement after a dental abscess, outpatient surgery, and oral antibiotics. The child was hospitalized with trismus and respiratory distress. In the CT scan, periodontitis and masticatory abscess were reported. Results: The culture results showed Nocardia otitidiscaviarum resistant to experimental antibiotics such as sulfonamides. Clinical symptoms improved with surgical intervention and appropriate antibiotics. The child is in good condition and is currently receiving treatment for the primary illness. Conclusions: Nocardia should be considered in patients with infectious complications following malignancy or other immunocompromised conditions, as failure to correct diagnosis results in inadequate response.

Fractionated Stereotactic Radiation for Central Nervous System Lymphoma: Retrospective Analysis of Initial Cases.

Primary central nervous system lymphoma (PCNSL) is primarily treated with combination chemotherapy, while whole-brain radiotherapy (WBRT) can be used as consolidative treatment or as a salvage option for central nervous system (CNS) relapse. We investigated whether fractionated stereotactic radiosurgery (fSRS) could replace WBRT in cases where patients had poor performance status or minimal disease at the time of consolidation, to spare patients the adverse effects of WBRT. We retrospectively identified 10 patients who completed 14 courses of fSRS for PCNSL or for CNS relapse of systemic lymphoma. Of 14 fSRS treatments, there were 10 distant brain recurrences among 6 patients, occurring on average 13.6 months after fSRS. A total of 4 of the 10 recurrences were treated with further fSRS, and 4 were treated with WBRT. There was one late in-field recurrence after both fSRS and WBRT, which occurred 27 months after fSRS. The median survival after fSRS was 36 months, and side effects after fSRS were minimal. This case series represents a potential treatment option for patients with CNS lymphoma, for whom WBRT is indicated but where the toxic effects of this treatment would be prohibitive.

Leukemic presentation and progressive genomic alterations of MCD/C5 diffuse large B-cell lymphoma (DLBCL).

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of CD79B, MyD88, TP53, TBL1XR1, and PIM1 genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of TP53 heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as PRDM1 loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of BTK and FOXO1 mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.

Alternative splicing of its 5′-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies

AbstractAberrant skipping of coding exons in CD19 and CD22 compromises the response to immunotherapy in B-cell malignancies. Here, we showed that the MS4A1 gene encoding human CD20 also produces several messenger RNA (mRNA) isoforms with distinct 5′ untranslated regions. Four variants (V1-4) were detected using RNA sequencing (RNA-seq) at distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma, only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform contained upstream open reading frames and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, whereas V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed chimeric antigen receptor T cells were able to kill both V3- and V1-expressing cells, but the bispecific T-cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on 4 postmosunetuzumab follicular lymphoma relapses and discovered that in 2 of them, the downregulation of CD20 was accompanied by a V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.

Response to ifosfamide, carboplatin, etoposide (ICE) vs. dexamethasone, cytarabine cisplatin (DHAP) as salvage chemotherapy in patients with relapsed/refractory lymphoma.

Non-Hodgkin's lymphomas are the eighth-most prevalent malignancy in females and the eleventh in males. No research has been conducted comparing dexamethasone, cytarabine cisplatin (DHAP) vs. ifosfamide, carboplatin, etoposide (ICE) as salvage chemotherapy regimens for relapsed or refractory lymphomas in Pakistan. This study aims to compare the response of ICE vs. DHAP as salvage chemotherapy in patients with relapsed/refractory lymphomas. A prospective follow-up study was conducted at the tertiary care hospital in Karachi, Pakistan, from 2019 to 2020. A total of 58 lymphoma patients after first-line chemotherapy were included in the study. The treatment response was evaluated after two cycles of salvage chemotherapy using WHO assessment criteria, and Cox regression was used to determine the hazard ratios considering the P value ≤0.05 significant. Of 58 patients, 19 (32.8%) patients achieved complete response (CR), and 8 (13.8%) patients achieved partial response (PR), with an overall response rate of overall response rate of 46.6%. In the ICE group, the response was assessed in 19 patients. Overall response was 42.1%, CR was 31.6% and PR was 10.5%. In the DHAP group, response was evaluated in 39 patients, the overall response rate was 48.7%, CR was 33.3% and PR was 15.4%. The hazard ratio for survival in patients with relapsed/refractory lymphomas who received DHAP was 1.40 times (95% CI: 1.27-3.63, P=0.001) compared to patients who received ICE as salvage chemotherapy. DHAP seems to have a marginally better overall response rate than the ICE regimen in patients with refractory or relapsed lymphoma. However, the toxicity profile of patients in both groups was similar.