Cell non-Hodgkin Lymphoma Research Articles

P1203: THE OPTIMIZED HLH INFLAMMATORY (OHI) INDEX IDENTIFIES LYMPHOMA PATIENTS WITH UNEXPECTEDLY HIGH MORTALITY NOT RELATED TO DISEASE PROGRESSION

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). We recently developed a simplified diagnostic and prognostic index termed the ‘optimized HLH inflammatory’ (OHI) index comprising the combined elevation of sCD25 (> 3,900 U/mL) and serum ferritin (> 1,000 ng/mL), which in HM patients both identifies HLH and predicts mortality more accurately than conventional criteria for HLH. Aims: In this study, we examined whether mortality in our cohort is directly related to progressive malignancy vs. HLH-associated causes in OHI+ and OHI- patients. Methods: We performed a multicenter, retrospective study of patients with newly diagnosed Lymphoma from Israel, the USA, and Japan for whom sCD25 and ferritin levels were measured either as routine surveillance or during investigation for HLH classified patients by their OHI status. The International Prognostic Index, International Prognostic Score, and Follicular Lymphoma International Prognostic Index were used to estimate the predicted prognosis of T/B cell non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, and follicular Lymphoma, respectively. The predicted five-year overall survival was calculated for each patient based on the relevant prognostic index and compared between OHI+ and OHI- patients using the unpaired t-test. The actual survival at five years/last follow-up was recorded, as was the cause of death. Finally, the odds ratios (ORs) for observed vs. predicted mortality and HLH- vs. malignancy-related death were calculated using the Chi-square test. Results: 100 lymphoma patients were studied: 65% with B cell NHL, 18% with natural killer/ T cell lymphoma, 17% with Hodgkin’s Lymphoma; 37 were OHI+, and 63 were OHI-. The disease-relevant international prognostic index-predicted five-year survival did not differ between OHI + and OHI- patients (a mean of 58% n OHI+ and 57% in OHI- p = 0.62). However, the observed five-year survival in OHI+ patients was lower (12%) than predicted, reflecting a mortality incidence that was four times higher than predicted by the relevant prognostic score (OR 3.9; CI 1.3-12.1). By contrast, OHI- patients had better survival (79%) than predicted by their prognostic scores (OR 0.15; CI 0.07-0.34). More than half of the OHI+ patients died from non-malignant causes (39% multi-organ dysfunction or HLH, 18% infection), while most OHI- patients (92%) died from progressive malignancy. The likelihood of dying from multi-organ dysfunction or HLH was 26 times higher in OHI+ vs. OHI- patients (OR 26.2; CI 4.1-286.7). Image:Summary/Conclusion: OHI index status strongly correlated with mortality in patients with lymphoma within our cohort, and death in OHI+ patients was largely due to causes other than progressive malignancy. The OHI index appears to identify a harmful inflammatory state and deserves further prospective study.

P1103: INMIND: A PHASE 3 STUDY OF TAFASITAMAB PLUS LENALIDOMIDE AND RITUXIMAB VERSUS PLACEBO PLUS LENALIDOMIDE AND RITUXIMAB FOR RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA (FL) OR MARGINAL ZONE LYMPHOMA (MZL)

Background: Patients (pts) with indolent non-Hodgkin lymphoma (NHL) subtypes FL or MZL respond to first-line treatment but relapse is common; there is no standard treatment for pts with relapsed/refractory (R/R) FL or MZL. Tafasitamab (TAFA) is an Fc-engineered humanized monoclonal antibody (mAb) against CD19, which is broadly expressed in FL and MZL and regulates proliferation via B-cell receptor signaling. In preclinical studies, TAFA has shown activity against NHL cell lines in combination with rituximab (anti-CD20 mAb) and lenalidomide (LEN). TAFA monotherapy demonstrated promising clinical activity in a phase 2a study in pts with R/R NHL (NCT01685008), with an ORR of 29% (n/N=10/34) in pts with FL and 33% (n/N=3/9) in pts with MZL. In an ongoing phase 2, single-arm study (L-MIND, NCT02399085), TAFA + LEN followed by TAFA alone demonstrated an ORR of 57.5% (n/N=46/80) with CR of 40% (n/N=32/80) and median DOR of 34.6 mo (95% CI: 26.1–NR), in pts with R/R diffuse large B-cell lymphoma (FDA approved indication). These observations suggest a potential clinical benefit of TAFA + LEN and rituximab for pts with R/R FL or MZL. Aims: Phase 3 double-blind, placebo-controlled, randomized study designed to investigate whether TAFA + LEN and rituximab provides improved clinical benefit compared with LEN and rituximab in pts with R/R FL or MZL. Methods: Pts will be randomized 1:1 to receive TAFA (12 mg/kg IV on days 1, 8, 15, and 22 of 28-day cycle [cycles 1–3], then days 1 and 15 [cycles 4–12]) + LEN (20 mg PO QD [or starting dose 10 mg PO QD if creatinine clearance ≥30 to <60 mL/min], days 1–21/cycle for 12 cycles) and rituximab (375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, then day 1 of cycles 2–5), or placebo (0.9% saline solution IV) + LEN and rituximab. Stratification will include progression of disease within 24 mo (FL; yes vs no), refractoriness to prior anti-CD20 mAb therapy (FL; yes vs no), and number of prior lines of therapy (FL or MZL; <2 vs ≥2). Radiological (PET) assessment will be performed at baseline, every 12 (± 2) weeks in year 1, 16 (± 2) weeks in years 2–3, and 24 (± 3) weeks in years 4–6; additional assessment performed within 4 (± 2) weeks if progressive disease confirmed before end-of-treatment (EOT) visit. The primary study endpoint is PFS (investigator assessed [INV] by Lugano 2014 criteria) for pts with FL. Key secondary endpoints are PFS (INV) in the overall population (FL and MZL), PET-CR rate (INV) at EOT (90 days after last treatment) and OS in pts with FL. Other secondary endpoints include PET-CR rate (INV) at EOT and OS in the overall population, and ORR (INV), DOR (INV), health related quality of life, safety, and minimum residual disease-negativity rate at EOT in FL and the overall population. Inclusion criteria include age ≥18 y, histologically confirmed FL (grade 1, 2, or 3a) or MZL (nodal, splenic, or extranodal), documented R/R disease, ≥1 prior systemic anti-CD20 therapy (including anti-CD20 refractory disease), ECOG PS ≤2, adequate systemic organ function, and high tumor burden (per GELF criteria). Exclusion criteria include prior rituximab + LEN treatment, history of radiotherapy for other diseases (≥25% of bone marrow), nonhematologic malignancy, congestive heart failure (LVEF <50%), active systemic infection, known CNS lymphoma, or severe immunocompromised state. inMIND (NCT04680052, EudraCT2020-004407-13) is currently enrolling pts; planned enrollment is 528 pts with R/R FL and 60–90 pts with R/R MZL across North America, Europe, and Asia Pacific. Results: Not applicable. Summary/Conclusion: Not applicable.

