Relapsed non-Hodgkin Lymphoma Research Articles

Risk assessment of cardiovascular adverse events with BTK inhibitors in hematological malignancies: Insights from FAERS.

12145 Background: Burton tyrosine Kinase inhibitors (BTKi) have revolutionized the care of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHL) – including relapsed/refractory mantle cell, ABC diffuse large B cell lymphoma and and lymphoplasmacytic lymphoma. Ibrutinib was the first BTKi to be approved. The newer covalent BTKi include acalabrutinib and zanubrutinib, both of which are approved for frontline and relapsed CLL as well as relapsed NHL. All these agents have cardiovascular adverse events. We aimed to assess the pharmacovigilance (PV), reporting rate, severity, and reaction outcomes of different approved BTKi in the CLL as cancer reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We analyzed cardiovascular events in 86,370 patients on BTKi. Cardiovascular event reports were submitted to FAERS between 2004-2023 and analyzed using the AERS Mine framework. We compared these incidences within different BTKI. We divided cardiovascular events to three categories: cardiac arrythmia, major coronary or vascular event (MACE) and pericardial complication including effusion or hemorrhage. Our primary composite endpoint was the PV of cardiovascular events caused by BTKI. To mitigate confounding, BTKI were analyzed as mutually exclusive cohorts: Ibrutinib (n = 79,278), acalabrutinib (5200), and zanubrutinib (1354). Two-way ANOVA testing was done to evaluate for statistical significance across the different groups. Results: Across the 86,370 patients on BTKI, we identified 8500 reports of cardiovascular events – ibrutinib (10.15%), acalabrutinib (5.73%), and Zanubrutinib (4.72%). Arrythmia risk was higher with ibrutinib (6.6%) compared to acalabrutinib (3.12%) and zanubrutinib (2.29%). The major difference in the groups was driven by atrial fibrillation (5.1% vs 2.1% vs 1.8%). The MACE rate was 2.79% vs. 2.4% vs. 2%, and pericardial events were 0.72% vs. 0.21% vs. 0.44% in the ibrutinib, acalabrutinib, and zanubrutinib groups, respectively. All the AEs were to have statistical significance (p = 0.011) across all the BTKI as mentioned in table 1. Conclusions: We report the prevalence rate of BTKI-related cardiovascular events in a large cohort of patients. Ibrutinib has demonstrated a higher incidence of toxicity, especially in cardiac arrythmias, while smaller but significant differences exist in other toxicities, including major cardiovascular events and pericardial effusion or hemorrhage. Patient selection and toxicity monitoring are important aspects of the care of these patients, who stay on these therapies for indefinite periods. [Table: see text]

A First in Human Phase I Trial (LS1681) of Abraxane/Rituximab 160 Nm Nanoparticle (AR160) in Relapsed Refractory B-Cell Lymphomas Including Transformed Follicular Lymphoma: A Final Report

Introduction: Nanotechnology for cancer therapy aims to increase drug delivery to tumor sites while lowering toxicity. AR160 is a novel 160 nm nano-immunoconjugate consisting of commercial grade nab-paclitaxel (NP) nanoparticles non-covalently coated with rituximab (R) for targeted delivery into tissues expressing CD20. The drug delivery system and clinical grade product was developed in the laboratory of Svetomir N. Markovic, M.D.,Ph.D. Single agent rituximab at a dose of 375 mg/m 2 in relapsed patients with aggressive lymphomas is not utilized and has limited activity in patients with multiple relapses. Taxanes (Younes 1995, Wilson 1995) have modest clinical activity as a single agent with overall response rates of 23% and 17%, respectively, when administered at doses of 200 mg/m 2 and 140 mg/m 2 in previously treated patients with non-Hodgkin lymphoma (NHL). We hypothesized that utilizing the targeted ability of rituximab that the AR160 taxane nanoparticle would have activity in relapsed B-cell NHL and offer a new class of agents for relapsed B-cell NHL. Methods: A 3+3 phase I clinical trial was conducted in patients with relapsed refractory non-Hodgkin lymphoma to determine the maximum tolerated dose of AR160 administered intravenously on days 1, 8, and 15 of a 28-day cycle. Patients were required to have had prior systemic treatment with no other therapy with clinical benefit. Patients with aggressive lymphoma were required to have a stem cell transplant if transplant eligible. AR160 was prepared on-site in the Mayo Clinic Cancer Center Research Pharmacy, and the product was reconstituted by mixing the two agents delivering as one combined infusion at a specific concentration. The starting dose level (DL1) was NP at 100mg/m 2 with R at 40 mg/m 2. These doses were significantly lower than standard doses. Disease evaluations were conducted after every 2 treatment cycles using CT based criteria from the revised 2014 Lugano Classification or PET scans. Patients were treated until disease progression or intolerability. Samples were collected for pharmacokinetic (PK) studies. Results: Nine (7 males and 2 females) patients with a median age of 61 (range 55-84 years) were enrolled (2 follicular lymphoma (FL), 1 previously transformed from FL to diffuse large B-cell lymphoma (DLBCL) followed by FL relapse, 1 high-grade B-cell lymphoma with MYC and BCL2 rearrangements transformed from FL, 1 transformed FL to DLBCL, 2 high-grade B-cell lymphoma with MYC and BCL2 rearrangements, 1 high-grade B-cell lymphoma NOS and 1 mantle cell lymphoma. The median number of prior treatments was 4 (range 3-16). At dose level 1, all 3 of the first 3 patients experienced grade 3 or 4 neutropenia (C1D15, C4D1, and C1D15) with the C4D1 a grade 4 and unlikely related. After the first three patients, de-escalation to dose level -1 was implemented per protocol with NP at 75 mg/m 2 and rituximab at 30 mg/m 2. There was one patient with a grade 3 non-hematological adverse event all possibly related to treatment (anorexia, diarrhea, and enterocolitis). There were 6 partial responses (71%), 1 complete response (14%) with high-grade B-cell lymphoma with MYC and BCL2 rearrangement, 1 stable disease with mantle cell lymphoma and 1 patient had progressive disease. Six of the 9 patients were alive with subsequent therapies. PK evaluation is pending. Conclusion: AR160 therapy is a novel drug delivery system incorporating significantly lower doses of paclitaxel and rituximab that is safe and demonstrates promising clinical activity in patients with low-grade and high-grade previously treated B-cell lymphomas. This principle of treatment is applicable to other disorders. Further clinical testing is warranted in these patient populations.

