Systemic non-Hodgkin Lymphoma Research Articles

Splenic Lymphoma: A Series of Seven Cases

Splenic Lymphoma (SL) is a lymphoproliferative disorder characterised by involvement of the spleen, with or without bone marrow involvement. However, advancements in imaging modalities have led to more frequent diagnosis of isolated splenic lesions. There is always a dilemma in diagnosis as to whether the pathology truly originates from the spleen or if it is part of systemic involvement in Non-Hodgkin Lymphoma (NHL). Clinical manifestations vary widely, and treatment outcomes for SL depend on accurate diagnosis. However, prognosis still remains poor in these cases compared to systemic NHL. The present case series provide a comprehensive overview of patients diagnosed with SL, focusing on their clinicopathological characteristics, therapeutic details, prognosis and outcomes. Previously isolated case reports have been published, and there is still a lack of consensus on the management of this entity. The present case series included seven cases over a two-year period, from January 2022 to December 2023. In the current case series, authors have highlighted the heterogeneity and variability in the presentation of SL and how the clinical behaviour ranges from indolent to highly aggressive. Nevertheless, the presenting clinical, laboratory and pathological features of these diseases often display significant overlaps and pose confusion in arriving at an exact diagnosis. The authors emphasise how flow cytometry helps facilitate the diagnosis and systemic therapy is the modality of choice for treatment decided based on the histology type; however, outcomes still remain dismal, highlighting the unmet need to improve accurate diagnosis and explore newer treatment options. The novelty in this series lies in the detailed analysis and comparison of different subtypes of SL, a rare group of lymphomas primarily originating in the spleen. The present case series discusses the latest World Health Organisation (WHO) classification, which redefines the Hairy Cell Leukaemia (HCL) variant as Splenic B-cell Leukaemia/ Lymphoma with Prominent Nucleoli (SBLPN). Detailed molecular and genetic characteristics of various SLs are highlighted, such as the presence of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) p.V600E mutation in HCL, Mitogen-activated Protein Kinase 1 (MAP2K1) and Immunoglobulin Heavy Variable 4-34 (IGHV4-34) mutations in the HCL-variant, and 7q distortion in Splenic Marginal Zone Lymphoma (SMZL). Emphasis is placed on the individualised treatment approach based on specific patient profiles, genetic markers and disease characteristics. The study underscores the need for further research and clinical trials to validate emerging therapies, such as the use of Rituximab plus Doxorubicin, Bleomycin, Vinblastine and Dacarbazine (R-ABVD) in Hodgkin lymphoma and combinations of novel agents in aggressive SLs like HCL-variant and CD20-negative B-cell NHL.

Radiotherapy dose de-escalation in patients with high grade non-Hodgkin lymphoma in a real-world clinical practice.

The standard treatment of non-Hodgkin lymphoma (NHL) comprises combined modality treatment, radiotherapy (RT), and chemotherapy with rituximab which has significantly improved both disease-free survival (DFS) and overall survival (OS). However, there is no uniformity in radiation dose usage in these patients. In this retrospective study, we compared lower radiation dose with higher in patients with aggressive NHL. From 2007 to 2017, treatment records of all high-grade NHL or diffuse large B-cell lymphoma and non-central nervous system NHL were included. We compared response rates, OS and DFS of patients who received ≤30 Gy RT to those with >30 Gy. Univariate and multivariate analyses were done to determine factors affecting prognosis, i.e., age, sex, stage, International Prognostic Index (IPI), adding rituximab, and radiation dose. A total of 184 NHL patients treated with combined modality or radiation alone having complete follow-up details were analyzed. At median follow-up of 66.8 months, 5-year OS was 72.8% in high-dose group versus 69.9% in low-dose group (p = 0.772) and 5-year DFS 64.7% versus 64.1% (p = 0.871). Patients having early-stage disease receiving low dose and those with advanced disease treated with >30 Gy had better OS and DFS though not statistically significant. Adding rituximab was associated with significantly better OS and DFS irrespective of radiation dose delivered. High IPI score and omitting rituximab were the only factors that significantly worsened both OS and DFS. Acute radiation toxicities were comparable in both groups (p = 0.82). Among late toxicities, no patient developed a second malignancy and 5% died due to cardiovascular complications (p = 0.595) though only two patients (1.1%) had received thoracic radiation. The two groups had comparable response rates, acute toxicities, DFS and OS. This study suggests that RT dose reduction may be possible in high-grade NHL without compromising the DFS and OS.

