Extranodal non-Hodgkin Lymphoma Research Articles

A novel inflammation-related prognostic model for predicting the overall survival of primary central nervous system lymphoma: A real-world data analysis.

Primary central nervous system lymphoma (PCNSL) is a type of extranodal non-Hodgkin lymphoma. Although there are widely used prognostic scores, their accuracy and practicality are insufficient. Thus, a novel prognostic prediction model was developed for risk stratification of PCNSL patients in our research. We retrospectively collected 122 patients with PCNSL from two medical centers in China from January 2010 to June 2022. Among them, 72 patients were used as the development cohort to construct a new model, and 50 patients were used for the validation. Then, by using univariate and multivariate Cox regression analsis and Lasso analysis, the Xijing model was developed and composed of four variables, including lesion number, β2-microglobulin (β2-MG), systemic inflammation response index (SIRI) and Karnofsky performance status (KPS). Finally, we evaluated the Xijing model through internal and external validation. Compared with the original prognostic scores, the Xijing model has an overall improvement in predicting the prognosis of PCNSL according to the time-dependent area under the curve (AUC), Harrell's concordance index (C-index), decision curve analysis (DCA), integrated discrimination improvement (IDI) and continuous net reclassification index (NRI). For overall survival (OS) and progression-free survival (PFS), the Xijing model can divide PCNSL patients into three groups, and shows more accurate stratification ability. In addition, the Xijing model can still stratify and predict prognosis similarly better in the elderly with PCNSL and subgroups received high-dose methotrexate (HD-MTX) or Bruton's tyrosine kinase inhibitors (BTKi). Finally, external validation confirmed the above results. Integrating four prognostic factors, including imaging findings, tumor burden, systemic inflammation response index, and comprehensive physical condition, we provided a novel prognostic model for PCNSL based on real-world data and evaluated its predictive capacity.

First approach on gastrointestinal lymphoma classification based on histopathology and immunohistochemistry

Background: The gastrointestinal tract is the most common site of extranodal Non-Hodgkin lymphoma, accounting for 20% to 40% of all extranodal lymphomas. This study aims to accomplish the objective: classify the prevalent histopathological patterns of gastrointestinal lymphoma according to WHO 2019 classification based on histopathology and immunohistochemistry. Subjects and methods: A cross-sectional study sampled on 76 gastrointestinal lymphoma patients to be examined and treated at The Hue University of Medicine and Pharmacy Hospital and Viet Nam National Cancer Hospital from January 2021 to June 2022. Results: B cell and T cell Lymphoma made up 97.4% and 2.6%, respectively; among them, the most common pattern was diffuse large B-cell lymphoma (59.2%,), Mucosa-associated lymphoid tissue lymphoma (17.1%), Mantle cell lymphoma (15.8%), Follicular lymphoma (2.6%), High-grade B-cell lymphoma (1.3%), and Small lymphocytic lymphoma (1.3%). The most frequent position was the stomach (60.5%), the rectum and colon, small intestine, and ileocecal region at 19.7%, 10.5%, and 9.3%, respectively. Conclusions: Using histopathology and immunohistochemistry can classify the majority of gastrointestinal Non - Hodgkin lymphoma according to the WHO 2019 classification. Immunohistochemistry plays an important role in the classification of gastrointestinal lymphomas. Key words: gastrointestinal lymphoma, WHO 2019 classification, immunohistochemistry

Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.

Disparities in Cutaneous T-Cell Lymphoma Incidence by Race/Ethnicity and Area-Based Socioeconomic Status.