Texture analysis of conventional magnetic resonance imaging and diffusion-weighted imaging for distinguishing sinonasal non-Hodgkin's lymphoma from squamous cell carcinoma.

To evaluate the value of texture analysis (TA) of conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in the differential diagnosis between sinonasal non-Hodgkin's lymphoma (NHL) and squamous cell carcinoma (SCC). Forty-two patients with sinonasal SCC and 30 patients with NHL were retrospectively enrolled. TAs were performed on T2-weighted image (T2WI), apparent diffusion coefficient (ADC) and contrast-enhanced T1-weighted image (T1WI). Texture parameters, including mean value, skewness, kurtosis, entropy and uniformity were obtained and compared between sinonasal SCC and NHL groups. Receiver-operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic value and identify the independent TA parameters. The mean value and entropy of ADC, and mean value of contrast-enhanced T1WI were significantly lower in the sinonasal NHL group than those in the SCC group (all P < 0.05). ROC analysis indicated that the entropy of ADC had the best diagnostic performance (AUC 0.832; Sensitivity 0.95; Specificity 0.67; Cutoff value 6.522). Logistic regression analysis showed that the entropy of ADC (P = 0.002, OR = 26.990) was the independent parameter for differentiating sinonasal NHL from SCC. TA parameters of conventional MRI and DWI, particularly the entropy value of ADC, might be useful in the differentiating diagnosis between sinonasal NHL and SCC.

Abstract 1759: PRO1160, a novel CD70-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse models of renal cell carcinoma and non-Hodgkin lymphoma

Abstract PRO1160 is an antibody-drug conjugate directed toward CD70, an antigen that is aberrantly overexpressed in multiple hematologic malignancies and carcinomas with limited normal tissue expression. PRO1160 is comprised of a 1) human monoclonal antibody that selectively binds to CD70, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. Upon binding to CD70 on the surface of malignant cells, PRO1160 is internalized and exatecan released through enzymatic cleavage of the linker. Exatecan blocks the ligation step of the cell cycle and generates DNA single- and double-strand breaks, which leads to cell death. PRO1160 demonstrated robust anti-tumor activity, in vitro and in vivo. In multiple cell-derived xenograft mouse models, PRO1160 demonstrated more potent tumor growth inhibition compared to an MMAE-conjugated ADC with the same parent antibody. PRO1160 was well tolerated in mice with no to minimal impact on body weight gain. The in vivo pharmacokinetics in rats showed that PRO1160 is stable in circulation. These nonclinical data suggest the potential for a broad therapeutic window and further development of PRO1160 is warranted. PRO1160 has the potential for an expanded therapeutic index. PRO1160 is being developed for the potential treatment of patients with CD70-expressing hematologic and solid tumor cancers. Citation Format: Lei Wang, Haidong Liu, Xiao Shang, Tae Han, Baiteng Zhao. PRO1160, a novel CD70-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse models of renal cell carcinoma and non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1759.