Clinicopathological analysis and specific discriminating markers of interleukin detection in cerebrospinal fluid with primary central nervous system lymphoma: results from a retrospective study.

Primary central nervous system lymphoma (PCNSL) is special extranodal malignant non-Hodgkin lymphomas. This study analyzed clinical features and prognostic factors of PCNSL and evaluated the difference of interleukin (IL) concentrations incerebrospinal fluid (CSF) between PCNSL and systemic non-Hodgkin lymphoma (sNHL). Patients consecutive newly diagnosed with PCNSL were recruited, the demographic and clinicopathological data were retrospectively analyzed, and the potential prognostic factors for overall survival (OS) were identified with survival analysis. 27 patients with PCNSL and 21 patients with sNHL collected CSF IL-5, IL-6, and IL-10 concentrations at diagnosis. The difference in interleukin (IL) concentrations in two diseases was analyzed to evaluate the value of IL concentrations. A total of 64 patients with PCNSL were enrolled, the median age was 54.50years (range 16-85years); male: female ratio was 1.91. Headache was the most common complaint symptom involved in 42.19% (27/64) of patients. Diffuse large B-cell lymphoma (DLBCL) accounted for 89.06% (57/64) of patients; other uncommon types accounted for 3.13% (2/64). In prognostic analysis, multiple lesions and Ki67 ≥ 75% expression exhibited a worse prognosis(P = 0.041), and patients with autologous hematopoietic stem cell transplantation (auto-HSCT) treatment presented superior OS (P < 0.05). In multivariate analysis, BCL2 expression was revealed as an unfavorable prognostic marker, and auto-HSCT was revealed as a favorable prognostic marker. CSF IL-10 concentration in patients with PCNSL was significantly higher than sNHL (P = 0.000) and excluded other histopathology of NHL; IL-10 value was still significantly different between DLBCL of PCNSL and sDLBCL (P = 0.003). In ROC curve analysis, the cutoff value of IL-10 was 0.43pg/mL for the diagnosis value of PCNSL, sensitivity was 96.3%, specificity was 66.67%, and AUC was 0.84 (0.71-0.96). Although IL-6 concentration did not differ in the two groups, IL-10/IL-6 ratio was meaningful, with a cutoff value of 0.21, sensitivity of 81.48%, specificity of 80.95%, and AUC of 0.83 (0.71-0.95). This study highlights the characteristics of patients with PCNSL, potential prognostic makers also have been explained. CSF interleukin (IL) concentrations revealed IL-10 levels, and IL-10/IL-6 ratio may represent a useful biomarker in the differential diagnosis of PCNSL and sNHL.

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

Diagnosis and management of primary central nervous system lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Primary central nervous system lymphoma is a clinicopathological disease entity that accounts for 1% of all non-Hodgkin lymphoma (NHL). Advanced patient age, adverse disease biology and complexities of diagnosis and treatment render outcomes markedly inferior to systemic NHL. Despite this, an increasing evidence base, including limited randomised controlled clinical trial data, is informing optimal therapeutic strategies with methotrexate-based induction chemotherapy schedules and intensified consolidation in selected patients. This practice statement represents an evidence-based review of the literature and has been devised to assist healthcare professionals in the diagnosis and management of this disease.

Chimeric antigen receptor engineered T-cell therapy for central nervous system lymphoma