Cutaneous T-cell lymphoma (CTCL) is a rare type of extranodal non-Hodgkin lymphoma (NHL). This study uses population-based data from the New Jersey (NJ) State Cancer Registry to examine geographic variation in CTCL incidence and evaluates whether CTCL risk varies by race/ethnicity and census tract socioeconomic status (SES). The study included 1163 cases diagnosed in NJ between 2006 and 2014. Geographic variation and possible clustering of high CTCL rates were assessed using Bayesian geo-additive models. The associations between CTCL risk and race/ethnicity and census tract SES, measured as median household income, were examined using Poisson regression. CTCL incidence varied across NJ, but there were no statistically significant geographic clusters. After adjustment for age, sex, and race/ethnicity, the relative risk (RR) of CTCL was significantly higher (RR = 1.47, 95% confidence interval: 1.22-1.78) in the highest income quartile than in the lowest. The interactions between race/ethnicity and SES indicated that the income gradients by RR were evident in all groups. Compared to non-Hispanic White individuals in low-income tracts, CTCL risk was higher among non-Hispanic White individuals in high-income tracts and among non-Hispanic Black individuals in tracts of all income levels. Our findings suggest racial disparities and a strong socioeconomic gradient with higher CTCL risk among cases living in census tracts with higher income compared to those living in lower-income tracts.

Primary breast T cell lymphoma – a rare case report

Primary breast lymphomas (PBL) are an exceptionally rare form of extranodal non-Hodgkin lymphoma (NHL), occurring in less than 0.5% of all breast malignancies.1 Primary breast T-cell lymphoma (TCL) is an even rarer entity, accounting for only 6% of breast lymphomas. It has an aggressive but poorly understood clinical course, and non-specific features that can mimic inflammatory breast carcinoma (oedema, skin changes and mastalgia).1 Currently, there is no standard treatment protocol for PBL, but a multimodal approach using diagnostic lumpectomy combined with chemotherapy and/or radiation therapy is recommended, versus radical mastectomy alone with no overall survival benefit and higher all-cause mortality rates.2 We present a case of a 64 year old female with a 12 month history of right breast pain with skin changes. Clinical and radiological examination (mammogram and ultrasound) revealed no focal lesion or lymphadenopathy. Multiple biopsies showed no evidence of malignancy. The patient was also treated with IV antibiotics with no improvement. Due to persistent symptoms and concern of inflammatory breast carcinoma, a mastectomy was performed. Haematoxylin and eosin (H&E) stained sections and molecular testing (immunohistochemistry and T cell gene rearrangement) confirmed primary breast T cell lymphoma.

Imaging Diagnosis of Testicular Lymphoma in Young Male Patient: Incidental Finding in Ultrasonography

BACKGROUND: Ultrasonography is a common diagnostic procedure in patients with testicular abnormalities. Primary testicular lymphoma (PTL) is rarely discovered and is more common among elderly populations. CASE PRESENTATION: This case describes a young male patient with a history of painless testicular enlargement. Ultrasonography reveals an incidental finding of hypoechoic echo structural mass and increased vascularity using color Doppler ultrasonography. The further pathological examination discovered the findings indicative of a non-Hodgkin, diffuse, and large B-cell lymphoma. These distinctive features should be helpful in suggesting a diagnosis of PTL on imaging. CONCLUSION: PTL is a rare and aggressive extranodal NHL. Despite its low incidence, it is an extremely rare testicular cancer at a young age. Careful ultrasound imaging examination should be applied in patients with testicular enlargement. The presence of hypoechoic echostructural and an increase in vascularity should be considered for the possibility of a diagnosis of primary testicular tumor.

"Exploring Diverse Presentations of extra nodal Non-Hodgkin's Lymphoma: A Comprehensive Study of Clinical Staging, Treatment, and Controversies.

Lymphoma involves abnormal lymphoid cell growth, often originating in lymphatic tissue, but in this case series non-Hodking's lymphoma is visible in the extra-nodal region. This research explores different lymphoma cases, focusing on diverse presentations and utilizing modern imaging for evaluation. Four cases are detailed, involving an 18-year-old woman with tonsillar lymphoma, a 69-year-old man with ocular lymphoma, a 38-year-old lady with abdominal lymphoma, and a 30-year-old man with gastric lymphoma. All cases received adjuvant chemotherapy (RCHOP), leading to significant symptom relief after four cycles. The discussion highlights the debate surrounding the classification of primary extranodal non-Hodgkin's lymphoma (NHL), challenging the existing Ann Arbor classification's applicability. A major challenge in managing primary extranodal lymphomas is the absence of specific treatment guidelines. Evaluation criteria, defining complete response as the disappearance of all evidence of the disease, guided the study. In conclusion, this case series underscores the importance of a multidisciplinary approach in diagnosing, staging, and managing non-Hodgkin’s lymphoma. Despite challenges in defining and treating primary extranodal non-Hodgkin’s lymphoma, the study demonstrates the effectiveness of adjuvant chemotherapy in providing relief, as all the cases revealed recovery after 4 continuous cycles of chemotherapy.