Efficacy and Safety of TLR2 Co-Stimulated CAR T Cells in CD19-Positive Lymphoid Malignancies with Central Nervous System Involvement

Background CD19 chimeric antigen receptor (CAR) T cell therapy showed remarkable remission rates in patients with refractory or relapsed (R/R) non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, data on outcomes of CAR T cell therapy for patients with central nervous system (CNS) involvement are limited, as most of them have been excluded from most pivotal CAR-T studies because of concerns about treatment-related neurotoxicity. Here, we show results of a third generation of CD19 CAR T cells for patients with R/R B cell cancers with CNS involvement in a single-center cohort study. Methods A total of 21 patients with R/R B cell malignancies (including ALL and NHL) with CNS involvement were included in this study. Patients derived peripheral lymphocytes were collected through apheresis and lentivirally transduced with a 3 rd generation CAR containing CD28 and TLR2 co-stimulatory domains. The cells were expanded ex vivo and administered in a single infusion (1×10 6 or 2×10 6 CAR T cells per kilogram of body weight) after a conditioning regimen of cyclophosphamide and fludarabine. Results Of the 21 patients with CNS involvement, 11 patients with ALL and 10 with NHL were included in this study, with a data cutoff of July 2023. All 11 patients with ALL had both bone marrow (BM) and cerebrospinal fluid (CSF) involvement. Of the 10 patients with NHL, 5 of the 10 lymphoma patients had parenchyma involvement, 6 patients (6/10) had CSF infiltration and 1 had oculus sinister involvement; the majority of patients (8/10) were diagnosed with secondary CNS lymphoma, whereas 2 patient was primary CNS lymphoma. Of the 21 patients who were treated, the overall response rate (ORR) was 71% (15/21), with 73% (8/11) in ALL and 70% (7/10) in NHL. 67% of patients with ALL (7/11) had a complete remission in both BM and CSF, while 40% of NHL patients (4/10) had a complete response and 30% (3/10) received a partial response. The median overall survival (OS) of ALL was 14.3 months, with a median follow-up of 20.3 months, while the median OS of NHL was not reached with a median follow-up of 14.2 months. Median progression-free survival (PFS) of ALL and NHL were 11.1 months (95% CI, 0.7-29.9 months) and 4.8 months (95% CI, 1.0-15.3 months), respectively (P = 0.84). In the total CNS cohort, cytokine release syndrome (CRS) of any grade was seen in 20 patients (95%), grade 3 in 3 patients (14%). ICANS occurred in 9 patients (42.8%, including 5 ALL and 4 NHL patients), grade 3 in 5 patients (23.8%), and there was no grade 4 event. Median time to ICANS was 5 days (range, 2-10 days) after CAR-T infusion. All the CRS or ICANS were manageable. No significant difference in occurrence of and time to ICANS was seen between ALL and NHL patients (P = 0.22 and 0.96). CAR T cells were identified in CSF of patients following infusion, and the median time to peak CAR T cells in CSF of ALL and NHL were 6.5 days and 10 days post-infusion, respectively (P = 0.141). Median time to last documented follow-up of all patients (alive or dead) was 18.1 months (range 1.0-31.2 months). At the end point of observation, 5 of the 11 ALL patients and 5 of 10 NHL patients were still alive with sustained CR of CNS disease and systemic disease (Figure 1). Conclusion TLR2-costimulated CAR T cell therapy for patients with R/R B cell malignancies with CNS involvement is safe, feasible, and results in high response rates and durable remission in both ALL and NHL patients with CNS disease. The clinical trial was registered at www.clinicaltrials.gov as # NCT04605666.

The nutritional impact of CD19-targeted CAR-T therapy versus BEAM chemotherapy for adult patients with lymphoma.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapy demonstrating durable remissions in patients with refractory or relapsing non-Hodgkin's B-cell lymphoma. Maintaining a patient's nutritional status has been demonstrated to improve outcomes in cancer treatment. However, no studies have investigated how CAR-T therapy affects nutritional status, nor compared its impact with other cancer treatments for this patient group. The primary aim of the present study was to investigate the effect of CAR-T therapy on the prevalence of nutrition impact symptoms (NIS) and nutritional status within 30 days post-treatment of patients with lymphoma compared to a conditioning regimen for autologous haematopoetic stem cell transplant (carmustine/BCNU, Etoposide, cytarabine/Ara-C, Melphalan [BEAM] auto-haematopoetic stem cell transplant [HSCT]). Clinical notes of patients with lymphoma who underwent either CAR-T therapy or BEAM auto-HSCT between 2018 and 2021 were reviewed. Data extracted included body weight measurements and NIS, including decreased appetite, nausea, vomiting, diarrhoea, constipation, mucositis, cytokine release syndrome (CRS) and neurotoxicity at baseline and 30 ± 7 days post-treatment. In total, 129 adults with lymphoma (n = 88 CAR-T vs. n = 41 BEAM) were included. Nutritional status was assessed in both groups at baseline prior to treatment. Mean absolute weight change was significantly different between groups (3.05 kg in CAR-T, -5.9 kg in BEAM, p ≤ 0.001). This was also significant when weight loss was categorised into percentage weight loss (p = 0.01). CAR-T patients experienced a significantly lower prevalence of decreased appetite (52.3% vs. 97.6%) nausea (25% vs. 78%,) vomiting (10.2% vs. 53.7%), diarrhoea (43.2% vs. 96.7%) and mucositis (5.7% vs. 75.6%) combined across all levels of severity compared to BEAM chemotherapy (all p ≤ 0.01). CRS and neurotoxicity, which are specific side effects of CAR-T therapy, were moderately positively associated with weight loss. Weight loss, percentage weight loss and NIS were significantly reduced in CAR-T compared to BEAM treatment. However, patients who experienced neurotoxicity during treatment did have significant weight loss.

Lenalidomide maintenance following high-dose therapy and autologous haematopoietic stem cell transplantation in chemo-resistant or high-risk non-Hodgkin lymphoma: A phase I/II study.

Improved maintenance treatments are needed for patients with relapsed/refractory aggressive lymphomas after autologous haematopoietic stem cell transplantation (ASCT). Several studies with lenalidomide have been found to have activity in the treatment of relapsed/refractory aggressive lymphomas. In the present phase I/II, single-arm, open-label study, 59 patients with high-risk relapsed non-Hodgkin lymphoma received pretransplant BEAM chemotherapy and ASCT followed by 12 months of maintenance lenalidomide once daily on Days 1-21 (28-day cycles) beginning at post-transplantation Day 100. The most common histologies were mantle cell lymphoma (56%) and diffuse large B-cell lymphoma (24%). The maximum tolerated dose in the dose-finding part of the study was 15 mg, but cytopenias led to the subsequent adoption of a 10 mg dose in the final study. Sixteen patients (27%) completed 12 cycles of lenalidomide maintenance. The most common reason for discontinuation was adverse events (31%). These were primarily haematologic, and 56% of patients experienced Grade 3-4 events. Two-year PFS rates (95% CIs) were 70% (56%-80%), 45% (19%-68%) and 81% (66%-90%); 2-year OS rates (95% CIs) were 91% (80%-96%), 93% (61%-99%) and 90% (76%-96%) in all patients, patients completing and patients not completing 12-month maintenance respectively. These results do not support the use of lenalidomide maintenance in this setting.

EZH1-PRC2 Identifies a Potential Reservoir for Disease Relapse in Quiescent Cancer Cells Refractory to EZH2 Enzymatic Inhibition

Recurrent disease relapse and remission is a hallmark of indolent non-Hodgkin lymphoma (NHL). Remissions are often characterised by long periods of clinical inactivity without detectable disease. Furthermore, it is now standard practice to clinically monitor carefully selected asymptomatic patients with indolent lymphoma, often for years, reserving therapy for symptomatic disease progression, without adversely affecting the patient's prognosis. Identification and targeting of the putative cellular reservoir recurrently seeding disease relapse and progression in NHL has long tantalised researchers and would represent a significant advance in the field given the hypothetical prospect of deferring or preventing impending relapse. The oncogene EZH2 is upregulated in the lymphoid germinal center and forms the enzymatic core of Polycomb Repressive Complex 2 (PRC2) alongside essential core components EED and SUZ12, writing all methylation of H3K27, with H3K27me3-mediated silencing of the B-cell terminal differentiation programme. The EZH2 small molecule enzymatic inhibitor Tazemetostat has been approved as monotherapy beyond second line for relapsed/refractory EZH2-mutant and wild-type follicular lymphoma, with responders benefiting for a modest median duration of 10.9 months (Morschauser et al., Lancet Oncology, 2020). The mechanism(s) for disease progression in patients have not yet been published. Using TIG3-T human diploid fibroblasts as a model of cellular quiescence, we discover that a novel form of PRC2 predominates in non-dividing cells, which contains EZH1, EED, SUZ12 and the polycomb-like protein, PHF1, but crucially lacks EZH2. RNA-Seq and Western blot analysis revealed reciprocal expression patterns of EZH1 and EZH2 in serum-starved, quiescent (non-dividing) cells compared to asynchronous cycling cells. Using EED immunoprecipitation with subsequent mass spectrometry, we demonstrated that EZH1 replaces EZH2 as the predominant H3K27 methyltransferase in quiescent cells. Quantitative ChIP-sequencing with exogenous reference genome spike-in (ChIP-Rx) confirms that EHZ1-PRC2 largely replaces EZH2-PRC2 at polycomb target genes. While the EZH2 enzymatic inhibitor GSK343 and the EED allosteric inhibitor A395 significantly reduced H3K27me2 and H3K27me3 in cycling cells, those markes are unchanged in quiescent cells. This alludes to a function of EZH1-PRC2 in quiescent cells that is independent of its function as a H3K27 methyltransferase, and therefore not targetable by PRC2 enzymatic inhibitors. The EED PROTAC UNC6852 degrades EED (Figure 1), thereby destabilising both EZH1-PRC2 and EZH2-PRC2, as confirmed by Western blot and ChIP-Rx. Strikingly, this molecule resulted in a marked reduction of H3K27me2 and H3K27me3 in proliferating cells, but had no such effect in treated quiescent cells. Degradation of PRC2, however, did result in a modest reduction in protein levels and chromatin occupancy of the canonical PRC1 component CBX7, suggesting an interplay between EZH1-PRC2 occupancy and local cPRC1-mediated chromatin of compaction of Polycomb target genes. EZH2 and Ki-67 immunohistochemistry and EZH1 RNA in situ hybridization (RNA-ISH) were performed on lymph node biopsy specimens from two well-matched patients with histological grade 2 follicular lymphoma (Figure 2). Patient 1 has multiply relapsed follicular lymphoma, rapidly requiring therapy following this biopsy. Patient 2 presented with a right inguinal mass and stage 3A disease, though did not require therapy for 14 years from the time of this biopsy. Interestingly, while both patients harbour abundant EZH1-positive cells (approximately 60% of cells within neoplastic follicle), only patient 1 whose tumour expressed abundant EZH2 and Ki-67 had clinically active disease requiring therapy. Although this requires validation in a larger series, these cases illustrate the presence of lymphoma cells in both patients likely to be refractory to PRC2 enzymatic inhibitors in vivo. In summary, we propose that EZH1-PRC2 delineates a non-proliferating, PRC2 enzymatic inhibitor-resistant population of cells that could serve as a disease reservoir in indolent NHL. These cells are targetable by PROTAC-mediated EZH1-PRC2 degradation, with the resultant disruption reflecting the non-enzymatic roles of EZH1-PRC2. EZH1-PRC2 should be addressed as a therapeutic target to treat NHL in the future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Non-Hodgkin lymphoma treatment in middle-income countries in Latin America: perspective of the Latin American Study Group of Lymphoproliferative Disorders [Grupo de Estudio de Linfoproliferativos de Latino América (GELL)

ABSTRACT Introduction Non-Hodgkin lymphomas (NHL) are the most frequently recognized entities among lymphoproliferative syndromes and rank fifth among neoplasms not associated with gender. There is scarce information on the clinical characteristics of the most frequent NHL, and no data on treatment regimens and their outcomes in Latin America. Although many factors affect a patient’s possibilities of receiving treatment, the annual income per person/country is pivotal in Latin America. Aim We present the clinical characteristics, risk groups, and treatment regimens of the three most frequent lymphoma subtypes in Latin America [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and peripheral T-cell lymphoma (PTCL)], based on the data collected by the largest study group of lymphoproliferative diseases in Latin America: The Latin American Study Group of Lymphoproliferative Disease [Grupo de Estudio de Linfoproliferativos de Latino America (GELL)]. Outcomes The most frequent treatment regimen for B-cell lymphomas is immunochemotherapy (R-CHOP ≥70%), and CHOP for PTCL. Survival is similar to that reported by industrialized nations. We have no solid data on the results of treatment with salvage regimens nor stem cell transplantation in refractory/ relapsed NHL. Conclusion In Latin America, the same treatment regimens are used as in highly developed countries, although we lack the necessary technology to apply CAR T-cell therapies or a network of trials sponsored by the pharmaceutical industry.

Bilateral CMV Retinitis in a Patient with Relapsed Non-Hodgkin Lymphoma on Oral Metronomic Chemotherapy: Case Report and Review of Literature

AbstractCytomegalovirus (CMV) retinitis is one of the common complications in profoundly immunosuppressed patients such as those with acquired immune deficiency syndrome. It has been rarely reported in patients with lymphoma on aggressive chemotherapy. We encountered a patient with bilateral CMV retinitis who developed this vision-threatening complication while on low-dose palliative metronomic chemotherapy with oral drugs (cyclophosphamide, procarbazine, etoposide, and prednisolone). Though the infection resolved with treatment, there was residual vision loss. This case is presented to sensitize clinicians to the possibility of unusual infections in patients on long-term oral chemotherapies.

Gemcitabine, Dexamethasone, Cisplatin with Rituximab in Treatment Transplant- Ineligible Relapsed Non-Hodgkin B-cell Lymphoma Patients

We conducted this study to find out the effectiveness of treatment as well as some prognostic factors when using R-GDP (Rituximab- Gemcitabine, Dexamethasone, and Cisplatin) regimen to treat transplant-ineligible relapsed non-Hodgkin B-cell lymphoma patients. 49 patients diagnosed with relapsed non-Hodgkin B-cell lymphoma treated with R-GDP (Rituximab- Gemcitabine, Dexamethasone, and Cisplatin) regimen were retrospectively analyzed. Patients who subsequently underwent autologous stem cell transp

Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations.

Simple SummaryDespite very poor survival, controversies remain in the treatment for refractory or relapsed non-Hodgkin lymphoma (r/r NHL) in children and adolescents. The current project identifies and reports international experience on re-induction treatment of r/r NHL, hematopoietic stem cell transplantation, risk factors associated with outcome, and suggests treatment recommendations.Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Purpose177Lu-lilotomab satetraxetan targets the CD37 antigen and has been investigated in a first-in-human phase 1/2a study for relapsed non-Hodgkin lymphoma (NHL). Tumor dosimetry and response evaluation can be challenging after radioimmunotherapy (RIT). Changes in FDG PET/CT parameters after RIT and correlations with tumor-absorbed doses has not been examined previously in patients with lymphoma. Treatment-induced changes were measured at FDG PET/CT and ceCT to evaluate response at the lesion level after treatment, and correlations with tumor-absorbed doses were investigated.MethodsForty-five tumors in 16 patients, with different pre-treatment and pre-dosing regimens, were included. Dosimetry was performed based on multiple SPECT/CT images. FDG PET/CT was performed at baseline and at 3 and 6 months. SUVmax, MTV, TLG, and changes in these parameters were calculated for each tumor. Lesion response was evaluated at 3 and 6 months (PET3months and PET6months) based on Deauville criteria. Anatomical changes based on ceCT at baseline and at 6 and 12 months were investigated by the sum of perpendiculars (SPD).ResultsTumor-absorbed doses ranged from 35 to 859 cGy. Intra- and interpatient variations were observed. Mean decreases in PET parameters from baseline to 3 months were ΔSUVmax-3months 61%, ΔMTV3months 80%, and ΔTLG3months 77%. There was no overall correlation between tumor-absorbed dose and change in FDG PET or ceCT parameters at the lesion level or significant difference in tumor-absorbed doses between metabolic responders and non-responders after treatment.ConclusionOur analysis does not show any correlation between tumor-absorbed doses and changes in FDG PET or ceCT parameters for the included lesions. The combination regimen, including cold antibodies, may be one of the factors precluding such a correlation. Increased intra-patient response with increased tumor-absorbed doses was observed for most patients, implying individual variations in radiation sensitivity or biology.Trial registrationClinicalTrials.gov Identifier (NCT01796171). Registered December 2012

A Phase 1 Study of HMPL-689, a Small Molecule, Highly Selective, and Potent Inhibitor of Phosphoinositide 3 Kinase-Delta, in Patients with Relapsed or Refractory Lymphoma

Background: The B-cell receptor (BCR) signaling pathway plays a critical role in the pathogenesis of lymphomas, particularly in non-Hodgkin lymphomas (NHL). Despite availability of therapeutic agents targeting BCR pathway, there is an unmet medical need for more effective and well-tolerated therapeutic agents for patients with advanced relapsed, refractory, or resistant NHL. HMPL-689 is a novel, orally available, highly selective, and potent small molecule inhibitor of phosphosinositide 3 kinase-delta (PI3Kδ), a crucial signaling transduction molecule in the BCR signaling pathway. A global clinical study of HMPL-689 is currently ongoing in the USA and the EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of this study are expected soon. Herein is the description of an ongoing phase 1, open-label, multi-center, single-arm study of HMPL-689 in patients with advanced relapsed, refractory, or resistant (R/R) NHL (NCT03786926). Study Population: Target patient population is adult patients with histologically confirmed advanced relapsed, refractory, or resistant NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available. Patients are ineligible for the study if they have primary central nervous system lymphoma. Objectives and Endpoints: The primary objective is to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) of HMPL-689. The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities The secondary objective is to evaluate the pharmacokinetic (PK) parameters and preliminary efficacy. The secondary endpoints include concentration-time profiles, PK parameters, and efficacy parameters, including objective response rate, time to response, duration of response, and progression-free survival. Study Design: Study consists of a dose escalation and dose expansion stages. The dose-escalation stage utilizes a mTPI-2 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses for escalation cohorts are 10, 15, 20, 25, 30, 35, 40, 45, and 50 mg, QD, PO in a 28-day cycle. Patients will be treated until disease progression, intolerable toxicity, no further benefit, withdrawal, end of study, or death. The expansion stage will be dosed at the MTD. Approximately 10 patients will be enrolled in each of the following cohorts: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),Mantle cell lymphoma (MCL),Follicular lymphoma (FL)Marginal zone lymphoma (MZL)Peripheral T-cell lymphoma (PTCL)Cutaneous B-cell lymphomaWaldenström's macroglobulinemia / lymphoplasmacytic lymphoma (WM) Statistical Methods: The maximum sample size in the dose-escalation stage will be determined based on the accumulated safety data and the mTPI-2 design. The maximum sample size under the mTPI-2 method is k × (d + 1), where k denotes the cohort size and d denotes the number of doses. The minimum cohort size in this study is 3 patients per cohort. To ensure that the highest dose (if needed) is reached, it is estimated that approximately 33-39 patients will be needed in this study. For dose expansion, approximately 70 patients (10 in each cohort) will provide robust safety data in the patient populations studied. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. For preliminary assessment of anti-tumor activity based on ORR, if at least 8 patients in a specific lymphoma subtype are evaluable for tumor response, the chance of observing at least one response is 94.2%, if the true ORR is 30%. Data will be summarized by dose level, subtype of malignancy, and overall as appropriate. Continuous assessments will be summarized by number of patients (n), mean, standard deviation, median, minimum and maximum. Significance: This study is the first global clinical study of HMPL-689, a novel inhibitor of the BCR signaling pathway, which is currently enrolling patients with advanced relapsed, refractory, or resistant NHL who have exhausted all approved therapeutics options available. Disclosures Lawrence: Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Hahka-Kemppinen:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo:Consultancy;Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics:Research Funding.Kania:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.

A Phase 1 Study of HMPL-523, Highly Selective and Potent a Small Molecule Inhibitor of Spleen Tyrosine Kinase in Patients with Relapsed or Refractory Lymphoma

Background: The B-cell receptor (BCR) signaling pathway plays a critical role in the pathogenesis of lymphomas, particularly in non-Hodgkin lymphomas (NHL). Despite availability of therapeutic agents targeting BCR pathway, there continue to be unmet medical need for more effective and less toxic therapeutic agents for patients with advanced relapsed, refractory or resistant lymphoma. HMPL-523 is a novel, orally available, highly selective, and potent small molecule inhibitor of spleen tyrosine kinase (SYK), a crucial component of BCR signaling pathway. A clinical study is currently ongoing in the USA and in EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of these trials are expected soon. Herein is the description of an ongoing phase 1 open-label, multi-center, single-arm study of HMPL-523 in patients with advanced relapsed, refractory or resistant (R/R) NHL (NCT03779113). Study Population: Targeted patient population is adult patients with histologically confirmed advanced relapsed, R/R NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available. Objectives and Endpoints: The primary objective is to assess safety and tolerability of HMPL-523 and to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities The secondary objectives are to characterize the pharmacokinetic (PK) parameters and to evaluate the safety and preliminary efficacy of HMPL-523. The secondary endpoints are the incidence of treatment-emergent adverse events (TEAE), PK parameters, and efficacy parameters, including objective response rate, duration of response, time to response, and progression-free survival. Study Design: Study consists of a dose escalation stage and an expansion stage. The dose-escalation utilizes a modified 3+3 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses of escalation cohorts are 100, 200, 400, 600 and 800 mg, QD, PO in a 28-day cycle. Patients will be treated until disease progression, intolerable toxicity, no further benefit, withdrawal, end of study, or death. The expansion stage will be dosed at the MTD to further evaluate safety, tolerability, PK, drug exposure, target engagement, PD and their correlation with clinical benefit of HMPL-523. Approximately 10 patients will be enrolled in each of the following cohorts: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),Mantle cell lymphoma (MCL),Follicular lymphoma (FL)Marginal zone lymphoma (MZL)Peripheral T-cell lymphoma (PTCL)Cutaneous B-cell lymphomaWaldenström's macroglobulinemia / lymphoplasmacytic lymphoma (WM) Statistical Methods: For the escalation stage, the sample size is based on the dose-escalation rules of the 3+3 design. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in a given cohort of 6 patients is 46.9%, 26.5%, and 5.8%, respectively. For the dose expansion stage, a total of 70 patients (10 patients per expansion cohort) will provide robust safety data in the study patient populations. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. For preliminary assessment of anti-tumor activity based on ORR, if at least 8 patients in a specific lymphoma subtype are evaluable for tumor response, the chance of observing at least one response is 94.2%, if the true ORR is 30%. Safety parameters, including DLTs, recorded TEAEs, clinical laboratory parameters, vital signs, 12-lead ECG parameters and physical examination findings, will be summarized by dose level across both dose escalation and dose expansion stages. Efficacy endpoints will be summarized by dose level for each type of malignancy. Significance: This study is the first global clinical study of HMPL-523, a novel inhibitor of the BCR signaling pathway currently enrolling patients with advanced relapsed, refractory or resistant NHL who have exhausted all approved therapeutics options available. Disclosures Lawrence: Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Hahka-Kemppinen:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Kania:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.

Cardiovascular effects of chimeric antigen receptor t-cell therapy for refractory or relapsed non-hodgkin lymphoma

Abstract Purpose Cardiovascular complications of chimeric antigen receptor T-cell (CAR T-cell) therapy are poorly understood. We examined the incidence, predictors and impact of new or worsening cardiomyopathy in patients undergoing CAR T-cell therapy. Methods All patients with refractory or relapsed non-Hodgkin's lymphoma, undergoing CAR T-cell therapy at collaborative institutes underwent serial echocardiograms at baseline and within 7 days after developing high-grade cytokine release syndrome (CRS), and were followed for all-cause mortality. New or worsening cardiomyopathy was defined as a reduction in left ventricular ejection fraction (LVEF) &amp;gt;10% from baseline to &amp;lt;50% during the index hospitalization. Results Among 187 consecutive CAR T-cell therapy patients, 116 (50 Grade ≤1 CRS, 66 Grade ≥2 CRS) had &amp;gt;1 echocardiogram performed and were included in this analysis. The median age was 63 (range 19–80) years, 42% were women, 91% were Caucasian. A total of 12 (10.3%) patients developed new or worsening cardiomyopathy with a decline in LVEF from 58±6% to 36±7% within a median of 12.5 (range 2–24) days of CAR T-cell infusion. In multivariable analyses, older age, prior stem cell transplantation, baseline angiotensin-converting enzyme inhibitor use and CRS grade ≥2 were associated with the development of cardiomyopathy. Patients who developed cardiomyopathy were more likely to require vasopressor support (p=0.004) and mechanical ventilation (p=0.014). LVEF improved in 9/12 (75%) patients. CAR T-cell associated cardiomyopathy did not impact overall mortality or cancer response to CAR-T cell therapy. Conclusions Patients undergoing CAR T-cell therapy are at risk of developing cardiomyopathy and hemodynamic instability. Pre-CAR T-cell therapy cardiovascular risk stratification and echocardiogram surveillance during therapy should be considered for prompt identification and mitigation of cardiac complications. Predictors of Cardiomyopathy Development Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): Anju Nohria, MD is supported by the Gelb Master Clinician Award at Brigham and Women's Hospital.

Risk Factors for Skin Toxicities Associated with Bendamustine-Based Chemotherapy in Patients with Non-Hodgkin Lymphoma.

Bendamustine plays an especially important role as a treatment for non-Hodgkin lymphoma (NHL). However, patients administered bendamustine alone or in combination with rituximab (BR) may experience drug-associated skin toxicities that can profoundly impact their health-related QOL through both physical discomfort and psychological distress. Moreover, worsening skin symptoms may lead to dose reduction or termination in the management of cancer chemotherapy. We retrospectively investigated patient backgrounds and pretreatment characteristics from medical records of NHL patients treated with bendamustine alone or BR therapy and identified predictive factors for skin toxicities at the start of chemotherapy. Patients were eligible for the study if they were 20 years older, diagnosed with NHL, and received bendamustine alone or BR therapy at the Department of Hematology, Kobe City Medical Center General Hospital, between April 1, 2011, and March 31, 2018. This study included 95 patients with newly diagnosed or refractory or relapsed NHL. Multivariate stepwise logistic regression analysis with backward selection revealed that baseline non-prior chemotherapy (odds ratio (OR), 15.72; 95% confidence interval (CI), 4.24-83.13, p < 0.001) was a significant factor influencing the occurrence of skin toxicity. Our results demonstrated that non-prior chemotherapy was a significant risk factor for skin toxicities in patients with NHL receiving bendamustine alone or BR therapy. No patient experience serious side effects of grade 3 or higher and that bendamustine is very useful as a first-line treatment.

Recurrent mantle cell lymphoma in the uterine cervix: a case report

BackgroundMantle cell lymphoma is one of several subtypes of non-Hodgkin lymphoma. Cervical relapse of non-Hodgkin lymphoma is a very rare condition that has a variable and nonspecific presentation and may resemble other neoplastic or inflammatory conditions.Case presentationOur patient was a 58-year-old Caucasian woman who experienced relapse of mantle cell lymphoma with cervical localization. She complained of postmenopausal vaginal bleeding, bladder pressure, and rapid growth of a cervical lesion. An irregular tumor mass of the cervix was visualized during gynecological examination, with findings highly suggestive of locally advanced cervical cancer. Surprisingly, the biopsies showed an extra nodal relapse of mantle cell lymphoma in the cervix. The rarity of this presentation and the scarcity of clinical studies make this type of recurrence very aggressive and difficult to treat.ConclusionsObtaining a definitive histological diagnosis by biopsy or surgical resection and starting appropriate therapy are essential for recovery and treatment of these patients, even if the prognosis is poor.

Overcoming resistance to rituximab in relapsed non-Hodgkin lymphomas by antibody-polymer drug conjugates actively targeted by anti-CD38 daratumumab

B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.

Effect of Integrated Ayurveda and Yoga Therapy (IAYT) on remission management of non-Hodgkin lymphoma: A single case study

Non-Hodgkin lymphomas are lymphoid malignant neoplasms and the prognosis depends on the staging and response to therapy. Stress is an independent factor which can affect the prognosis of the disease. The purpose of the current case study was to evaluate the impact of Yoga and Ayurveda as complementary therapy on the prognosis of the disease and the effect of the same on perceived stress level. A 36 year patient diagnosed with relapsed Non-Hodgkin Lymphoma (NHL) after receiving 3 rounds of chemotherapy and bone marrow transplant visited Union Yoga Ayurveda Clinic in Singapore for therapy. Perceived stress, complete blood count and hemoglobin were assessed pre and post intervention. A 6 month follow up was also done with similar evaluations. The patient was given holistic Yoga therapy and Ayurveda herbal treatment including patrapindasweda (herbal compress) and pichu(herbal soaked gauze pieces). The patient reported improvement in day to day energy levels and immunity with increase in WBC count. The perceived stress scores also showed distinct improvement post intervention. The current case study suggests that the integrative yoga and Ayurveda therapy was feasible and showed improvement in stress and complete blood count in patients with Non-Hodgkin lymphomas.

Live Attenuated Salmonella enterica Expressing and Releasing Cell-Permeable Bax BH3 Peptide Through the MisL Autotransporter System Elicits Antitumor Activity in a Murine Xenograft Model of Human B Non-hodgkin's Lymphoma.

The survival of patients with non-Hodgkin's lymphoma (NHL) has substantially improved with current treatments. Nevertheless, the appearance of drug-resistant cancer cells leads to patient relapse. It is therefore necessary to find new antitumor therapies that can completely eradicate transformed cells. Chemotherapy-resistant cancer cells are characterized by the overexpression of members of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein family, such as Bcl-XL, Bcl-2, and Mcl-1. We have recently shown that peptides derived from the BH3 domain of the pro-apoptotic Bax protein may antagonize the anti-apoptotic activity of the Bcl-2 family proteins, restore apoptosis, and induce chemosensitization of tumor cells. In this study, we investigated the feasibility of releasing this peptide into the tumor microenvironment using live attenuated Salmonella enterica, which has proven to be an ally in cancer therapy due to its high affinity for tumor tissue, its ability to activate the innate and adaptive antitumor immune responses, and its potential use as a delivery system of heterologous molecules. Thus, we expressed and released the cell-permeable Bax BH3 peptide from the surface of Salmonella enterica serovar Typhimurium SL3261 through the MisL autotransporter system. We demonstrated that this recombinant bacterium significantly decreased the viability and increased the apoptosis of Ramos cells, a human B NHL cell line. Indeed, the intravenous administration of this recombinant Salmonella enterica elicited antitumor activity and extended survival in a xenograft NHL murine model. This antitumor activity was mediated by apoptosis and an inflammatory response. Our approach may represent an eventual alternative to treat relapsing or refractory NHL.

Safety and Efficacy of Mitoxantrone Hydrochloride Liposome in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma and Extranodal NK/T-Cell Lymphoma: A Multicenter, Single-Arm, Open-Label, Phase 2 Clinical Trial

Background: Peripheral T cell lymphoma (PTCL) and Extranodal NK/T cell lymphoma (ENKTCL) are rare types of non-Hodgkin's lymphoma (NHL), with a higher incidence in Asian countries. Outcomes for patients (pts) with relapsed or refractory(R/R) PTCL and ENKTCL are very poor, there is still lack of effective treatment for this patients population. Mitoxantrone is a syntheticc anthracenedione anticancer drug, which is effective on lymphoma, leukemia and other solid tumors. Tissue distribution or accumulation in tumor tissue of hydrochloride liposome (PLM60) was increased in our preclinical investigation. The pharmacokinetic parameters especially half-life of PLM60 was prolonged significantly in phase 1 trial. Phase Ib clinical studies showed good results of PLM60 in relapsed NHL. Therefore, we conduct this phase II clinical studies to evaluate the efficacy and safety of PLM60 in patients with R/R PTCL and ENKTCL. At present time, this is the first clinical study to evaluate PLM60 in treating R/R PTCL and ENKTCL worldwide. Methods : This is a single-arm, open-label, multi-center, phase II clinical study. The major inclusion criteria include age≥18 years old, pts with histologically confirmed PTCL (mainly including peripheral T cell lymphoma, NOS,PTCL-U; angioimmunoblastic T-cell lymphoma,AITL; anaplastic large cell lymphoma,ALCL; and other invasive NHL derived from T cells) and ENKTCL that was treated at least 1st line of chemotherapy, ECOG performance status 0 or 1. The main exclusion criteria included cumulative dose of doxorubicin &gt;360mg/m2 and patients has clinically significant cardiac malfunction and uncontrollable underlying cardiovascular diseases. PLM60 20mg/m2 was administered intravenously , every 4 weeks for up to 6 cycles or until disease progression, intolerable toxicity, death or withdrawal due to the investigator's decision. The primary endpoint was objective response rate (ORR) based on investigator and independent central review (ICR) per Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma 2007. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Adverse events will be rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.03. This trial is registered at ClinicalTrials.gov, number NCT03776279. Results: 62 eligible patients were treated in 18 institutions in China between April 2018 and July 2019. Patient characteristics are summarized in Table 1. Median number of previous chemotherapy regimens was 2(1-7). At the cut-off day of July 20, 2019, 9 pts remained on treatment and 3 pts withdrew due to protocol violation and lost follow-up. 50 patients were evaluable for response, the investigator-assessed ORR was 54.0%(27/50)with CR rate 20.0%(10/50) (CR). The subtype CR rate were 17.6%(3/17), 17.6%(3/17), 18.2%(2/11), 13.3%(2/15)for PTCL-U, AITL, ALCL and ENKTCL respectively. The ORR were 42.1%(8/17), 42.1%(8/17), 45.5(5/11), 40.0(6/15), respectively (Figure 1). The median time to response was 8 weeks (ranged from 4 to 24 weeks) . Median follow-up was 3.8 (ranged from 0.2 to 14.4 m) months. Median PFS was 8.0months (95% CI, 6.1-9.9m), with a 6-month PFS rate of 73.1±9.4%. Median OS was not reached, with a 6-month OS rate of 77.3±6.9%(Figure 2a,b). All-grade treatment-emergent adverse events (TEAEs) are listed in Table 2. The most common toxicity of PLM60 was myelosuppression. The most common grade 3/4 toxicity(&gt;10% TEAEs) was neutropenia(25.8%) and lymphocytopenia(11.3%). There were no treatment-related deaths. Conclusion: PLM60 monotherapy yielded promising results for patients with R/R PTCL and ENKTCL with moderate toxicities. Further investigation is urgently needed. Disclosures No relevant conflicts of interest to declare.