Central nervous system lymphoma (CNSL) includes primary and secondary subtypes. It is associated with poor prognosis even after aggressive therapies. Primary CNSL involves mainly the brain, eyes, leptomeninges and spinal cord, without evidence of systemic non-Hodgkin’s lymphoma (NHL). Secondary CNSL refers to involvement of the CNS secondary to systemic NHL. Chimeric antigen receptor T (CAR-T) cells are genetically engineered T-cells directed against tumor target antigens. CAR-T-cells have shown encouraging results in treating B-cell malignancies. Clinical data on CAR-T-cells in CNSL treatment are limited, because of concerns regarding the immunoprivileged status of the CNS and the possibility of immune effector cell-associated neurotoxicity syndrome. Clinical trials on CAR-T therapy for CNSL are increasingly being conducted to evaluate its efficiency and safety since CAR-T-cells have been detected in the cerebrospinal fluid from a patient with PMBCL who received CAR-T-cell therapy. Current data suggest that CAR-T-cells are an emerging therapeutic modality for CNSL with clinical benefits and acceptable adverse effects. However, whether CAR-T therapy may be a promising therapeutic avenue remains controversial, because evidence from large-scale randomized clinical trials remains lacking. Herein, we provide a review of existing clinical data on CAR-T-cell therapy for CNSL, discuss the limitations of CAR-T-cells in CNSL treatment and hypothesize strategies to overcome these challenges.

A multicenter, real-world analysis of primary central nervous system lymphoma in those with and without human immunodeficiency virus.

A multicenter, real-world analysis of primary central nervous system lymphoma in those with and without human immunodeficiency virus.

Diagnosis, treatment, and outcome of primary CNS lymphoma—a single-center experience

Primary CNS lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma (NHL) that occurs in the CNS (e.g. brain, meninges, spinal cord, cerebrospinal fluid, or intraocular involvement) in the absence of systemic NHL. Tumor resection does not improve survival, and neurosurgical intervention is generally limited to stereotactic biopsy to provide a histopathological diagnosis. The objective of this single-center study was to evaluate the management and outcome of PCNSL patients diagnosed by biopsy, using overall survival and progression-free survival as endpoints. At our department of neurosurgery, 140 patients were diagnosed with PCNSL by biopsy between January 1, 2009, and December 31, 2018. Of these, 37 patients were included in the study and were divided into three groups according to their postoperative therapy. Median OS was 35.7months for the intensive treatment group, 29.5months for the moderate treatment group, and 8.6months for the palliative treatment group. The intensive and moderate treatment groups had similar progression-free survival, while the palliative treatment group had poor overall and progression-free survival. Six patients were long-term survivors (> 80months). Age under 65years was the main significant parameter affecting overall survival. In this cohort, patients with PCNSL had an overall fair prognosis if they (1) were under 65years old, (2) had a performance score < 2 at the time of diagnosis, and (3) received either intensive or moderate chemotherapeutic treatment. Biopsy is still the primary diagnostic tool; other methods have been investigated but are not yet recommended.

Severe GI Toxicities Remain a Significant Source of Clinical Meaningful Morbidity Especially in Older Patients Receiving Autologous Transplant for Lymphoma