Primary Cardiac Lymphoma: Case Series

Primary cardiac lymphoma (PCL) is an extranodal non-Hodgkin's lymphoma exclusively located in the heart and/or pericardium. It is frequently found in immunocompromised patients and is fatal unless timely diagnosed and treated. Untreated, it has a mean survival time of 6 months. The differential diagnosis includes other malignant cardiac neoplasms. Among the imaging modalities, echocardiography is emerging as an indispensable investigation for the early diagnosis and follow-up of these patients, although histopathology gives the final diagnosis. Here, we present three cases of PCL in immunocompetent patients, out of whom two were adults and one was a child. Two patients presented with pericardial tamponade and a third with complete heart block. On echocardiography, lymphoma was located in the right heart chambers in all three cases with the presence of significant pericardial effusion. Histopathological examination showed diffuse large B-cell lymphoma in adults and T-cell lymphoblastic lymphoma in the child. All three patients received chemotherapy. Only two patients survived. The child remained asymptomatic, while the adult male had a relapse after 6 months of completion of the first chemotherapy regimen. The diagnosis of PCL is difficult due to nonspecific clinical manifestations. At present, the main course of treatment is chemotherapy, although surgery may be required in some cases. Among the available imaging modalities, echocardiography is a cost-effective and readily available investigation for the early detection of the tumor.

Phosphoproteome analysis of cerebrospinal fluid extracellular vesicles in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare but highly aggressive extra-nodal non-Hodgkin's lymphoma, mostly of the diffuse large B-cell lymphoma (DLBCL) type. The present invasive diagnosis and poor prognosis of PCNSL propose an urgent need to develop molecular markers for early detection, real-time monitoring and treatment evaluation. Cerebrospinal fluid (CSF)-derived extracellular vesicles (EVs) are promising biomarker carriers for liquid biopsy of CNS diseases and brain tumors; however, research remains challenging due to the low concentration of EVs in the limited available volume of CSF from each individual patient and the low efficiency of existing methods for EV enrichment. Here, we introduce functionalized magnetic beads called EVTRAP (extracellular vesicles total recovery and purification) for rapid and efficient EV isolation from CSF. By coupling with high-performance mass spectrometry, over 19 000 peptides representing 1841 proteins were identified from just 30 μL of CSF. Furthermore, up to 3000 phosphopeptides representing over 1000 phosphoproteins were identified from about 2 mL of CSF. Finally, we analyzed the EV phosphoproteomics of CSF samples from PCNSL patients and non-PCNSL controls. Among them, multiple phosphoproteins related to PCNSL, including SPP1, MARCKS, NPM1 and VIM, were shown to be up-regulated in the PCNSL group. These results demonstrated the feasibility of the EVTRAP-based analytical strategy in CSF EV phosphoproteomic analysis of PCNSL molecular markers.