Abstract 6303: Activity and tolerability of combination of venetoclax with the Aurora kinase B Inhibitor AZD2811 in preclinical diffuse large B-cell lymphoma models

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) and the most common form of adult lymphoma. Despite efforts to develop new therapies, the standard of care for DLBCL remains chemotherapy based. The current standard of care is comprised of a regimen of 4 drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone) combined with immunotherapy using a chimeric mAb against the protein CD20 (rituximab), R-CHOP. Unfortunately only 50 to 60% of patients with DLBCL achieve and maintain complete remission after first-line therapy and 40 to 50 % relapse or have refractory disease. In addition, the average age at the time of diagnosis for DLBCL is 64 which makes intensive chemotherapy challenging. Therefore, the development of new treatment options is critical. We explored preclinical activity of AZD2811 nanoparticle, a potent and selective inhibitor of Aurora B kinase combined with venetoclax, an inhibitor of BCL2 currently used as standard of care in treatment of Haematological cancers, in B-Cell non-Hodgkin lymphoma models. Twenty five B-cell NHL cell lines including 11 Diffuse Large B-cell Lymphoma (DLBCL) cell lines were exposed to a 7 x 7 matrix of AZD2811 and venetoclax for 72 hrs. Cell viability was assessed using Celltiter-glo. Strong combination activity (HSA &amp;gt; 0.1 and combination Emax &amp;gt; 0.5) was observed in 6 cell lines including 2 DLBCL cell lines (WSU-DLCL2 and KARPAS_422). Moreover, pre-treatment with pan caspase inhibitor Q-VD-OPH, increased cell viability in cells treated with the combination. Next we explored the significant gene expression and mutation biomarkers (effect size &amp;gt; 1, p &amp;lt; 0.05) for this combination associated with Bliss and combination Emax in B-cell NHL cell lines. We found downregulation of 4 genes (FLT4, TIE1, PRKN) and mutations in 2 genes (EP300 and PTEN) to be associated with Bliss score and upregulation of one gene (FGR) associated with combination Emax. In vivo, antitumor activity of AZD2811 combined with venetoclax was assessed in mice bearing WSU-DLCL2luc xenografts. Once weekly intravenous administration of 25 mg/kg AZD2811 resulted in a statistically significant tumor growth inhibition (TGI) of 74%, while daily oral gavage of 100 mg/kg venetoclax resulted in 49% TGI but failed to reach statistical significance. While both monotherapies were unable to prevent progressive tumor growth, a combination dosing regimen of AZD2811 and venetoclax drove progressive tumor regression resulting in statistically significant complete regression (98% regression) by the third week of dosing. These results suggest combining AZD2811 with venetoclax has potential to be active in DLBCL patients. Citation Format: Azadeh Cheraghchi-Bashi, Brandon Willis, Kevin. Mongeon, Jacob Gordon, Krishna Bulusu, Elizabeth Coker, Patricia Jaaks, Mathew Garnett, Jerome Mettetal. Activity and tolerability of combination of venetoclax with the Aurora kinase B Inhibitor AZD2811 in preclinical diffuse large B-cell lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6303.

Mucosal-Associated Invariant T Cells in T-Cell Non-Hodgkin Lymphomas: A Case Series.

Simple SummaryMucosal-associated invariant T (MAIT) cells are a subgroup of T lymphocytes whose role has recently been investigated in several types of diseases, including cancer. However, little is known about these cells in lymphomas. In this case series, we investigated the presence of MAIT cells in biopsies obtained from patients diagnosed with T-cell non-Hodgkin lymphomas, uncommon hematological malignancies with often not clearly defined etiopathology.Background: Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T lymphocytes expressing a semi-invariant α/β T-cell receptor (TCR). The physiological functions of these cells, which are particularly abundant in normal liver and mucosal sites, have become clear only in recent years, but their role in most human diseases is still unknown. Since the cellular origin and etiopathogenesis of most T-lymphomas are still elusive, we decided to explore the presence of MAIT cells in biopsies from these neoplasms. Methods: Sixteen biopsies obtained from patients with a T-cell lymphoma diagnosis were analyzed via immunofluorescence staining using an anti-Vα7.2 antibody and the MR1-antigen tetramer. Positive cases were subjected to a polymerase chain reaction for the detection of Vα7.2–Jα33, Vα7.2–Jα20, or Vα7.2–Jα12 rearrangements, followed by sequencing of the CDR3α region. Results: CD3+/Vα7.2+ and CD3+/MR1-Ag-tetramer+ cells were found in 4 of 16 samples analyzed. The identification of specific TCR rearrangements confirmed the presence of these cells in all four samples. PCR and sequencing results documented the presence of multiple clones of MAIT cells in each positive sample. Conclusions: MAIT cells are frequently found in T-cell lymphomas. More in-depth studies and a larger number of samples are needed to better clarify the contribution of MAIT cells to this rare neoplasm.

The Role of NOTCH1, GATA3, and c-MYC in T Cell Non-Hodgkin Lymphomas.

Simple SummaryPeripheral T cell lymphomas (PTCLs) comprise 10–15% of all non-Hodgkin lymphomas, and are more aggressive with worse prognosis. Due to their rarity and significant molecular abnormalities, the pathogenesis of PTCLs is not well understood. The expressions of NOTCH1, GATA3, and c-MYC have been linked to a poorer prognosis in PTCL, and are implicated in downstream processes. The aims of this review are to elucidate the role of NOTCH1, GATA3, and c-MYC in patients with PTCLs to provide additional information about the disease’s pathogenesis and to investigate the master regulator between these genes that will provide a basis for new therapeutic strategies and improve PTCL patients’ survival rates. NOTCH1 greatly influences the progression, pathogenicity, and development of PTCLs. Because NOTCH signalling does not rely on enzymatic signal amplification, and all Notch ligands and receptors include extracellular domains that are essential for receptor binding and activation, making them accessible to circulating therapies and targeting for different therapeutic strategies.Lymphomas are heterogeneous malignant tumours of white blood cells characterised by the aberrant proliferation of mature lymphoid cells or their precursors. Lymphomas are classified into main types depending on the histopathologic evidence of biopsy taken from an enlarged lymph node, progress stages, treatment strategies, and outcomes: Hodgkin and non-Hodgkin lymphoma (NHL). Moreover, lymphomas can be further divided into subtypes depending on the cell origin, and immunophenotypic and genetic aberrations. Many factors play vital roles in the progression, pathogenicity, incidence, and mortality rate of lymphomas. Among NHLs, peripheral T cell lymphomas (PTCLs) are rare lymphoid malignancies, that have various cellular morphology and genetic mutations. The clinical presentations are usually observed at the advanced stage of the disease. Many recent studies have reported that the expressions of NOTCH1, GATA3, and c-MYC are associated with poorer prognosis in PTCL and are involved in downstream activities. However, questions have been raised about the pathological relationship between these factors in PTCLs. Therefore, in this review, we investigate the role and relationship of the NOTCH1 pathway, transcriptional factor GATA3 and proto-oncogene c-MYC in normal T cell development and malignant PTCL subtypes.

Clinical laboratory mutation analysis performed on aggressive B cell non-Hodgkin lymphoma patient biopsies.

e19561 Background: Results from comprehensive genomic analysis performed on aggressive B cell non-Hodgkin lymphomas (aBNHL) patient (pt) biopsies (bx) have identified mutations (mut) which may be predictive of pt survival. However, results from mut analysis (MA) performed on aBNHL pt bx in clinical laboratories are not well-described. Methods: Bx diagnostic of non-Burkitt aBNHL obtained from 7/2015-2/2021 with MA performed in the Penn Center for Personalized Diagnostics clinical laboratory using 3 consecutive versions of lymphoma sequencing panels were retrospectively analyzed. Mut tested varied by panel. Mut detected with variant allele frequency (VAF) ≥10% were included. Results: MA was performed on 293 aBNHL pt bx with a successful assay for 270 (7.8% failure rate). Request for MA was made by interpreting hematopathologist 93% and treating clinician 7%. Median turnaround time (TAT) from receipt of bx to result report was 18 (range 8-53) days. Notable pt characteristics included prior/concurrent indolent lymphoma (IL) 31% and prior systemic therapy received for IL and/or aBNHL 38%. Notable bx characteristics included bx type paraffin-embedded tissue 85% and bone marrow 12%, histologic classification diffuse large B cell lymphoma 86% and high grade B cell lymphoma 13%, cell of origin (COO) by Hans algorithm non-germinal center B (non-GCB) 51% and GCB 44%, known double expressor lymphoma 30%, known MYC rearrangement 18%, known double hit lymphoma 9% and any mut detected with VAF ≥10% 82%. Number and percentage of mut occurring in ≥10% of bx (minimum tested bx for mut ≥92) with associated COO are listed in the table. Subset analysis of 147 bx obtained from pts with newly-diagnosed aBNHL (15% with previously-untreated IL) had similar bx characteristics to the entire population were analyzed for the presence of mut reported in poor-prognosis COO-associated classifications: Cluster 5 for non-GCB and Cluster 3 for GCB (PMID: 29713087), double-hit signature (DHITsig) for GCB (PMID: 30523716) and molecular high grade (MHG) for GCB (PMID: 30523719). For 77 non-GCB bx, 19% had Cluster 5 mut. For 59 GCB bx, 56% had at least one of Cluster 3, DHITsig or MHG mut. Conclusions: Clinical laboratory MA performed on nearly 300 aBNHL pt bx was highly successful with a short TAT and demonstrated recurrent gene mut associated with aBNHL development. In the subset of bx from previously-untreated pts, MA identified mut associated with poor-prognosis genetic subtypes of aBNHL.[Table: see text]

The utility of the novel optimized HLH inflammatory (OHI) index for predicting the risk for mortality and causes of death in lymphoma.

7570 Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). We recently developed a simplified diagnostic and prognostic index termed the ‘optimized HLH inflammatory’ (OHI) index comprising the combined elevation of sCD25 ( &gt; 3,900 U/mL) and serum ferritin ( &gt; 1,000 ng/mL), which in HM patients both identifies HLH and predicts mortality more accurately than conventional criteria for HLH. In this study, we examined whether mortality in our cohort is directly related to progressive malignancy vs. HLH-associated causes in OHI+ and OHI- patients. Methods: We performed a multicenter, retrospective study of patients with newly diagnosed lymphoma from Israel, the USA, and Japan for whom sCD25 and ferritin levels were measured either as routine surveillance or during investigation for HLH and classified patients by their OHI status. The International Prognostic Index, International Prognostic Score, and Follicular Lymphoma International Prognostic Index were used to estimate the predicted prognosis of T/B cell non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, and follicular lymphoma, respectively. Predicted five-year overall survival was calculated based on the relevant prognostic index and was compared between OHI+ and OHI- patients using the unpaired t-test. The actual survival at five years/last follow-up was recorded, as was the cause of death. The odds ratios (ORs) for observed vs. predicted mortality, and for HLH- vs. malignancy-related death were calculated using the Chi-square test. Results: 100 lymphoma patients were studied: 65% with B cell NHL, 18% with natural killer/ T cell lymphoma, 17% with Hodgkin’s lymphoma; 37 were OHI+, and 63 were OHI-. The disease-relevant international prognostic index-predicted five-year survival did not differ between OHI + and OHI- patients (a mean of 58% n OHI+ and 57% in OHI- p = 0.62). However, the observed five-year survival in OHI+ patients was lower (12%) than predicted, reflecting a mortality incidence that was four times higher than predicted by the relevant prognostic score (OR 3.9; CI 1.3-12.1). By contrast, OHI- patients had better survival (79%) than predicted by their prognostic scores (OR 0.15; CI 0.07-0.34). More than half of the OHI+ patients died from non-malignant causes (39% multi-organ dysfunction or HLH, 18% infection), while most OHI- patients (92%) died from progressive malignancy. The likelihood of dying from multi-organ dysfunction or HLH was 26 times higher in OHI+ vs. OHI- patients (OR 26.2; CI 4.1-286.7). Conclusions: OHI index status strongly correlated with mortality in patients with lymphoma within our cohort, and death in OHI+ patients was largely due to causes other than progressive malignancy. The OHI index appears to identify a harmful inflammatory state and deserves further prospective study.

Chest Wall Mass as the Dominant Presentation of Low-Grade B-Cell Non-Hodgkin's Lymphoma: A Case Report.

Low-grade B cell non-Hodgkin's lymphoma with dominant presentation of chest wall mass is presented in this report. The patient, a 65-year-old woman, presented with pain, rising skin temperature and redness, and swelling on the right lower chest wall. The histopathological examination revealed non-Hodgkin's lymphoma; the staging fluorodeoxyglucose-positron emission tomography/computed tomography demonstrated stage IVE disease, with hypermetabolic active disease in the right anterolateral chest wall in the form of large soft tissue mass and subcutaneous tissue with underlying bony erosion with extension into right anterior cardiophrenic space and superiorly up to right second costosternal region along the right internal mammary vessels. This was along with hypermetabolic active right axillary, right supraclavicular and left inguinal lymphadenopathy, and thickened hypermetabolic posterior right pleura with ametabolic right-sided pleural effusion. Bone marrow biopsy revealed uninvolved bone marrow. On follow-up after eight cycles of R-CHOP chemotherapy, the mass had completely resolved on contrast-enhanced computed tomography.

Predictors of severe CRS in longitudinal CAR T-cell clinical trial data.

2540 Background: Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor (CAR) T-cell therapy and there is a limited understanding of its risk factors. Known markers of severe CRS lack specificity or require central lab facilities, making them unsuitable for safety surveillance during trials. Using data from anti-CD19 CAR-T trials from the Medidata Enterprise Data Store (MEDS) we analyzed laboratory tests with repeated measurements to identify differences in trends that persist across a variety of study designs, sponsors and indications. Our aim was to capture the dynamic response to lymphodepletion (LD) and CAR-T infusion events in the time course values of laboratory markers and compare these in the severe CRS (grade 3 and higher) and non severe CRS groups. Methods: Subjects in the anti-CD19 CAR-T trials obtained from MEDS had relapsed or refractory disease in one of the following: B Acute Lymphoblastic Leukemia (B-ALL), Mantle Cell Lymphoma (MCL), Non-Hodgkin Lymphoma (NHL) and Diffuse Large B-cell Lymphoma (DLBCL). Laboratory markers with repeated measurements across all studies were included in the analysis. Response to LD, CAR-T infusion and the onset of hematologic recovery was modeled with piecewise linear splines with knots at the boundaries of the pre LD (-18d to LD), the LD - infusion and post infusion (1d to 6d and 6d to 18d) intervals using linear mixed effects regression. Results: The dataset consisted of 542 patients: 24.1% B-ALL, 44.4% NHL, 16.8% MCL, 14.6% DLBCL; mean age 54.8 (SE = 0.021) years, 67.7% males. 27.3% had CRS 3+ with a median time-to-event of 4.5 days. Average rates of change (units per day) for the severe CRS subjects in the pre LD, LD-infusion and post infusion intervals relative to the rest are shown (table). None of the markers had a significant relative rate of change prior to LD. The average change in Albumin, Platelets and Hematocrit was consistently lower in severe CRS patients. Conclusions: Longitudinal laboratory marker data may be used to derive predictors of severe CRS in patients undergoing anti-CD19 CAR-T therapy. While some of the laboratory markers discussed above corroborate earlier findings, modeling the pre and post infusion kinetics can yield novel markers with improved precision in severe CRS prediction and better patient safety. [Table: see text]

InMIND: A phase 3 study of tafasitamab plus lenalidomide and rituximab versus placebo plus lenalidomide and rituximab for relapsed/refractory follicular or marginal zone lymphoma.

TPS7583 Background: Most patients with the indolent non-Hodgkin lymphoma (NHL) subtypes follicular (FL) or marginal zone (MZL) respond to first-line treatment but relapse is common, and there is no single standard treatment for patients (pts) with relapsed/refractory (R/R) FL or MZL. Tafasitamab (TAFA) is an Fc-engineered humanized monoclonal antibody (mAb) against CD19 which is broadly expressed in FL and MZL, and regulates B-cell proliferation via B-cell receptor signaling. In preclinical studies, TAFA has shown activity against NHL cell lines in combination with rituximab (anti-CD20 mAb) and lenalidomide (LEN). Monotherapy with TAFA has shown promising clinical activity in a phase 2a study in pts with R/R NHL (NCT01685008), with an ORR of 29% (n/N = 10/34) in pts with FL and 33% (n/N = 3/9) in pts with MZL. In an ongoing phase 2, single-arm study (L-MIND, NCT02399085), TAFA + LEN followed by TAFA alone demonstrated an ORR of 57.5% (n/N = 46/80) in pts with R/R diffuse large B-cell lymphoma (FDA approved indication). These preclinical and clinical observations from phase 2 trials suggest a potential clinical benefit of TAFA + LEN and rituximab for pts with R/R FL or MZL. Methods: This phase 3 double-blind, placebo-controlled, randomized study is designed to investigate whether TAFA + LEN and rituximab provides improved clinical benefit compared with LEN and rituximab in pts with R/R FL or R/R MZL. Pts will be randomized 1:1 to receive TAFA (12 mg/kg IV on days 1, 8, 15, and 22 of a 28-day cycle [cycles 1–3], then days 1 and 15 [cycles 4–12]) + LEN (20 mg PO QD, days 1–21/cycle for 12 cycles) and rituximab (375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, then day 1 of cycles 2–5), or placebo (0.9% saline solution IV) + LEN and rituximab. Stratified randomization will be performed separately for pts with R/R FL and R/R MZL. The primary study endpoint is PFS (investigator assessed [INV] by Lugano 2014 criteria) for pts with FL. Key secondary endpoints are PFS (INV) in overall population (FL and MZL), PET-CR rate (INV) at end of treatment (90 days after last treatment) and OS in pts with FL. Inclusion criteria include age ≥18 y, histologically confirmed FL (grade 1, 2, or 3a) or MZL (nodal, splenic, or extranodal), documented R/R disease, ≥1 prior systemic anti-CD20 therapy (including pts with anti-CD20 refractory disease), ECOG PS ≤2, adequate systemic organ function, and high tumor burden (per GELF criteria). Exclusion criteria include prior rituximab + LEN treatment, history of radiotherapy for other diseases (≥25% of bone marrow), nonhematologic malignancy, congestive heart failure (LVEF &lt; 50%), active systemic infection, known CNS lymphoma, or severe immunocompromised state. inMIND (NCT04680052, EudraCT2020-004407-13) is currently enrolling pts; planned enrollment is 528 pts with R/R FL and 60–90 pts with R/R MZL across North America, Europe, and Asia Pacific. Clinical trial information: NCT04680052 / EudraCT2020-004407-13.

Clinical features, predictors and outcome of posterior reversible encephalopathy syndrome (PRES) in children with hematolymphoid malignancies.

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological syndrome characterized by a neurotoxic state with vasogenic edema. We studied the clinical profile, predisposing factors, imaging features, and outcome of PRES in children receiving treatment for hematolymphoid malignancies. Retrospective analysis of the clinical data and radiological features of patients with PRES diagnosed between June 2014 and December 2019. Fifty-two patients (boy: girl = 3:1) were diagnosed with PRES during the study period with a median age of 11 (range:1-15) years. Primary diagnoses were acute leukemias (n = 42), non-Hodgkin lymphoma (n = 8), Hodgkin lymphoma (n = 1), and Langerhan's cell histiocytosis (n = 1). Most common presenting symptoms were seizures (n = 52), altered sensorium (n = 42), headache (n = 39), and visual disturbances (n = 8). Hypertension at time of diagnosis was noted in 50 (96%) patients. Classic hyper-intense lesions on FLAIR and diffusion weighed (DW) images were noted in parieto-occipital region in 39 patients (75%). Central PRES involving basal ganglia was seen in 3 (6%) patients. A subsequent neuro-imaging was done in 18 patients (MRI: 13; CT: 5) at a median interval of 16.2weeks. Neurological sequelae were observed in 10 (19%) patients, whereas 1 succumbed due to PRES. PRES is an important clinico-radiological syndrome in patients undergoing chemotherapy for hematological malignancies. High index of suspicion, early diffusion-weighted images on MRI in children with classic symptoms help in early diagnosis. A small minority of patients may develop long-term sequelae.

Gingival and alveolar ridge overgrowths: A histopathological evaluation from Saudi Arabia

BackgroundFocal tissue overgrowths on the gingiva and edentulous alveolar ridge are occasionally perplexing to periodontists, owing to the wide variety of differential diagnoses that may be responsible. As such, biopsy and microscopy are often required to establish a definitive diagnosis. The present study aimed to retrospectively evaluate focal gingival and alveolar ridge overgrowths at a single institution in Saudi Arabia. Materials and MethodsHistopathology reports and slides from patients presenting to King Saud University Hospital between 1984 and 2016, particularly those with focal gingival enlargements other than those due to gingivitis and periodontitis, were collected and analyzed based on age, sex, and location. ResultsA total of 624 patient records were evaluated, with a mean age of 35 years (range, 1 week–91 years), peak incidence in the third decade of life, male-to-female ratio of 1:1.4, and a slightly higher prevalence of lesions in the mandible. The majority (88%) of the lesions were reactive or hyperplastic, followed by malignant (10%) and benign (2%) tumors. A total of 24 distinct histological entities were diagnosed across the three groups. The most common histologically diagnosed lesions were pyogenic granulomas (38%), fibromas (33%), peripheral ossifying fibromas (9%), squamous cell carcinomas (7%), peripheral giant cell granulomas (6%), neurofibromas (1%), and non-Hodgkin lymphomas (1%). ConclusionSimilar to what has been reported by most previous studies, reactive hyperplastic lesions were the most prevalent focal overgrowths found in the gingival and alveolar mucosae. Carcinomas at these sites, however, may be an understated but significant clinical and epidemiological problem in Saudi Arabia. Gingival and alveolar ridge lumps can serve as a nexus for cooperation between periodontologists and oral pathologists to improve diagnosis, disease classification, and patient management.

Genetic Variants of MicroRNA-146a and MicroRNA-196a2 are Associated with Poor Outcome but not Risk of High-Grade B- Cell Non-Hodgkin Lymphoma

Genetic Variants of MicroRNA-146a and MicroRNA-196a2 are Associated with Poor Outcome but not Risk of High-Grade B- Cell Non-Hodgkin Lymphoma

B-cell activating factor (BAFF), BAFF promoter and BAFF receptor allelic variants in hepatitis C virus related Cryoglobulinemic Vasculitis and Non-Hodgkin's Lymphoma.

Cryoglobulinemic Vasculitis (CV) is an autoimmune/lymphoproliferative disorder associated with HCV infection that in 5%-10% of cases evolves into a B cell Non-Hodgkin's Lymphoma (NHL). B-cell activating factor (BAFF) is a key regulator in B-cell development and survival. Particular genetic variants are responsible for BAFF signaling impairment in autoimmune and neoplastic diseases. We evaluated BAFF and BAFF-receptor (BAFF-R) polymorphisms in order to determine if they predispose to HCV-related CV and NHL. The analysis was performed on 416 HCV-chronically infected patients: 136 HCV without signs/symptoms of lymphoproliferations/autoimmunity (HCV), 166 HCV with CV (HCV-CV) and 114 HCV with NHL (HCV-NHL). Rs9514828 SNP on BAFF promoter, rs61756766 on BAFF-R and rs12428930 on the BAFF gene were evaluated by Real-Time PCR. Concerning rs9514828, the frequency of C/T genotype was significantly higher in HCV-CV than in HCV. The difference in the distribution of the T/T mutant genotype in HCV-CV compared to HCV was significant as well as the distribution of C/T and T/T genotype in HCV-NHL versus HCV. T minor allele was more frequent in HCV-NHL and HCV-CV than in HCV. The distribution of C/T + T/T (for the dominant model of penetrance C/T + T/T vs. C/C) was significantly higher in HCV-CV and HCV-NHL than in HCV. Genotyping of rs61756766 on BAFF-R coding gene, revealed C/T heterozygosis at a frequency of 11% in HCV-NHL versus 3% in HCV. The T minor allele frequency was higher in HCV-NHL than in HCV. No differences emerged by genotyping rs12428930 SNP on BAFF coding gene. Our results reinforce the hypothesis that BAFF/BAFF-R genetic pattern has a role in the pathogenesis of HCV-related lymphoproliferations. BAFF/BAFF-R variants could identify a risk haplotype for HCV related CV and NHL and a BAFF/BAFF-R genetic profile assessment could potentially contribute to tailoring anti-BAFF therapy by identifying patients with BAFF alterations in which the treatment could be more beneficial.

Elevated circulating myeloid-derived suppressor cells associated with poor prognosis in B-cell non-Hodgkin's lymphoma patients.

IntroductionMyeloid‐derived suppressor cells (MDSCs) are a heterogeneous cell population with the ability to suppress immune responses. MDSCs usually cluster in cancer, inflammation, and autoimmune diseases. Although there have been some studies on MDSCs in non‐Hodgkin lymphoma (NHL), the correlation between the peripheral levels of MDSCs in patients with various subtypes of B cell NHL and clinical features and prognosis remains inconclusive. This study aimed at the issue.Methods101 patients with B cell NHL and 15 age‐matched healthy controls were included in this study. Flow cytometric detection of monocytic‐MDSCs (M‐MDSCs) and granulocytic‐MDSCs (G‐MDSCs) was done.ResultsIn this study, we found that counts of circulating M‐MDSCs and G‐MDSCs were significantly increased in different clinical statuses of B‐NHL patients compared to healthy controls. Similarly, a significant increase in the levels of M‐MDSCs and G‐MDSCs was found among the diverse types of B‐NHL compared with healthy donors. Stratification studies indicated MDSCs expansion was closely associated with disease progression (tumor stage, LDH levels and B syndromes). Moreover, the overall survival time of patients with G‐MDSCs (%) ≥ 98.70% was shorter than patients with G‐MDSCs (%) < 98.70% in newly diagnosed B‐NHL subgroup, meanwhile, there was a significant difference in survival of patients with M‐MDSCs (%) ≥ 7.19% compared to patients with M‐MDSCs (%) < 7.19% in relapsed B‐NHL subgroup.ConclusionOur results suggested that M‐MDSCs and G‐MDSCs may be a potential and efficient index to evaluate the prognosis of B‐NHL patients.

Long-term efficacy of CAR-T cell therapy for patients with relapsed/refractory B cell non-Hodgkin lymphoma.

To evaluate the long-term efficacy of chimeric antigen receptor (CAR) T cell therapy in treatment of relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL). Clinical data of 27 patients with relapsed/refractory B-NHL treated with CAR-T cell in Bone Marrow Transplantation Center, the First Affiliated Hospital of Zhejiang University School of Medicine from June 2016 to June 2020 were analyzed. Patients were followed up to February 1, 2022. The overall survival rate, progression free survival (PFS) rate were evaluated by Kaplan-Meier analysis, and the adverse reactions were recorded. The median follow-up time of 27 patients was 32 (1, 56) months. The total response rate was 85.2% (23/27), the complete response rate was 63.0% (17/27), and the partial response rate was 22.2% (6/27). The 3-year overall survival rate was (50.0±10.1)%, and the PFS rate was (44.4±9.6)%. After CAR-T cell therapy, the overall survival and PFS of patients in the complete response group were significantly better than those in the non-complete response group [overall survival rate: (66.9±12.7)% vs. (20.0±12.6)%, P=0.01; PFS rate: (64.7±11.6)% vs. (10.0±9.5)%, P<0.01]. There was no significant difference in overall survival rate and PFS rate between CD19 targeted and CD19/CD22 dual-targeted CAR-T cell therapy (both P>0.05). Cytokine release syndrome developed in 92.6% (25/27) of patients, and 88.9% (24/27) of patients had grade Ⅲ-Ⅳ myelosuppression. Other adverse reactions include immune effector cell-associated neurotoxicity syndrome, hepatitis B virus activation, and lung or gastrointestinal infections. No long-term adverse reactions occurred. CAR-T cell therapy is effective for patients with relapsed/refractory B-NHL, and the adverse reactions are controllable. The patients who obtain complete response after CAR-T cell therapy or survive for one year after therapy may have better long-term survival.

An Unusual Presentation of Supraglottic Low-Grade B-Cell Non-Hodgkin's Lymphoma with Tracheostomal Myiasis.

60-year-old male patient presented with dysphagia and a change in voice for eight months. It was established after Direct laryngoscopy surgery and biopsy, that it was a low-grade B cell non-Hodgkin lymphoma. The primary lesion is resolved with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone regimen. Four months later, patient presented with a discharge and maggots at the tracheostomy site. Ifosfamide, Etoposide, Carboplatin was started after a secondary recurrence of disease progression. Hereby we infer this is an unusual case presentation, myiasis with lymphoma recurrence and tough exacting to the otolaryngologist as there are more chances of misdiagnosing as squamous cell carcinoma..

Surface-Functionalized Polymeric siRNA Nanoparticles for Tunable Targeting and Intracellular Delivery to Hematologic Cancer Cells.

To date, the application of RNA therapeutics to hematologic malignancies has been challenging owing to the resistance of blood cancer cells against conventional transfection methods. Herein, triple-targeting moiety-functionalized polymeric small interfering RNA (siRNA) nanoparticles were systematically developed for efficient targeted delivery of RNA therapeutics to hematologic cancer cells. Polymeric siRNAs were synthesized using rolling circle transcription and were surface-functionalized with three types of targeting moieties─a natural ligand and two additional combinations of cell-specific antibodies─for tunable targetability. As a proof of concept, the optimization of the hyaluronic acid/antibody conjugation ratio was performed for selective intracellular delivery to various non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Raji, Ramos, and Toledo cells) via receptor-mediated endocytosis. The engineered nanoparticles showed almost 10-fold enhanced NHL-specific intracellular delivery and induced significant in vitro anticancer effects. This multitargeted nanoparticle platform may effectively support the intracellular delivery of polymeric siRNA sequences, and thus promote therapeutic effects in hematopoietic malignancies.