Introduction:High-dose chemotherapy and autologous hematopoietic cell transplant (HDT-AHCT) is considered a standard-of-care (SOC) consolidation therapy for patients with aggressive systemic non-Hodgkin (NHL) and Hodgkin lymphomas (HL). This therapy is associated with improved survival in relapsed/refractory NHL and HL as well as in first complete remission in mantle cell lymphoma. The most widely used HDT regimen consists of carmustine, etoposide, cytarabine and melphalan (BEAM). Although potentially curative, significant morbidities occur with HDT, especially in older patients. Aside from the expected severe hematologic toxicities, the most common clinically meaningful morbidities include signs and symptoms related to severe alimentary tract mucositis such as CTCAE Grade ≥ 3 nausea/vomiting, diarrhea and oral mucositis and febrile neutropenia (FN). The majority of FN, other infectious complications and sepsis are thought to occur due to translocation of the normal gut flora into the peripheral circulation in the presence of oral/GI mucositis. In the present study, we retrospectively analyzed patients undergoing HDT-AHCT for lymphoma in a contemporary cohort from 2 academic transplant centers, focusing on rates of oral/GI severe regimen related toxicity (SRRT) and febrile neutropenia.Methods:We conducted a retrospective analysis of 143 consecutive adult patients from 2 transplant centers undergoing HDT-AHCT as SOC consolidation for a diagnosis of NHL or HL between 2018 and 2020. The protocol was approved by the IRB at both institutions. Standard prophylactic and supportive care were provided as per institutional guidelines for HDT-AHCT. Toxicities were graded by CTCAE v5 criteria. SRRT was defined as oral/GI grade 3 or higher (G≥3) including adverse events related to alimentary tract mucositis. Partial response (PR) and complete response (CR) were defined by Lugano criteria. Statistics presented are descriptive only with no multiplicity adjustments.Results:143 patients were included in the analysis, 99% (n=141) of whom received BEAM for the HDT regimen, while 1% (n=2) received BeEAM (bendamustine in place of carmustine) (Table 1). 71% had NHL, while 29% had HL. Median prior lines of therapy were 2 (range, 1-4). Median CD34+ cell count was 4.3 x10 6 cells/kg (range, 1.9-19.6).Oral/GI SRRT occurred in 45% (n=65) of patients, with the most common G≥3 GI toxicities being diarrhea (26%), nausea / vomiting (20%), and oral mucositis (10%) (Table 2). Importantly, rates of SRRT were higher among patients ≥65 (63% vs 41%, p=0.031). The predominant differences were higher rates of G≥3 diarrhea (44% vs 21%, p=0.011), nausea (28% vs 18%, p=0.214) and oral mucositis (16% vs 8%, p=0.215).Considering only oral/GI SRRT of oral mucositis, nausea / vomiting, diarrhea (SSRT4), the overall rate of SRRT4 was 41%, with 56% and 37% occurring in patients ≥65 yo and <65 yo respectively.Rates of SRRT were similar regardless of gender, disease, number of prior lines of therapy or best response at the time of HDT-AHCT (Table 3).Interestingly, rates of FN were also numerically higher among older adults (75% vs 64%, p=0.247). Consistent with the notion that GI toxicity predisposes to bacterial translocation from the gut, patients with SRRT had numerically higher rates of FN compared to those without (74% vs 60%, p=0.088). Time to engraftment and length of hospital stay did not appear to vary by age group (Table 4).Conclusion:We identify severe GI toxicities including alimentary mucositis as a significant source of morbidity in patients receiving HDT-AHCT for lymphoma. Older age increases risk with 63% of the elderly experiencing ≥G3 GI toxicities and 72% experiencing FN. New therapies that have the potential to revive the alimentary tract repair mechanism will not only have impact on reducing severe oral/GI toxicities but will also enhance innate immunity by preventing translocation of bacteria into the bloodstream from the GI tract, as indicated by the association between SRRT and FN in our cohort of patients. [Display omitted] DisclosuresShouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria. Aggarwal: Kadmon: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Angiocrine Bioscience: Current Employment, Current holder of stock options in a privately-held company. Kavalerchik: Angiocrine Bioscience: Current Employment, Current holder of stock options in a privately-held company. Frazer: Angiocrine Bioscience: Current Employment, Current holder of stock options in a privately-held company. Finnegan: Angiocrine Bioscience: Current Employment, Current holder of stock options in a privately-held company. Fakhri: Loxo/Lilly: Research Funding.

Low-Coverage Whole Genome Sequencing of Cell-Free DNA From Immunosuppressed Cancer Patients Enables Tumor Fraction Determination and Reveals Relevant Copy Number Alterations.

Cell-free DNA (cfDNA) analysis is a minimally invasive method that can be used to detect genomic abnormalities by directly testing a blood sample. This method is particularly useful for immunosuppressed patients, who are at high risk of complications from tissue biopsy. The cfDNA tumor fraction (TF) varies greatly across cancer type and between patients. Thus, the detection of molecular alterations is highly dependent on the circulating TF. In our study, we aimed to calculate the TF and characterize the copy number aberration (CNA) profile of cfDNA from patients with rare malignancies occurring in immunosuppressed environments or immune-privileged sites. To accomplish this, we recruited 36 patients: 19 patients with non-Hodgkin lymphoma (NHL) who were either human immunodeficiency virus (HIV)-positive or organ transplant recipients, 5 HIV-positive lung cancer patients, and 12 patients with glioma. cfDNA was extracted from the patients’ plasma and sequenced using low-coverage whole genome sequencing (LC-WGS). The cfDNA TF was then calculated using the ichorCNA bioinformatic algorithm, based on the CNA profile. In parallel, we performed whole exome sequencing of patient tumor tissue and cfDNA samples with detectable TFs. We detected a cfDNA TF in 29% of immune-suppressed patients (one patient with lung cancer and six with systemic NHL), with a TF range from 8 to 70%. In these patients, the events detected in the CNA profile of cfDNA are well-known events associated with NHL and lung cancer. Moreover, cfDNA CNA profile correlated with the CNA profile of matched tumor tissue. No tumor-derived cfDNA was detected in the glioma patients. Our study shows that tumor genetic content is detectable in cfDNA from immunosuppressed patients with advanced NHL or lung cancer. LC-WGS is a time- and cost-effective method that can help select an appropriate strategy for performing extensive molecular analysis of cfDNA. This technique also enables characterization of CNAs in cfDNA when sufficient tumor content is available. Hence, this approach can be used to collect useful molecular information that is relevant to patient care.

Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.

Secondary Central Nervous System Lymphoma as a Complication from a Systemic Non-Hodgkin Lymphoma

Secondary central nervous system lymphoma is a complication from non-Hodgkin lymphoma not very well known. NHL can present in a variety of neurological clinical presentations varying from primary central nervous system lymphoma to complications from a systemic disease like metastasis or peripheral nerve involvement. We present a case of a 78-year-old male with Diffuse large B-cell lymphoma, treated with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. Six months later of the diagnosis, the patient presented to the emergency department, complaining of five days with progressive weakness in the left upper limb, and two days before the weakness developed in the left lower limb. On the neurologic examination with inattention, dysarthria, left central facial nerve palsy, severe weakness on the left hemibody with hyperreflexia, and left extensor plantar response. Brain Magnetic resonance imaging reported three metastatic lesions, with a final diagnosis of secondary central nervous system lymphoma.

Patients with Central Nervous System Lymphoma Undergoing Thiotepa, Busulfan, and Cyclophosphamide-Conditioned Autologous Stem Cell Transplantation Are at a Higher Risk for DNA Virus Infections Than Patients with Systemic Non-Hodgkin Lymphoma Receiving Traditional Conditioning

Background: Consolidative high-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC)-conditioning results in highly favorable outcomes in patients with central nervous system lymphoma (CNSL), but it is met with regimen-related toxicity. In a recent analysis, we noted a higher than expected incidence of DNA virus reactivations and several cases of serious viral organ disease (Scordo et al., BBMT 2017). We aimed to compare the incidence of DNA virus infections between patients with CNSL undergoing TBC-conditioned ASCT and those with systemic non-Hodgkin lymphoma (NHL) undergoing carmustine, etoposide, cytarabine, and melphalan (BEAM)-conditioned ASCT. We hypothesized that patients receiving TBC are at a higher risk for viral infections, and may require unique post-ASCT surveillance and follow-up.Methods: We retrospectively evaluated adults with chemosensitive CNSL undergoing TBC-conditioned ASCT and those with systemic, chemosensitive diffuse large B-cell lymphoma undergoing BEAM-conditioned ASCT between 2013 and 2016. We recorded all positive DNA virus reactivations infections by serum polymerase chain reaction (PCR) from the start of conditioning until 6 months post-ASCT, and then assessed for evidence of clinically relevant viral infection. We used a combined viral infection endpoint that included: cytomegalovirus (CMV), adenovirus (ADV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6). The cumulative incidences (CI) of combined viral PCR reactivation and clinically relevant viral infection were compared by the log rank test. Cox proportional hazard analysis was used to compare the risk of viral infection between both groups. Variables with p-values of < 0.2 in the univariate analysis were included in the multivariate analysis.Results: We evaluated 67 patients that underwent BEAM-conditioned and 54 patients that underwent TBC-conditioned ASCT. Baseline patient characteristics including age, gender, disease status, pre-ASCT absolute lymphocyte count (ALC), day +30 ALC, and steroid use during the first 30 days post-ASCT (prednisone 40 mg equivalent or higher) were similar between groups, and are shown in Table 1. There were 6 viral reactivations (5 HHV-6 and 1 CMV) among the BEAM patients (CI 9.1%), and 19 (1 ADV, 5 CMV, 13 HHV-6) among TBC patients (CI 35.2%), p=0.0003, as shown in Figure 1. No BEAM patients had a clinically significant viral infection, while there were 7 clinically significant viral infections (2 CMV, 1 ADV, 4 HHV-6) among TBC patients, p=0.0003, as shown in Figure 2. Among all patients in the univariate analysis, receiving TBC conditioning was the only characteristic that was associated with a higher risk of viral reactivation/infection, hazard-ratio (HR) 4.78 (1.91-12.0), p<0.001. In the multivariate analysis, receiving TBC conditioning was associated with an increased risk of viral reactivation [HR 5.43 (2.1-13.8), p<0.001], and advanced age [HR 0.97, (0.94-0.99), p=0.03] was associated with a slightly reduced risk of viral reactivation as shown in Table 2.Conclusions: Patients with CNSL undergoing TBC-conditioned ASCT are at an increased risk for DNA virus reactivation and clinically relevant DNA virus infections when compared to patients receiving BEAM. This may reflect the higher myeloablative intensity of TBC compared to BEAM, and possibly inherent differences in immune function in patients with CNSL compared to systemic NHL. These data highlight the need to implement early post-ASCT viral serum PCR monitoring for patients undergoing TBC-conditioned ASCT, with the goal of pre-emptive treatment of clinically relevant infections. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lympho- and Myeloproliferative Malignancies Occurring in the Same Host: Description of a Nationwide Discovery Cohort

Background: So far, myeloid and lymphoid malignancies have been considered as diseases with distinct pathogenetic mechanisms. However, recent studies (Frederiksen H et al, Blood 2011) have reported an increased risk of lymphoid malignancies in patients with chronic myeloproliferative neoplasms (MPN). Moreover, genomic studies in patients with angioimmunoblastic T-cell lymphoma (AITL) have revealed mutations in epigenetic modifier genes, such as IDH-2, TET2, and DNMT3A4, which are usually not seen in lymphomas, while they are commonly found in patients with myeloid diseases.Aim: The aim of our work was to identify and validate a nationwide cohort of patients, who were diagnosed with MPN as well as a lymphoid malignancy either simultaneously or sequentially. The establishment of this cohort is currently serving as a discovery platform for possible shared pathogenetic pathways in myeloid and lymphoid disease entities.Methods: Patients diagnosed with both MPN and a lymphoid malignancy within the period 1990-2015 were identified through the National Danish Pathology Registry. In order to minimize the occurrence of therapy related secondary myelodysplasias, only patients diagnosed either with both diseases simultaneously (i.e. within maximum half a year from each other) or with MPN first and later with a lymphoid malignancy were selected for further histopathological revision. Formalin-fixed paraffin-embedded tissue specimens from 16 different pathology departments throughout Denmark were collected. All specimens were reviewed by an experienced hematopathologist (TLP) at a tertiary referral center.Results: The algorithm leading to the establishment of the study cohort is shown in Figure 1. Ninety-seven patients fulfilled the described inclusion criteria. Demographically, 48.5% of the patients were females. The age at diagnosis ranged between 18.5-93.7 years and the median age at MPN diagnosis was 70.8 years (interquartile range 62.8-79.9 years). The average time between the diagnosis of MPN and that of lymphoid malignancy was 1.5 years and in the majority of the patients (90%) both diagnoses were established within 5 years from each other. The myeloid and lymphoid diagnoses for each individual patient are shown in Table 1. If one looks at mature, non-primary leukemic non-Hodgkin lymphomas, i.e. excluding lymphoblastic lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, and Hodgkin lymphoma, an excess of peripheral T-cell lymphomas (PTCL) was observed (17%), at a frequency almost double as high as the one expected in a Caucasian population-based non-Hodgkin lymphoma cohort (8-10%). Interestingly, most PTCL diagnoses were of AITL type.Conclusion: The establishment of this unique series of tissue specimens from patients with co-existing myelo- and lymphoid malignancies revealed, among primary systemic non-Hodgkin lymphomas, an excess of PTCL in general and AITL in particular. Genomic studies are ongoing to search for shared pathogenetic steps explaining the co-occurrence of MPN and lymphoid malignancies in the same host. [Display omitted] Disclosuresd'Amore:Nordic Nanovector: Other: Advisory Board; Les Laboratoires Servier: Honoraria, Other: Advisory Board; Takeda Pharma: Honoraria, Other: Advisory Board, Research Funding; Sanofi: Research Funding.

Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant

Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.

Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome

ObjectiveTo determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes.MethodsIn our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed.ResultsFour definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic PRF1 mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic UNC13D mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3).ConclusionsIn our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Allogenic Stem Cell Transplantation for Secondary CNS Lymphoma: A Retrospective Review of 21 Patients

INTRODUCTION: Allogeneic blood or marrow transplant (alloBMT) is widely used in relapsed/refractory systemic non-Hodgkin lymphoma. The graft-versus-tumor effect has been thought to be blunted by the immune privilege of the central nervous system (CNS). Communication between the CNS and the systemic immune system suggests that CNS disease could benefit from the graft versus lymphoma (GVL) effect provided by alloBMT. METHODS: The charts of all patients who received post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 2004 and October 2018 were reviewed. Survival statistics were calculated using the Kaplan-Meier method. Differences in time to death between groups were estimated using Cox proportional hazards models. RESULTS: Twenty-one patients with systemic lymphoma involving the CNS were identified. The median age was 59 years (range 24-73); 7 were over the age of 60 and 13 were male. Histology types included diffuse large B cell (71%), Burkitt (10%), T cell (10%), follicular (5%), and anaplastic large cell (5%). Prior to transplant, 12 patients were in complete remission, 9 had residual disease, and 5 had residual CNS disease by imaging. Induction therapy included CNS radiation therapy in 11 of 21 patients (52%) and high-dose methotrexate (HD-MTX) in 10 (48%). Only 1 patient was in first remission, with the remaining 20 in second or later remission. All but 1 patient received non-myeloablative conditioning using fludarabine, cyclophosphamide, and total-body irradiation; the other patient received busulfan and cyclophosphamide. Fifteen patients (71%) had haploidentical donors. Graft source was bone marrow in 18 patients and G-CSF-stimulated peripheral blood in 3. Median overall survival (OS) for the entire cohort was 1375 days (95% confidence interval [CI] 184-NR) and median progression free survival (PFS) was 1375 days (95% CI 112-NR). Three-year overall survival was 51% (95% CI 27-71%). The cumulative incidence of relapse was 29% (95% CI 9-49%) at 3 years, and non-relapse mortality was 20% (95% CI 2-38%) at 1 year. Of the 6 patients who relapsed, 2 were CNS only, 2 were systemic only, and 2 were combined CNS / systemic. There were 2 cases of grade III-IV acute GVHD and 1 case of chronic GVHD involving the mouth. Univariable analysis revealed no predictors of survival in our small data set: age &gt; 60 (hazard ratio [HR] 1.48, 95% CI 0.42-5.29, p-value 0.54), haploidentical donor (HR 4.2, 95% CI 0.53-33.66, p-value 0.17), residual disease (HR 1.3, CI 0.37-4.52, p-value 0.68), and prior CNS radiation (HR 1.5, 95% CI 0.42-5.31, p-value 0.53). DISCUSSION: Allogeneic BMT with non-myeloablative conditioning is potentially curative in patients with secondary CNS lymphoma. Post-transplant cyclophosphamide is well tolerated in this older group. Myeloablative conditioning directed at the CNS is not required for long-term survival. Given its biologic plausibility and potential as a viable treatment option in certain patient populations, the role of alloBMT in CNS lymphoma deserves further investigation. Figure Disclosures Wagner-Johnston: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy.