A An Unusual Presentation of Primary Extra Nodal Non-Hodgkin Lymphoma

Patients presented with soft tissue lesions without any β symptoms can be a case of Primary extranodal Non- non-Hodgkins lymphoma. According to the World Health Organization classification system, there are two types of Lymphoma with various sub-types of Hodgkins Lymphoma and Non-Hodgkin Lymphoma are classified to assess the disease burden Progression and metastasis Imaging modalities are helpful. Commonest site involvement in Non-Hodgkin Lymphoma in the gastrointestinal tract (44%) followed by Head and Neck and may Involve bone (8%) and Central Nervous System 5%. Diffuse large β-Cell Lymphoma is the most common subtype representing 30%-35% of all Non-Hodgkin Lymphoma Cases. Oral and Para oral sites were involved in 2.5% of the cases. A 27-year-old Male noticed a swelling in the flank which was progressively Increasing in size one year back later it was associated with pain which reduced mobility and pain was increased during walking. Due to the advancement of diagnostic techniques, it is easy to get the radiological picture and correlation with clinical presentation and pathological reports, but these facilities are not available at various centers. Usually, patients are present in very advanced stages because of a lack of awareness about the disease, and how to proceed for diagnosis and treatment resulting in poor outcomes for these patients. This presentation and clinical funding are rare in the case of Lymphoma. This case report allows us to think of another diagnosis rather than usual.

Challenges in the Diagnosis of Extranodal Non-Hodgkin’s Lymphoma of the Base of Tongue: A Rare Case Report

Introduction: Primary non-Hodgkin’s lymphomas (NHLs) of the oral cavity, especially in the tongue, are extremely rare and account for 1% of all malignant tumors of the oral cavity, accounting for 7% of all primary Waldeyer’s ring NHLs. Clinical features are non-specific ulcerative lesions that do not heal, making its diagnosis challenging. Fine-needle aspiration biopsy was helpful in the early diagnosis of the intraoral NHL involving a cervical lymph node. Case Report: we present a rare case of extranodal NHL of the base of tongue in a 55-year-old female who presented with a mass in the base of the tongue with cervical lymphadenopathy. The diagnosis was confirmed as primary NHL diffuse large B cell type by histopathological and immunohistochemistry results. Conclusion: A careful clinical evaluation supported by histopathological and radiologic investigations will help identify the disease early, resulting in a better prognosis.

Primary diffuse large B-cell lymphoma of maxillary sinus: Case Report and Literature

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma (ML), accounting for 30-40% of non-Hodgkin lymphoma (NHL) cases in adults. A specific type of NHL, primary paranasal sinus lymphoma (PPSL), is a rare neoplasm of extranodal NHL and can often be difficult to diagnose. It generally has a poor prognosis because of the complex anatomy of the region and it can usually be noticed at an advanced stage. Case presentation: In this case report, we present diffuse large B-cell lymphoma of the maxillary sinus in a patient who applied to our clinic with the complaint of swelling in the maxillary anterior region for 3 months. Before coming to our clinic,the patient was examined by several physicians who missdiagnosed her condition. After radiological evaluations and histopathological examination the correct diagnosis was made and the patient was referred to the Hematology Clinic where chemotherapy was planned . Coclusion: Despite the advancement of modern diagnostic methods, timely recognition of disease symptoms still forms the basis of early diagnosis. This case report demonstrates the need for systematically examination of anatomical structures during clinical and radiographic evaluation in terms of early diagnosis and to prevent delays in treatment.

Extranodal Diffuse Large B-Cell Lymphoma of the Small Bowel in Female Patient Causing Intestinal Obstruction: A Case Report

Diffuse large B cell lymphoma is the most common extranodal non-Hodgkin lymphoma of the small intestine accounting for more than 50% of cases. Forty percent of these cases initially present with small bowel obstruction. Therefore, the diagnosis is usually established after surgery for bowel obstruction. The treatment is then continued with a certain chemotherapy regimens. We present a case of a 46-years-old female patient with signs of small bowel obstruction due to previously undiagnosed diffuse large B-cell lymphoma. Postoperatively, the patient was treated with 7 cycles of R-CHOP protocol and complete response was achieved in the short follow-up period.

Primary meningeal central nervous system lymphoma: A case report and literature review

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma, and isolated meningeal PCNSL, without evidence of parenchymal involvement, is even less common, occurring in only 10% to 15% of cases. A 65-years-old female presented to our hospital with progressive lower extremity motor dysfunction and blurred vision. The initial neurological examination revealed decreased muscle strength in both lower extremities and sensory dysfunction of lower extremities, saddle area, and buttocks. Brain magnetic resonance imaging showed no abnormalities. Lumbar enhanced magnetic resonance imaging showed T11 to L3 horizontal meningeal enhancement. Cerebrospinal fluid (CSF) cytology revealed lymphoma cells. Immunohistochemistry and flow cytometry of the CSF were performed as auxiliary methods to establish the diagnosis of lymphoma. The patient was diagnosed primary meningeal central nervous system lymphoma. During hospitalization, the patient was treated with 2 courses of high-dose intrathecal methotrexate and rituximab combined with intrathecal chemotherapy and supportive treatment. After 2 years of follow-up, the patient was able to walk and take care of herself. Cases of PCNSL involving only the meninges are rare. Multimodal analysis of the CSF comprises an important component of the diagnostic work-up for patients with primary meningeal central nervous system lymphoma.

Primary CNS Lymphoma in an Immunocompetent Patient: An Unusual Case Illustrating the Usual Problems Facing Brain Tumour Management in a Lower-Middle-Income Country

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin lymphoma (NHL). It primarily affects the immunocompromised but is rarely seen in immunocompetent individuals. The pitfalls in the healthcare system of lower-middle-income countries produce many obstacles, impeding timely diagnosis, timely treatment, and optimal quality of care. A 57-year-old immunocompetent, diabetic female presented with progressive generalised fatiguability, forgetfulness, and subtle behavioural changes for the last one and a half years. MRI revealed an area of gyri from dense post-contrast enhancement in the right posterior parietal region. Her symptoms kept aggravating with periods of partial remission as steroids were being administered. Reasons for delays in diagnosis and hence timely treatment include lack of primary care referral, conflicting neurosurgical opinion, and absence of multidisciplinary team management. A right posterior parietal parasagittal craniotomy was performed to excise the lesion. The patient was subsequently referred for adjuvant therapy. We use our patient's clinical journey to exemplify the structural barriers to providing optimal and timely care for brain tumour patients in a developing country. Primary CNS Lymphomas in immunocompetent patients are rare. Poor infrastructure and referral pathways contribute to delayed diagnosis. Lack of multi-disciplinary care owing to organisational issues is a major problem faced by brain tumour patients in a lower-middle-income country like ours. Brain tumour management requires a specialist multidisciplinary team approach to ensure timely diagnosis and optimal treatment

GEN-13 PAIRED MUTATIONAL ANALYSIS IN SECONDARY NERVOUS SYSTEM LYMPHOMA AND PCNSL SYSTEMIC RELAPSE REVEALS DRIVER MUTATION CANDIDATES IN THE CENTRAL NERVOUS SYSTEM

Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, and the spinal cord. The mechanism of central nervous system (CNS) tropism in PCNSL has not been fully elucidated. Diffuse large B cell lymphomas (DLBCLs) occasionally present with distant recurrence, which can involve inside and outside the CNS. Secondary central nervous system lymphomas (SCNSLs) are CNS relapse of systemic lymphoma. PCNSLs also rarely present with systemic relapse. We have previously reported in our study of whole exome sequencing that PCNSLs harbor frequent mutations in genes of B cell receptor pathway members and aberrant somatic hypermutation (aSHM) target genes. Although several genetic alterations were identified as more frequent in PCNSLs compared with systemic lymphomas, specific genetic alterations which serve as the driver for CNS tropism in PCNSLs has not been identified. In order to search for mutations which might serve as driver mutations in the CNS, we have performed targeted sequencing in paired samples from patients with recurrent lymphomas, either SCNSLs or PCNSL systemic relapses, using Ion Torrent multiplex PCR. Mutational profiles were compared between the primary and recurrent tumor. Six cases (four SCNSL cases and two PCNSL systemic relapse cases) were analyzed. Of note, in the SCNSL cases, several de novo mutations were enriched only among the recurrent CNS tumors. Among these mutations, BTG2 mutations were observed in 3/4 (75%), and B2M and KLHL14 mutations were observed in 2/4 (50%) cases. In the two PCNSL systemic relapse cases, KMT2D mutations were enriched only in the recurrent systemic tumors. It is suggested that these de novo mutations in the recurrent CNS tumors might serve as driver mutations in the CNS. Further analysis in larger cohorts, and functional studies are required in order to validate these findings.