A Phase 2 Study of MT-3724 to Evaluate Safety, Pharmacodynamics and Efficacy of MT-3724 for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin Lymphoma (NHL) accounting for approximately 30-40% of NHL cases. Approximately 40% of all newly diagnosed DLBCL patients are either refractory or relapsed following initial response to therapy and represent a population with high unmet need for new therapeutic strategies to achieve or regain disease remission. Because of the near ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop compounds with novel mechanisms of action targeting CD20. However, CD20's non-internalizing nature has, to date, leveraged only cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity to which resistance can arise and has impeded the development of agents that internalize a cytotoxic payload. MT-3724 is a novel engineered toxin body designed to overcome this limitation by combining the specific target selectivity of a single chain variable fragment with the lethality of a genetically fused Shiga-like toxin A subunit that facilitates both internalization and cell killing by inactivating ribosomal protein synthesis. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro (IC50 &lt;1 nM) and in CB17 SCID and PDX mice (Rajagopalan 2016; Huang 2018). As a direct-kill immunotoxin against CD20, MT-3724 has achieved clinical response in subjects with relapsed NHL regardless of acquired resistance to other treatments. Thus, MT-3724 could be a valuable addition to the armamentarium of treating DLBCL. Study Design and Methods: MT-3724 is being evaluated in this Phase 2 study as monotherapy (NCT02361346) in adult subjects with histologically confirmed, relapsed or refractory DLBCL. The primary objective is to determine the efficacy of MT-3724 as monotherapy based on the overall response rate (ORR) by the revised Lugano Classification for Lymphoma adjusted according to immunomodulatory therapy criteria (LYRIC), hereinafter referred to as "revised Lugano Criteria" (Cheson 2014, 2016). Overall response rate is defined as the proportion of subjects with either a complete response or a partial response as determined by independent, blinded central review. Secondary objectives include safety, progression‐free survival, investigator‐assessed ORR, duration of response, and overall survival as well as pharmacokinetics and pharmacodynamics, immunogenicity, and quality of life. To be eligible, patients must have histologically confirmed, relapsed or refractory DLBCL, have received at least 2 standard of care systemic NHL treatment regimens, and have measurable disease according to the revised Lugano criteria. Since rituximab and MT-3724 compete for the same CD20 domain, subjects must have serum rituximab levels &lt; 500 ng/mL before the start of treatment to allow adequate binding of MT-3724. This single arm phase 2 study is being conducted in three stages, where the first two stages will follow the Simon two-stage optimal design [Simon 1989]. Subjects will be enrolled in successive cohorts with each cohort evaluated for efficacy before opening the subsequent cohort, toward a total sample size of 100 subjects. Subjects will receive MT-3724 as an IV infusion over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. All subjects will be treated with a 50 µg/kg/dose of MT-3724, which was the recommended Phase 2 dose, as determined in the Phase 1/1b portion of the trial. Sites are open and recruiting in the US, Canada, and Europe. Disclosures Persky: Sandoz: Consultancy; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee. Musteata:Arensia EM: Other: Principal Investigator; Institute of Oncology: Employment. Strack:Molecular Templates, Inc.: Employment. Burnett:Molecular Templates, Inc.: Employment. Wilson:Molecular Templates, Inc.: Employment. Baetz:Bristol Meyers Squibb: Other: Advisory board; Merck: Other: Advisory board; Gilead: Other: Advisory board; Roche: Other: Advisory board.

Kikuchi-Fujimoto disease: a case report and the evaluation of diagnostic procedures

BackgroundKikuchi-Fujimoto disease, known as histiocytic necrotizing lymphadenitis, is a benign, self-limiting and systemic disorder involving lymph nodes with unknown aetiology. First reported in Japan, there has been an increase in its incidence globally. Because of its non-specific clinical features, the disease can be easily mistaken for other forms of lymphadenitis with a high rate of misdiagnosis and mistreatment, posing a considerable challenge.Case presentationA case of young Chinese woman with fever and cervical lymphadenopathy is presented. Physical examinations and imaging techniques were used to rule out common forms of lymphadenitis (e.g. cat-scratch disease and tuberculous lymphadenitis). Laboratory tests were then conducted to exclude others such as systemic lupus erythematosus and non-Hodgkin lymphoma. After Kikuchi-Fujimoto disease was identified, the patient was managed with symptomatic treatments. Our case was compared with relevant cases in the literature. A diagnostic flow chart was proposed to facilitate the diagnosis and treatment.ConclusionsWith its shared clinical features, Kikuchi-Fujimoto disease can be mistaken for other forms of lymphadenitis. A combined use of medical imaging and laboratory tests is the effective way to avoid misdiagnosis.