Epidemiological data and diagnosis pitfalls in aggressive extranodal non-Hodgkin’s lymphomas: current issues

Introduction. Non-Hodgkin’s lymphoma is a group of malignant tumors that develop from hematopoietic cells located outside the medullary. They are one of the most common forms of hemoblastosis. Non-Hodgkin lymphoma develops in people of all ages. Morbidity of non-Hodgkin lymphoma increases with age reaching its highest level in people over 50 years of age. Material and methods. A study was carried out through a narrative review of the literature in the form of a synthesis article. The article summarized and systematized various primary studies, dedicated to the epidemiological and diagnostic aspects of aggressive extranodal NHL. Results. Aggressive extranodal NHL remains a major problem, with a fairly large increase in incidence globally. This trend is observed in several countries of the world, thus morbidity increases by 3% annually for women and by 4% for men. Globally, aggressive non-Hodgkin’s lymphoma continues to affect the working-age population. Although patients with primary extranodal NHL tend to report to a medical specialist at a lower stage than those with primary ganglion disease, the number of those addressing in advanced stages continues to be increased. Conclusions. Although diagnosing NHL does not involve great impediments, primary care physicians often detect patients in the late stages of the disease either because of delayed referral to the doctor or because of incorrect diagnosis. Despite the development of new methods of diagnosis and treatment, aggressive extranodal NHL continues to be a current problem of clinical medicine and public health, requiring increased managerial and financial efforts.

433 Single-cell characterization of primary cutaneous B-cell lymphomas reveals distinct clonal properties of marginal zone, follicle center and leg-type lymphomas

Primary cutaneous B-cell lymphomas (CBCL) comprise a group of extranodal non-Hodgkin lymphomas that are primarily confined to the skin. Primary cutaneous marginal zone lymphoma (MZL) and follicle center lymphoma (FCL) are associated with a rather indolent tumor behavior, while diffuse large B-cell lymphoma, leg type (DLBCL-LT) shows an aggressive clinical course. Besides distinct clinical and immune-histological features, the underlying molecular tumor biology is still only insufficiently understood.

HDACi Promotes the Occurrence of Ferroptosis in CTCL

Cutaneous T-cell lymphoma (CTCL) is a type of extranodal non-Hodgkin's lymphoma (NHL), a disease caused by clonal proliferation of T-lymphocytes originating in the skin. CHOP is the classic first-line treatment regimen for PTCL, working best for ALK-positive ALCL, while chemotherapy regimens are not very friendly for CTCL and other subtypes of PTCL. Currently, second-line treatment regimens have shown encouraging results with HDAC inhibitors in PTCL, and the anti-tumor mechanisms of HDAC inhibitors are being explored, including induction of apoptosis, cell cycle arrest inhibition of tumor angiogenesis, and so on. Ferroptosis is a new mode of cell death, which was mainly manifested by mitochondrial membrane lipid peroxidation, ferritin phagocytosis, the release of ferrous ions. And ferrous ions further leads to cellular lipid peroxidation, resulting in cell death. Our study shows that HDACi can significantly enhance ferroptosis inducer-mediated ferroptosis. WB and qPCR showed that ferroptosis-related molecules were significantly downregulated. In the case of HDACi combined with ferroptosis inducer, HDACi significantly enhanced the intensity of ferroptosis, and mitochondrial shrinkage and increased membrane density could be observed under electron microscopy. Intracellular iron content was detected by PGSK probe and detected by co Focused microscopy revealed that the fluorescence signal was significantly attenuated in the combination group. Reactive oxygen species assay indicated a significant increase in intracellular reactive oxygen species level, where we found the presence of ferroptosis in PTCL for the first time. In addition, we found that HDACi combined with ferroptosis inducer could enhance the apoptosis level of lymphoma cells, and the combination group significantly downregulated BCL-2, Caspase3,and significantly upregulated p-H2AX expression compared with the single drug.In terms of cycle arrest, CyclinD1 was significantly down-regulated in the combination group, and flow cytometry results were consistent with the above, while CCK8 and Edu showed significant down-regulation of cell viability and proliferation. SD rat transplantation tumor models showed a significant reduction in tumor volume in the combination group compared to the single agent and control groups, suggesting that HDACI combined with ferroptosis inducer is a promising therapeutic strategy.

A Pilot Study Evaluating Acalabrutinib for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphomas

Background: Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes, and/or spinal cord without evidence of systemic disease. While frontline PCNSL is potentially curable, relapsed PCNSL has a dismal prognosis, particularly if the relapse is within 1 year of frontline therapy. Secondary central nervous system lymphoma (SCNSL) is defined as systemic NHL that has CNS involvement either concurrently or at relapse. There is no standard of care for relapsed CNS lymphoma. Recently, though, novel targeted agents have shown promise. Bruton's tyrosine kinase (BTK) is a key enzyme in the B-cell receptor (BCR) signaling pathway. In some B-cell NHL, BTK is essential for proliferation and survival. The BTK inhibitor (BTKi) ibrutinib is effective for the treatment of both primary and secondary CNS lymphomas with response rates of 68% (CR=45%) and 56% (CR=17%), respectively. Acalabrutinib is an irreversible BTKi that has been evaluated in NHL. Phase 2 trials of acalabrutinib in relapsed/refractory MCL reported an ORR of 80.6% with a CR rate of 39.5%. Importantly, there were no cases of atrial fibrillation and only 1 case of grade 3 or higher gastrointestinal hemorrhage. We hypothesize that acalabrutinib, a more selective BTKi, may be an effective treatment for relapsed CNS lymphomas with fewer complications. Study Design/Methods: This is a multicenter, open-label, single-arm, pilot study designed to investigate the antitumor effects of acalabrutinib in subjects with relapsed PCNSL or SCNSL that is open to accrual (NCT04548648). All subjects receive acalabrutinib 100mg every 12 hours until progression or discontinuation of treatment due to an adverse event. Prophylactic administration of the antifungal agent isavuconazole will be mandatory while subjects receive acalabrutinib. This decision is based on cases of invasive aspergillosis in studies evaluating ibrutinib. As a moderate CYP3A4 inhibitor, isavuconazole may increase acalabrutinib levels. Pharmacokinetic studies have shown that coadministration may increase acalabrutinib dosing 2- to 3-fold. We feel that this possible increase in concentration is reasonable given the need for blood-brain-barrier penetration. During the study, 15 evaluable subjects will be enrolled and treated. Response will be assessed via brain magnetic resonance imaging (MRI) after 2, 4, 6, 9, 12, 18 and 24 months. After 24 months, patients will require yearly MRIs for response assessment. The primary endpoint is overall response rate (ORR) at 2 months of therapy. Secondary endpoints include toxicity, complete response (CR) rate, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Key inclusion criteria include: biopsy (can be from initial diagnosis) or MRI findings consistent with B-cell NHL in CNS; ocular and CSF involvement are allowed but there must be a parenchymal mass as well; at least one prior line of therapy; no systemic involvement; ECOG performance status < 2. Key exclusion criteria include: previous BTKi exposure; anticoagulation with warfarin; strong CYP3A4 inhibitor that cannot be stopped; severe hepatic insufficiency; inability to take oral medication. Correlative studies include blood and CSF pharmacokinetic studies of acalabrutinib and its active metabolite, ACP-5862 (collected on day 1 and 8 of cycle 1). Molecular testing will be performed on biopsy samples to evaluate the presence of mutations in the MYD88 and CXCR4 genes. Additionally, the utility of 82Rubidium as a positron emission tomography-radiotracer will be evaluated (at screening and prior to cycle 3 and cycle 7) in the first five subjects at the University of North Carolina who consent to this scan. Mental status and cognitive function will be evaluated with the mini-mental status examination (MMSE) at screening then every 6 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal