Liposomal Doxorubicin Research Articles

Gemcitabine and liposomal doxorubicin (GemDox) for the treatment of relapsed and refractory T-cell lymphomas

Aggressive T-cell lymphomas (TCL) account for 10–15% of non-Hodgkin lymphomas (NHL) with weaker responses and shorter durations to chemotherapy than other types of NHL. Current therapies for patients with relapsed/refractory Cutaneous T-cell lymphoma (CTCL) have limited efficacy, and short durations of response. Gemcitabine and liposomal doxorubicin have shown single-agent activity in TCL and combined have activity in relapsed B-cell lymphomas. We evaluated outcomes of 18 patients with relapsed/refractory aggressive TCL (13 CTCL, 5 PTCL) treated with a gemcitabine plus liposomal doxorubicin (GemDox) combination and evaluated outcomes with a specific focus on CTCL patients. Significant responses were observed in CTCL patients with an overall response rate of over 80%. In all patients, objective responses were seen in eight patients (50%), with six patients (5 CTCL) able to proceed to allogeneic stem cell transplant. Given limited treatment options for r/r CTCL, GemDox should be considered a therapeutic option in relapsed/refractory CTCL.

In Vitro and Preclinical Antitumor Evaluation of Doxorubicin Liposomes Coated with a Cholesterol-Based Trimeric β-D-Glucopyranosyltriazole.

The coating of liposomes with polyethyleneglycol (PEG) has been extensively discussed over the years as a strategy for enhancing the in vivo and in vitro stability of nanostructures, including doxorubicin-loaded liposomes. However, studies have shown some important disadvantages of the PEG molecule as a long-circulation agent, including the immunogenic role of PEG, which limits its clinical use in repeated doses. In this context, hydrophilic molecules as carbohydrates have been proposed as an alternative to coating liposomes. Thus, this work studied the cytotoxicity and preclinical antitumor activity of liposomes coated with a glycosyl triazole glucose (GlcL-DOX) derivative as a potential strategy against breast cancer. The glucose-coating of liposomes enhanced the storage stability compared to PEG-coated liposomes, with the suitable retention of DOX encapsulation. The antitumor activity, using a 4T1 breast cancer mouse model, shows that GlcL-DOX controlled the tumor growth in 58.5% versus 35.3% for PEG-coated liposomes (PegL-DOX). Additionally, in the preliminary analysis of the GlcL-DOX systemic toxicity, the glucose-coating liposomes reduced the body weight loss and hepatotoxicity compared to other DOX-treated groups. Therefore, GlcL-DOX could be a promising alternative for treating breast tumors. Further studies are required to elucidate the complete GlcL-DOX safety profile.

An Automated Electroanalytical Method for the Drug Release Profiling of Liposomal Doxorubicin HCl Formulations

Liposomes have emerged as a drug delivery system for various chemotherapeutics providing enhanced bioavailability and reduced toxicity. In vitro drug release profiling of liposomal formulations is one of the essential tests for the premarket approval and post market quality control. We developed an automated electroanalytical method for drug release profiling of liposomal doxorubicin formulation. In this electroanalytical method, square wave voltammetry mode was selected to determine the released drug, the only redox-active analyte, by measuring the current at the pulsed potential ranges. Therefore, no separation from liposomal encapsulated doxorubicin is needed. This electroanalytical method provided a continuous drug release measurement for 24 h. The drug release increased as the release media pH and temperature increased. At 37 °C, the drug release increased from 7 % to 40 % when the pH increased from 5.5 to 7.4, In addition, at pH 6.5, as the temperature increased from 37 °C to 52 °C, total drug release increased by more than two-fold. Complete drug release (more than 80 %) was obtained at pH 6.5 and 52 °C in less than 3 h. The brand name and the two generic formulations showed similar drug release profile in all experimental conditions. This method is an alternative to traditional methods which require separation steps such as dialysis or solid phase extraction to quantitate released doxorubicin. This method may be further applied in the in vitro release testing of other liposomal formulations containing redox-active drug substances, e.g., liposomes encapsulating daunorubicin.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer

BackgroundMirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody–drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States.MethodsWe conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator’s choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.ResultsA total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P=0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).ConclusionsAmong participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.)

Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.

To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas. This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events. One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m2 /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups. Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.

CCL2 chemokine inhibition primes the tumor vasculature for improved nanomedicine delivery and efficacy

Blood vessel functionality is crucial for efficient tumor-targeted drug delivery. Heterogeneous distribution and perfusion of angiogenic blood vessels contribute to suboptimal accumulation of (nano-) therapeutics in tumors and metastases. To attenuate pathological angiogenesis, an L-RNA aptamer inhibiting the CC motif chemokine ligand 2 (CCL2) was administered to mice bearing orthotopic 4T1 triple-negative breast cancer tumors. The effect of CCL2 inhibition on tumor blood vessel functionality and tumor-targeted drug delivery was evaluated via multimodal and multiscale optical imaging, employing fluorophore-labeled polymeric (10 nm) and liposomal (100 nm) nanocarriers. Anti-CCL2 treatment induced a dose-dependent anti-angiogenic effect, reflected by a decreased relative blood volume, increased blood vessel maturity and functionality, and reduced macrophage infiltration, accompanied by a shift in the polarization of tumor-associated macrophages (TAM) towards a less M2-like and more M1-like phenotype. In line with this, CCL2 inhibitor treatment improved the delivery of polymers and liposomes to tumors, and enhanced the antitumor efficacy of free and liposomal doxorubicin. Together, these findings demonstrate that blocking the CCL2-CCR2 axis modulates TAM infiltration and polarization, resulting in vascular normalization and improved tumor-targeted drug delivery.

Lower cardiotoxicity of CPX-351 relative to daunorubicin plus cytarabine free-drug combination in hiPSC-derived cardiomyocytes in vitro

Liposomal formulations are hypothesized to alleviate anthracycline cardiotoxicity, although this has only been documented clinically for doxorubicin. We developed an in vitro multiparametric model using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to assess the relative toxicity of anthracyclines across formulations. Proof of concept was established by treating hiPSC-CM with equivalent concentrations of free and liposomal doxorubicin. The study was then repeated with free daunorubicin plus cytarabine and CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine. hiPSC-CM were treated with free-drug or liposomal formulations for 24 h on Days 1, 3, and 5 at equivalent concentrations ranging from 0 to 1000 ng/mL and assessed on subsequent days. Free-drug treatment resulted in concentration-dependent cumulative cytotoxicity (microscopy), more profound decrease in ATP levels, and significant time- and concentration-dependent decreases in oxygen consumption versus liposomal formulations (p < 0.01). Repeated free-drug exposure also resulted in greater release of biomarkers (cardiac troponin I, FABP3) and lactate dehydrogenase, as well as in a biphasic rhythmicity response (initial increase followed by slowing/quiescence of beating) indicating significant injury, which was not observed after repeated exposure to liposomal formulations. Overall, liposomal formulations were considerably less toxic to hiPSC-CM than their free-drug counterparts. Clinical data will be needed to confirm findings for CPX-351.

Phase 2 Response-Adapted Study of Ibrutinib with Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, and Rituximab (TEDDI-R) for Secondary CNS Lymphoma

Background: Secondary CNS lymphomas (SCNSL) are aggressive and there are few treatment options. CNSLs often have underlying chronic active B-cell receptor signaling that responds to BTK inhibitors, but the response duration is short. TEDDI-R achieves durable remissions in primary DLBCL of the CNS (PCNSL), but the molecular profile of SCNSL tumors that are BTK-responsive is unknown. We present results from an ongoing response-adapted study of ibrutinib with TEDD-R in SCNSL [NCT03964090]. Methods: Pts with aggressive B-cell lymphomas with CNS +/- systemic involvement are eligible if age ≥18, PS&amp;lt;3, and adequate organ function. Pts are untreated with CNS involved or relapsed in the CNS after therapy. Prior BTKi is allowed. HIVis excluded. Baseline tests: brain MRI, PET/CT of body, bone marrow (BM), CSF flow cytometry, and fundoscopic exam. Pts receive isavuconazole as fungal prophylaxis throughout therapy. Pts first receive ibrutinib 560mg x 14d in a treatment window to determine ibrutinib-responsiveness. Pts with ≥20% reduction after ibrutinib receive TEDDI-R, and if &amp;lt;20% reduction receive TEDD-R (no ibrutinib). Chemotherapy is 4 cycles x21d as an outpatient and includes intrathecal chemotherapy. There is no maintenance therapy or planned consolidation. Response is assessed after cycles 2 and 4. Complete responses (CR) are confirmed with FDG-PET brain/body, CSF analysis, and BM. Surveillance scans are q3m for 1y, q4m x 1y, q6m x 1y, then annually. The primary endpoint is PFS. Results:50 pts enrolled between June 2019 and March 2023 with median age 63 (range 26-89), and 15 (30%) aged ≥70. 17 pts (34%) were female. 28 (56%) pts had DLBCL: 21 (42%) non-GCB, 5 (10%) GCB, 1 (2%) PMBL, and 1 (2%) unknown. 16 (32%) pts had HGBL: 10 (20%) with MYC/ BCL2-R and 6 (12%) with MYC/ BCL6-R. Two (4%) pts each had MCL and EBV-LPD, and 1 pt each had plasmablastic (2%) and Burkitt (2%). Five (10%) pts were treatment naïve and 45 (90%) were relapsed or refractory. 25 (50%) had synchronous CNS and peripheral disease, and 25 (50%) were isolated to the CNS. All relapsed or refractory pts had prior anthracycline, 29 (58%) prior HD-MTX, and 8 (18%) prior CAR-T. Forty-three pts completed the ibrutinib window and were evaluable for responsiveness; 25 (58%) were ibrutinib-responsive and 18 (42%) were ibrutinib-resistant (Figure 1). The overall response rate (ORR) to TEDDI-R (n=28) was 96%, including a CR rate of 71%. The overall response rate to TEDD-R (n=20) was 35%, with a CR rate of 25%. G3 or G4 neutropenia occurred in 43% and 31% of cycles, respectively, and febrile neutropenia occurred in 11%. G3 or G4 thrombocytopenia occurred in 31% and 12% of cycles, respectively, and G3 anemia occurred in 37%. G3 non-hematologic AEs (% pts) included UTI (20%), hypokalemia (22%), sepsis (14%), diarrhea (16%), hypotension (12%), fatigue (10%), anorexia (10%), adrenal insufficiency (10%), and atrial fibrillation (8%). Few G4 AEs were noted. No opportunistic infections (including Aspergillus) were observed. 14 (28%) pts had hand-foot syndrome. After a median follow-up of 24m, the 1-year PFS and OS of all patients were 37.8% and 59.9%, respectively. Pt deaths were due to disease progression (20 pts, 83%), pneumonia (3 pts, 13%), and a cardiac event (1 pt, 4%). The 1-year PFS and OS for pts with ibrutinib-responsive compared to ibrutinib-resistant tumors were 57.0% vs. 16.7% (p=0.0006) and 73.8% vs. 47.9% (p=0.06) (Figure 2). Most (86%) ibrutinib-responsive DLBCL/HGBL tumors were CD10-negative. CD10-negative DLBCL/HGBL pts had an ORR of 77% and a CR rate of 70%. The 1-year PFS and OS for pts with CD10-negative DLBCL/HGBL were 50.5% and 65.0%, respectively. There was no difference in PFS or OS in pts aged &amp;lt;70 versus ≥70 (p=0.87 and p=0.74, respectively). We performed comprehensive genomic profiling on 27 DLBCL/HGBL tumors according to the LymphGen algorithm. 80% (n=4) MCD, 75% (n=3) BN2, 50% (n=2) EZB, and 50% (n=7) unclassified tumors were responsive to ibrutinib. Conclusions: Pts with ibrutinib-responsive SCNSL achieve a high rate of CR to TEDDI-R, and preliminary data suggest these remissions are durable. Most ibrutinib-responsive tumors are CD10-negative and enriched for MCD and BN2. TEDDI-R can be delivered as an outpatient to pts of all ages.

Treatments and Outcomes of Lymphoma-Associated Hyperinflammation- a Report from the HLH in Adults Working Group for the Histiocyte Society

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome. Lymphoma is the most common cause of HLH in adults. Previous studies have indicated poor patient outcomes in lymphoma-associated HLH. The recently introduced optimized HLH inflammatory (OHI) index has improved prognostication and identification of the hyper-inflammatory phenotype of lymphoma; however, more comprehensive information on treatments and outcomes in a large cohort in the contemporary era is necessary. Our study aimed to investigate the clinical features, treatments, and outcomes of lymphoma-associated HLH through a multi-national effort by the HLH in Adults Working Group of the Histiocyte Society (NCT05898477). Methods: We conducted a multicenter, retrospective study evaluating patients diagnosed with lymphoma and hyperinflammation, defined by fulfilling 5/8 HLH diagnostic criteria or the OHI index from 2003-2022. Clinical characteristics were summarized using median and interquartile ranges (IQR). Survival analysis employed Kaplan-Meier curves and the log-rank test, considering HLH diagnosis as the zero time-point. Results: The analysis encompassed 181 patients with lymphoma: 55% had B-cell non-Hodgkin lymphoma (NHL), 35% had natural killer (NK) cell or T-cell lymphoma, and 10% had classical Hodgkin lymphoma. 35% of patients were from China, 21% from the USA, 17% from Israel, 16% from Europe, and 11% from Japan. Of the entire cohort, 157 (87%) patients met the HLH-2004 criteria, and 153 (83%) met the OHI index; The median age at HLH diagnosis was 60 years (IQR, 45-68), and 59% were males. 50% of patients presented with HLH before/at the time of lymphoma diagnosis (median time to lymphoma diagnosis 9 days), while 50% developed HLH after the initial lymphoma diagnosis (median time to HLH diagnosis 181 days). The median values of hemoglobin, absolute neutrophil count (ANC), and platelet count at HLH diagnosis were 8.6 g/dL, 2.1 K/microL, and 54.7 K/microL, respectively. The median values of triglycerides and fibrinogen were 241 mg/dL and 250 mg/dL, respectively. Interestingly, the median values for ANC, triglycerides, and fibrinogen fell outside the HLH-2004 diagnostic threshold. The median and interquartile ranges for ferritin and sCD25 (sIL-2r) were 3017 ng/mL (1337-8958) and 14098 U/mL (7894-39916), respectively. 48% of physicians altered their initial treatment approach due to the HLH diagnosis. Of these instances, 48% were treated with dexamethasone and etoposide outside of a formal treatment protocol, 11% with the HLH-94/2004 protocol, 24% with DEP regimen (liposomal doxorubicin, etoposide, and methylprednisolone), and 4% with DEP and ruxolitinib. Dexamethasone alone was used in 15% of the patients, while another 4% were treated with anakinra +/- steroids. After a median follow-up duration of 2.1y (range, 0.005-6.1), the median overall survival was 0.58 years. 46% of the patients died from multi-organ dysfunction/HLH, 17% from single-organ dysfunction, 16% from infection or septic shock, and 8% from bleeding. The risk of mortality among T-cell or NK cell lymphoma was higher than B-cell lymphoma (HR 1.7, 95% CI 1.16-2.61, Figure 1A). Finally, patients positive for the OHI index alone at diagnosis had a higher mortality risk (Figure 1B) compared to those positive for both the OHI index and HLH-2004 (HR 2.5; CI 1.26 - 4.8) or those positive for HLH-2004 alone (HR 3.72; CI- 1.62-8.58). Conclusions: Preliminary findings from this large multi-institutional study show that the overall survival for patients with lymphoma and HLH remains poor despite the institution of HLH-specific therapies. In nearly half of the cases, the physicians altered lymphoma treatment to control HLH, primarily through dexamethasone and etoposide-based or DEP regimens. Although B-cell lymphoma was our cohort's most common cause of HLH, overall survival was worse among those with T-cell or NK cell lymphoma, suggesting that the underlying lymphoma type might drive the prognosis even in cases with hyperinflammation. The most common causes of death included multi-organ dysfunction and infection. The OHI index-positive patients experienced higher mortality risk than those meeting the HLH-2004 criteria. The study is ongoing, and we plan to present data on the differential effects of treatment regimens at the meeting.

Biological Role of Extracellular Vesicles in Myeloid Neoplasms: A Systematic Review of the Current Literature

Background and aim: Extracellular vesicles (EVs) are lipid-bilayer membrane vesicles secreted by a variety of cells that carry bioactive molecules like proteins, lipids and nucleic acids. They are of increasing interest as they play an important biological role in cancer by a multitude of cell-extrinsic and cell-intrinsic mechanisms. However, the investigations of their biology in myeloid malignancies has not been systematically reviewed so far. Therefore, the aim of this review was to summarize the currently published literature in the field and provide an overview of their potential clinical applications. Method: We performed a systematic literature research with defined search strings in the Embase, Medline and PubMed Central databases and used a standardized data-extraction form to collect all relevant information. Results: 63 of 1529 studies met the inclusion/exclusion criteria and could be assigned to seven main investigational categories ( A). They comprised studies on their effect on i) prothrombotic activity (n=13), ii) tumor-microenvironment (n=14), iii) malignant transformation (n=5), iv) tumor progression (n=4), v) chemotherapy-resistance (n=5) as well as their use as vi) biomarkers (n=14) and vii) pharmacotherapeutic carriers (n=3) ( B). The most relevant biological mechanism is the transfer of microRNA (miRNA) by EVs from different clonal and non-clonal cells, which target the microenvironment, vascular system, as well as immune cells. All mechanisms identified in our review were assigned to one of the seven main categories and the most relevant are summarized in C: i) Prothrombotic activity: Leukaemic cells shed prothrombotic EVs containing tissue-factor (TF) and anionic phosphatidylserine (PS), which facilitate the recruitment of coagulation factors and a pro-coagulant state ( Zannoni, 2019). Reduction of EVs from platelets and leucocytes after chemotherapy attenuates this pro-coagulant state ( Van Aalderen, 2011). ii) Tumor microenvironment: EVs derived from MDS cells can disrupt the osteolineage differentiation of bone marrow mesenchymal stromal cells (BM-MSCs) and impair hematopoiesis ( Hayashi, 2022). iii) Malignant transformation: EVs containing BCR-ABL1 mRNA are integrated into BM-MSCs, which induce BCR-ABL1 expression and secretion of TGF-β1 leading to enhanced proliferation of BM-MSCs ( Fu, 2017). iv) Tumor progression: EVs derived from leukemic cells promote tumor progression by reducing apoptosis and tumor immune-surveillance. v) Chemotherapy resistance: AML-cells expel PEGylated liposomal doxorubicin (PLD) through EVs thus increasing their resistance ( Hekmatirad, 2021). vi) Disease biomarkers: AML patients at diagnosis have a higher number of EVs carrying the myeloblast markers CD34, CD117, CD33 and HLA-DR than AML patients in remission or healthy controls ( Tzoran, 2015). Based on differential abundancy and the content of proteins, lipids and nucleid acids EVs may be suitable as biomarkers for diagnosis, prognosis, and disease monitoring. vii) Pharmacotherapeutic role: Cytotoxic T-lymphocytes are more effective in killing the parental leukaemic cells after being exposed to their cell-derived EVs. The mechanism is related to leukemia antigen presentation on EVs to dendritic cells (DCs) using ICAM1 and Hsp70 ( Shen C, 2011). Finally, EVs can be used as carriers for bioactive compounds and may expand their potential use for cell-type specific delivery of drugs. Conclusions: EVs open the window for the future investigation of novel pathophysiological mechanisms that will improve our understanding of their role in the biology of myeloid malignancies, Moreover, they hold promise as potential biomarkers and drug carriers for cell-type specific treatment

Zanubrutinib, Lenalidomide Combined with R-CHOP As the Frontline Treatment for Mantle Cell Lymphoma

Objectives Mantle cell lymphoma (MCL) has poor prognosis with existing available therapies. Zanubrutinib, a novel BTK inhibitor, has shown promising outcomes in relapsed/refractory MCL. The aim of this retrospective study was to evaluate the efficacy and safety of zanubrutinib combined with R2-CHOP (lenalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in newly diagnosed MCL. Methods We retrospectively analyzed newly diagnosed MCL between September 2020, to March 2023 in a single-center in China. All patients received zanubrutinib 160 mg twice daily, lenalidomide 25 mg daily (days 1 to day 14), rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2 (day 1), doxorubicin 50 mg/m 2 or liposome doxorubicin 40 mg (day 1), vincristine 1.4 mg/m 2 (day 1), and prednisone 100 mg (day 1 to day 5) every 3 weeks. After 4 cycles, autologous hematopoietic stem cell transplantation (ASCT) was performed according to the patient's condition. After 6 cycles of induction or ASCT, patients with an objective response (complete or partial response) continued to receive zanubrutinib twice daily plus rituximab maintenance therapy, administered every 12 weeks for up to 8 additional doses. All patients underwent CT or PET-CT scans to evaluate mid-term efficacy. After 6 cycles, PET-CT scans were evaluated for patients whose mid-term efficacy did not achieve complete metabolic response (CMR). Results All of 5 patients treated with ZR2-CHOP were enrolled. The median age was 50 years (range: 44-66 years), 3 patients were females, 2 patients were males. 3 patients were classical MCL, 1 patient was pleomorphic MCL, and 1 patient was blastoid-variant MCL. The overall response rate was 100% (5 of 5), and all of them achieved CMR (Figure 1). Three patients achieved CMR after 4 cycles received ASCT, two received 6 cycles. At the mid-term evaluation after 4 cycles, 4 patients achieved CMR, 1 patient achieved PR but achieved CMR after 6 cycles. At data cutoff (22 March 2023), the median follow-up time was 26.1 (range, 12.5-32.4) months. The median PFS and OS rates were not reached. The 2-year PFS rate and the 2-year OS rates were both 100% (Figure 2). The most common grade 3/4 adverse events were neutropenia (60%) and thrombocytopenia (40%), all of which were controllable and resolved. The results of WES analysis showed that the most common gene mutations were KMT2D (frequency, 60%) and DDR2 (frequency, 40%). ctDNA was dynamically detected in four patients. Matched analysis of WES and ctDNA showed that gene mutations detected by these two methods were highly consistent, with 3 out of 4 patients being consistent. Among them, one showed negative ctDNA before and after treatment, while the other three patients indicated a decreasing trend in ctDNA mutation rate after 4 or 6 cycles, including a 50% decline or a change from baseline to negative. Conclusions: ZR2-CHOP showed promising preliminary efficacy and acceptable safety in previously untreated patients with MCL.

Role of Pegylated Liposomal Doxorubicin in Heavily Pretreated Relapsed Refractory Hodgkin Lymphoma Eligible for Autologous or Allogeneic Transplantation

In the context of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), various conventional single agents and salvage chemotherapy regimens have been explored, including bendamustine, brentuximab vedotin, nivolumab, and pembrolizumab. However, there is another drug, pegylated liposomal doxorubicin (PLD), which has shown interesting results but is comparatively less recognized and mostly used in combination. For heavily pretreated R/R cHL patients this drug, presenting a reduced cardiac toxicity compared to non-liposomal doxorubicin, may be considered as bridging therapy (BT) to transplantation (both autologous [ASCT] and allogeneic [alloSCT]). The present retrospective study aims to determine the role of PLD monotherapy in terms of safety and effectiveness in heavily pretreated R/R cHL patients as BT to ASCT or alloSCT. Our case series comprises 22 R/R cHL patients who were potentially eligible for transplantation and underwent PLD treatment successfully. These patients had a median of five previous treatments (range, 3-9), including ASCT in 50% of the cases and radiotherapy in 7 out of 22 cases. Of the total, 77% were primary refractory, and 63.6% remained refractory to the last previous therapy before PLD. Additionally, eight patients had advanced stage disease at the time of PLD treatment. PLD was administered at a fixed dose of 60 mg every 21 days with a median of 4 cycles (range, 1-8). No dose reduction was needed. Few toxicities occurred. In detail, four hematological adverse events (AE) were reported in 3 patients (all grade ≥3, drug related but rapidly resolved without sequalae). Only one grade 3 extra-hematological occurred (deep vein thrombosis). Final overall response rate (ORR) was 31.8%, with 4 complete and 3 partial responses (CR, PR). Best ORR of 54.5% was reached at the third cycle (5 CR and 7 PR). Five patients subsequently proceeded to ASCT and 2 to alloSCT with 5 final CR (two patients converted from a PR and 1 from a stable disease). At a median follow-up of 6 years, median overall survival was reached at 4 years. The findings from this retrospective analysis suggest that PLD monotherapy may be effective in treating a subset of patients with multi-relapsed or refractory cHL. PLD could be considered as a strategic and relatively low-toxicity bridging therapy option for patients undergoing transplantation.

A Multicenter, Prospective Clinical Study of the R-CDOP Regimen in Previously Untreated Non-Hodgkin Lymphoma with High Tumor Burden

Background: The treatment of non-Hodgkin lymphoma (NHL) with high tumor burden is facing severe challenges. The response rate and survival of R-CHOP treatment still need to be further explored in these patients. Pegylated liposomal doxorubicin (PLD) is a promising alternative drug to the current regimen, with a safety and efficacy profile through the enhanced permeability and retention effect and longer circulation1-3, and especially less cardiotoxic compared with traditional anthracyclines4. We conducted this prospective study to evaluate the efficacy and safety of PLD combined with R-COP (R-CDOP) regimen in treatment for previously untreated (TN) NHL with high tumor burden. Methods: This study was a single-arm, multicenter, prospective clinical trial (NCT05040555). TN Patients with CD20+ diffuse large B-cell lymphoma or grade 3b follicular lymphoma with high tumor burden were recruited. Patients are considered to have high tumor burden if they meet at least one of the following criteria: (1) presence of at least three lymph nodes with a diameter of 3 cm or more; (2) presence of any lymph nodes or extranodal masses with a diameter of 7 cm or more; (3) presence of hepatomegaly and splenomegaly confirmed by PET-CT; Spleen: female &amp;gt; 15cm, male &amp;gt; 16cm); (4) presence of pleural and peritoneal effusions determined through cytological examination, flow cytometry, or diagnosed by PET-CT, (5) LDH levels exceeding 3 times the upper limit of normal value, and (6) PET-CT TMTV exceeding 220cm3. The patients received PLD (30-35mg/ m2, d1) plus Rituximab (375mg/m2, d0), Cyclophosphamide (750mg/ m2, d1), Vindesine (3mg/ m2, d1) / Vincristine (1.4mg/m2, d1) and Prednisone (60mg/ m2, d1-5) Q3W for 4 (Limited-stage lymphoma) or 6 (Advanced lymphoma) cycles with an additional 2 cycles of Rituximab therapy. The primary endpoints was objective response rate (ORR). The secondary endpoint were complete response rate (CRR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: At the data cut-off of 5 June 2023, 44 eligible pts were enrolled (Table 1). The ORR and CRR was 84.2% (32/38) [95%CI, 68.8%-94.0%] and 60.5% (23/38) [95%CI, 43.4-76.0%], respectively. The DCR was 89.5% (34/38) [95%CI, 75.2%-97.1%]. The median PFS was 14.4 months [95%CI, 4.7%-24.2%], and the median OS was not reached. The median PFS and OS will be updated after long-term follow-up. The most common grade 3/4 AEs were neutropenia (29.5%), leucopenia (25.0%) and anemia (11.4%). Left ventricular ejection fraction (LVEF) declined in 1(1/44, 2.3%) pt, but did not fall below 50%. Congestive heart failure was not occurred. Dose adjustment and treatment delay due to AE occurred in only one pt, and no treatment termination due to AE occurred except for 1 patient death. Conclusions: The preliminary results of the study indicate that the R-CDOP regimen is safe and shows promising efficacy for treating TN NHL with a high tumor burden. References： 1. Hashizume H, Baluk P, Morikawa S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000;156 (4):1363-1380 2. Gabizon A, Shmeeda H, Grenader T. Pharmacological basis of pegylated liposomal doxorubicin: impact on cancer therapy. Eur J Pharm Sci. 2012;45(4):388-398. 3. Sadzuka Y, Sugiyama I, Tsuruda T, et al. Characterization and cytotoxicity of mixed polyethyleneglycol modified liposomes containing doxorubicin. Int J Pharm. 2006;312(1-2):83-89. 4. Lu B, Shen L, Ma Y, et al. Cardiovascular adverse events associated with cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone with or without rituximab ((R)-CDOP) in non-Hodgkin's lymphoma: A systematic review and meta-analysis. Front Pharmacol. 2022;13:1060668.

Preliminary Outcomes of Orelabrutinib Plus R-CHOP in Treatment-Naive Patients with Double-Expression Diffuse Large B-Cell Lymphoma

Background Double-expression lymphoma (DEL), a type of diffuse large B cell lymphoma (DLBCL) with co-expression of MYC and BCL2 proteins without gene rearrangements, is associated with poor prognosis for patients. The double expression of MYC and BCL2 may result in the activation of the B cell receptor (BCR) signaling pathway. Bruton tyrosine kinase (BTK) serves as a rational therapeutic target for DEL due to its crucial role in BCR signaling. The Phoenix study demonstrated that ibrutinib (first generation of BTK inhibitor) plus R-CHOP could improve event-free survival (EFS) and overall survival (OS) in younger patients with DEL. Orelabrutinib is a novel BTK inhibitor with high selectivity to BTK. Orelabrutinib has been shown in a preclinical study that it could preserve the NK-cell-mediated antibody-dependent cellular cytotoxicity induced by rituximab, and combination with R-CHOP (O-RCHOP) displayed higher anti-tumor activity than either alone in vivo or in vitro. This study aimed to evaluate the efficacy and safety of the O-RCHOP regimen in the treatment of naive patients with DEL DLBCL. Methods This was a prospective, single-arm, phase II study recruiting treatment-naive patients with DEL DLBCL. DEL was defined as≥40% positive rate for MYC and ≥50% for BCL2 by immunohistochemistry. The double-hit cases (with gene rearrangement) were excluded. All patients were treated for 6-8 cycles with 21 days per cycle. They received 150 mg of orelabrutinib once daily on days 1-14 combined with R-CHOP (Rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2, liposome doxorubicin 30 mg/m 2, vincristine 1.4 mg on day 1, and prednisone 100 mg daily on days 1-5). The primary endpoint was EFS. The response was assessed after 4 or 6 cycles using PET-CT. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events v 5.0. Results From March 27, 2021 to June 7, 2023, 15 patients with DEL were enrolled. All patients received an O-RCHOP regimen and 13 patients . The baseline characteristics of the patients were listed in Table 1. Thirteen patients who had received at least 4 cycles of treatment achieved CR (100.0%; Figure 1). After a median follow-up of 14.6 months (1.5-27.1 months), the estimated 12-month EFS rate was 100.0%. None of the 13 patients experienced disease progression or death at the cutoff date. Three of the 15 patients had the mutation of TP53 with or without other cytogenetic abnormalities tested by NGS. Grade 3/4 AEs were mainly hematological toxicity including febrile neutropenia (20%; 3/15), neutropenia (66.7%; 10/15), anemia (13.3%; 2/15), and thrombocytopenia (6.6%; 1/15), which were manageable. Neutropenia mainly occurred after the first cycle of chemotherapy, which improved after prophylaxis of PEG-rhG-CSF. The incidence of all-cause infection was 13.3% (2/15) . No atrial fibrillation, tumor lysis syndrome, or hemorrhage were observed. No patients discontinued treatment due to toxicity. Conclusion The combination of orelabrutinib and RCHOP showed encouraging efficacy and a tolerable safety profile in DEL DLBCL in this preliminary analysis. More updated data from this ongoing study will be provided in the future.

A Novel Nomogram Predicting Rituximab-Associated Interstitial Pneumonia in Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Single-Center

Background: The incidence rate of rituximab-induced interstitial lung disease (RILD) was reported to be 3.7%-16.7%. The onset of RILD was insidious, and the clinical symptoms were atypical. The course of the RILD progressed rapidly without timely treatment. However, there were no models reported to predict the risk of RILD. Herein, we investigated the incidence of RILD in consecutive patients with diffuse large B-cell lymphoma (DLBCL) and its correlation with clinicopathological features, and a novel nomogram was constructed to successfully predict the risk of RILD. Methods: The clinicopathological data of 110 consecutive patients with DLBCL who were treated in the Department of Hematology of Beijing Tongren Hospital from January 2020 to December 2022 were retrospectively collected, and all patients received first-line treatment regimens containing rituximab. The occurrence of interstitial pneumonia was assessed by chest CT or interim PET-CT. Efficacy was assessed according to Lugano criteria, and chi-square test was used to assess the difference in RILD in different characteristic groups. Results: The complete remission rate of 110 patients with DLBCL after treatment was 84.2%. Twenty-one patients (19.1%) developed RILD during treatment, and the median time of occurrence was the 4th cycle（range: 2~8). The median duration of treatment for RILD was 10 days (range: 5~60). Except for 5 patients with no obvious symptoms, all 16 patients received glucocorticoid-containing regimens, and all patients improved after treatment. The incidence of RILD was significantly higher in patients who received liposomal doxorubicin-containing regimens than those treated with adriamycin regimens (29.7% versus 13.7%, P=0.043). Smoking ( P=0.298) and advanced age ( P=0.156) were associated with a high incidence of RILD. Then we developed a RILD risk prediction model according to the risk factors, and the patients were divided into high-risk and low-risk groups, and the incidence of RILD was significantly different between the two groups ( P=0.027). Finally, a novel nomogram related to the occurrence of RILD in DLBCL patients was developed to scientifically and accurately predict the incidence of RILD. Conclusion: Patients with DLBCL should be alert to the occurrence of RILD after chemotherapy with rituximab-containing regimen, especially in smoking and elderly patients, and the prevention and monitoring of RILD should be strengthened after the application of liposomal doxorubicin.

The Mini-Teddi-R Treatment Demonstrated a High Rate of Remission in Patients with DLBCL Involving the CNS Who Had Previously Been Exposed to BTK Inhibitors

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a bleak prognosis. TEDDI-R has been successful in achieving lasting remission in relapsed/refractory primary DLBCL of the CNS (PCNSL), but the effectiveness of ibrutinib-responsive tumors in SCNSL remains unknown. This study presents initial findings from the use of mini-TEDDi-R in SCNSL. Methods: Efficacy and safety data of mini-TEDDi-R were retrospectively analyzed for patients with DLBCL involving the CNS. All patients experienced relapse in the CNS or/and peripheral region after initial therapy. Brain parenchyma involvement allowed for treatment with MTX, Ara-c, and/or BTK inhibitors. The dosage of the drugs used in the original regimen was reduced, leading to the adoption of the term “mini-TEDDi-R.” Each 21-day cycle involved the following treatments: intravenous rituximab at a dose of 375 mg/m 2/day on days 1-2, oral temozolomide at a dose of 150 mg/m 2/day on days 2-5, intravenous infusion of 30 mg/m 2/day etoposide on days 2-5, intravenous infusion of 25 mg/m 2 of pegylated liposomal doxorubicin on day 2, intravenous infusion of dexamethasone at a dose of 10 mg/m 2/BID on days 1-5, and oral zanubrutinib at a dose of 200mg/BID or oral orelabrutinib at a dose of 150mg/qd or oral ibrutinib at a dose of 560mg/qd from day 1 until neutrophil count &amp;lt;0.5*10^9/L or platelet count &amp;lt;30*10^9/L. Additionally, intrathecal administration of 70 mg of cytarabine occurred on days 1 and 5, All remissions observed on MRI were confirmed through FDG-PET and CSF analysis. Results: Between December 2019 and June 2023, 24 patients with a median age of 53 (range 28-69) received mini-TEDDi-R treatment. All patients had DLBCL, comprising 16 (66.7%) non-GCB, 6 (25%) GCB, and 2 (8.3%) transformed from FL. All patients experienced relapse in the CNS system after a median of 6 (range 1-17) prior therapies, and all (100%) patients received prior anthracycline treatment. A total of 21 patients (87.5%) had received multiple lines of therapy before mini-TEDDi-R. Among them, 19 patients (79.2%) had received HD-MTX based salvage therapy, 11 patients (45.8%) had received HD-Ara-c based salvage therapy, and 14 patients (58.3%) had been exposed to BTK inhibitors. Seven patients (29.2%) showed triple resistance to MTX, Ara-c, and BTK inhibitors. Six patients had previously undergone transplantation, and four patients had experienced failure of CD19 CART treatment. Thirteen patients (54.2%) had isolated CNS disease, while 11 patients (45.8%) had both CNS and peripheral disease. Thirteen patients (54.2%) underwent 1 cycle of mini-TEDDi-R, 8 patients (33.3%) completed 2 cycles, 2 patients (8.3%) finished 3 cycles, and 1 patient (4.2%) completed 4 cycles. The objective remission rate (ORR) was determined to be 70.8%, with a complete remission (CR) rate of 58.3%. Notably, patients (N=14) exposed to BTK inhibitors previously exhibited a similar CR rate compared to patients (N=10) who had not received prior BTK inhibitor treatment (50% vs. 70%, p = 0.348). Patients (N=19) who had undergone HD-MTX based salvage therapy achieved an ORR of 74% and a CR rate of 58%. No significant difference in response rate was observed between patients with peripheral and non-peripheral secondary CNS involvement. In patients who achieved complete remission, only one patient experienced a second CNS relapse. Four patients bridged to auto-HSCT, 2 patients bridged to CART treatment, and 4 patients underwent auto-HSCT combined with CART treatment for consolidation. The median overall survival and median PFS have not been reached within the 11.8-month follow-up period. Toxicity was evaluated over 39 cycles. Grade 3 and 4 neutropenia occurred in 51% and 16% of cycles, respectively, while febrile neutropenia was observed in 10% of cycles. The median duration of neutropenia was 6 days (range 4-10). Three cycles (8%) were complicated by infections graded as ≥G3, but no opportunistic infections (including Aspergillus) were observed. Grade 3 and 4 thrombocytopenia occurred in 26% and 14% of cycles, respectively. The median duration of neutropenia was 7 days (range 3-14). Conclusions: The mini-TEDDi-R regimen demonstrated a favorable remission rate in patients with DLBCL involving the CNS. The treatment was well-tolerated, and patients with tumors that were previously exposed to BTK inhibitors and HD-MTX treatment also showed positive responses to mini-TEDDi-R.

CD44-specific short peptide A6 boosts cellular uptake and anticancer efficacy of PEGylated liposomal doxorubicin in vitro and in vivo

Although liposomes have improved patient safety and the pharmacokinetic profile of free drugs, their therapeutic efficacy has only shown marginal improvement. The incorporation of active-targeted ligands to enhance cellular uptake has shown promise in preclinical studies. However, no active-targeted liposomes have successfully translated into clinical use thus far. This study aimed to evaluate the targeting ability and antitumor efficiency of A6, a specific short peptide (KPSSPPEE) when incorporated into PEGylated liposomal doxorubicin (PLD). The results revealed significantly enhanced cellular uptake. The cytotoxicity of the formulations was determined by 3 h and 6 h incubation of formulations with cells, followed by 48 h incubation to evaluate the targeted ability of the formulations and the results indicated the higher cytotoxicity of A6-PLD (IC50 of 7.52 µg/mL after 6 h incubation) in the CD44 overexpressing C26 cell line compared to non-targeted PLD (IC50 of 15.02 µg/mL after 6 h incubation). However, CD44-negative NIH-3T3 cells exhibited similar uptake and in vitro cytotoxicity for both A6-PLD (IC50 of 38.05 µg/mL) and PLD (IC50 of 34.87 µg/mL). In animal studies, A6-PLD demonstrated significantly higher tumor localization of doxorubicin (Dox) (~ 8 and 15 µg Dox/g tumor for 24 and 48 after injection) compared to PLD (~ 6 and 8 µg Dox/g tumor for 24 and 48 after injection), resulting in effective inhibition of tumor growth. The median survival time (MST) for Dextrose 5% was 10, PLD was 14 and A6-PLD was 22 days. In conclusion, A6-PLD, a simple and effective targeted liposome formulation, exhibits high potential for clinical translation. Its improved targetability and antitumor efficacy make it a promising candidate for future clinical applications.

Harnessing Nanomedicine to Potentiate the Chemo-Immunotherapeutic Effects of Doxorubicin and Alendronate Co-Encapsulated in Pegylated Liposomes.

Encapsulation of Doxorubicin (Dox), a potent cytotoxic agent and immunogenic cell death inducer, in pegylated (Stealth) liposomes, is well known to have major pharmacologic advantages over treatment with free Dox. Reformulation of alendronate (Ald), a potent amino-bisphosphonate, by encapsulation in pegylated liposomes, results in significant immune modulatory effects through interaction with tumor-associated macrophages and activation of a subset of gamma-delta T lymphocytes. We present here recent findings of our research work with a formulation of Dox and Ald co-encapsulated in pegylated liposomes (PLAD) and discuss its pharmacological properties vis-à-vis free Dox and the current clinical formulation of pegylated liposomal Dox. PLAD is a robust formulation with high and reproducible remote loading of Dox and high stability in plasma. Results of biodistribution studies, imaging with radionuclide-labeled liposomes, and therapeutic studies as a single agent and in combination with immune checkpoint inhibitors or gamma-delta T lymphocytes suggest that PLAD is a unique product with distinct tumor microenvironmental interactions and distinct pharmacologic properties when compared with free Dox and the clinical formulation of pegylated liposomal Dox. These results underscore the potential added value of PLAD for chemo-immunotherapy of cancer and the relevance of the co-encapsulation approach in nanomedicine.

Gemcitabine and Liposomal Doxorubicin (GemDox) for the Treatment of Relapsed and Refractory T-Cell Lymphomas

Introduction: Aggressive T-cell lymphomas (TCL) account for 10-15% of non-Hodgkin's lymphomas and have lower rates of complete response (CR), overall response (OR), and shorter duration of response (DOR) to chemotherapy than other types of NHL, particularly in the relapsed setting. Cutaneous T-Cell lymphoma (CTCL) is treated initially with skin directed therapies, but systemic therapy or cytotoxic chemotherapy may become necessary to control disease. Second-line chemotherapy benefits only a small minority of TCL patients and more effective treatment regimens are needed. Gemcitabine and liposomal doxorubicin have both shown single agent activity in TCL and have been used in combination in patients with relapsed B-cell lymphomas (BCL) and Hodgkin lymphomas (HL), though responses are typically not durable. Therefore, we evaluated a combination of gemcitabine and liposomal doxorubicin (GemDox) for patients with relapsed/refractory (r/r) TCL. Methods: In this single-center, retrospective study, we evaluated the safety, efficacy, and survival (PFS/OS using Kaplan-Meier method) of GemDox in TCL. Patients either received gemcitabine 1000 mg/m 2 and liposomal doxorubicin 15 mg/m 2 either on days 1 and 8 every 21 days (21-day regimen) or gemcitabine 1000 mg/m 2 and liposomal doxorubicin 15 mg/m 2 on days 1 and 15 every 28 days (28-day regimen). Results: 18 patients (13 CTCL, 5 PTCL) with r/r aggressive TCL were treated with GemDox, with 16 evaluable for treatment response. Patients were heavily pre-treated with a median number of 4 prior therapies (range 2-7). This included 62% of CTCL patients with nodal involvement. The overall response rate (ORR) was 50% (19% CR and 31% PR) with a median PFS and OS of 5 and 15 months respectively. In patients that had a response to treatment, the median PFS was 11 months while median OS was not reached. The clinical benefit rate [CR/Partial response (PR)/stable disease (SD)] for CTCL and PTCL was 82% and 40% respectively. The median PFS and OS for CTCL patients was 6 months and 14 months respectively, with an ORR of 55% (18% CR and 36% PR). For PTCL , the median PFS and OS were 4 and 21 months respectively, with an ORR of 40% (20% CR and 20% PR). The clinical benefit (CR/PR/SD) rate for the 21-day vs 28-day regimen was 71% and 67%, respectively, with similar PFS and OS, and no significant difference in toxicities. The median duration of response (DOR) for patients that obtained a response (CR/PR) in evaluable patients was 13 months; 17 months for CTCL, and 5 months for PTCL. We observed a substantial decrease in CTCL skin manifestations, as patients that had a CR/PR had a mean decrease of 76% in mSWAT BSA of 70%. Further, six patients (38%) (5 CTCL, 1 PTCL) were able to proceed to allogeneic stem cell transplant (allo-HSCT). Interestingly, 4 CD30+ CTCL patients were previously treated with brentuximab vedotin (BV). Of those, three (75%) had a response to GemDox, while only one achieved a response (PR) to BV. This demonstrates that GemDox is a potentially effective regimen in heavily refractory CD30+ CTCL patients that fail treatment with BV. 11 patients (61%) experienced any grade 3/4 toxicity and hematologic toxicities were the most common including: anemia (33%), neutropenia (22%), lymphopenia (17%) and thrombocytopenia (17%)., GemDox was very well tolerated with the most common grade 3/4 non-hematologic toxicity being fatigue (17%). 11% of patients discontinued therapy due to adverse events. Conclusion: GemDox produced an excellent ORR of 50%, with an impressive ORR of 82% in CTCL, suggesting this is an effective regimen for heavily pre-treated TCL patients. Additionally, a large number of patients with CTCL with heavy skin burden, including those refractory to BV, were able to achieve remarkable skin responses. Importantly, in this study, 75% of patients who responded to GemDox were able to proceed to allo-HSCT, with 66% experiencing a sustained response. Based on these findings, GemDox should be further investigated as a therapeutic option in relapsed aggressive TCL, particularly in CTCL and considered as a potential bridging therapy patients with a treatment goal of obtaining allo-HSCT and providing a long-term benefit.

Interim Results of the Launch Study-a Multicenter, Open-Label Study of Selinexor, Dexamethasone and Chemotherapy Drugs in Relapsed/ Refractory Multiple Myeloma

Background: Exportin 1 (XPO1) is involved in the nuclear export of tumor suppressor proteins (TSPs) and associated with poor prognosis and drug resistance in multiple myeloma. Selinexor is a novel, oral, first-in-class selective inhibitor of XPO1 that was approved by the US FDA for the treatment of patients with relapsed/ refractory multiple myeloma (RRMM) based on the STORM study of selinexor (80mg biweekly) in combination with dexamethasone (20mg biweekly) (Xd). Furthermore, in pre-clinical studies, selinexor played a synergistic anti-tumor role with chemotherapy drugs, however clinical data is lacking on such combination treatment. Methods: The LAUNCH study is a multicenter, open-label study (NCT04877275) which enrolled RRMM patients at least one prior treatment. There are two arms in this study, with 25 patients in each arm. XDd Arm: Selinexor 80mg d1,8,15,22, Dexamethasone 40mg d1,8,15,22, and Liposomal Doxorubicin 25-35 mg/m 2 d1; XCd Arm: Selinexor 100mg d1,8,15,22, Dexamethasone 40mg d1,8,15,22, and Cyclophosphamide 300mg/m2 d1,8,15,22. 28d per cycle in both arms. The primary endpoint is objective response rate (ORR), secondary endpoints including clinical benefit rate (CBR), duration of response (DOR) and 1-year progression free survival (PFS) Results: As of July 26, 2023, 44 patients were enrolled (25 in XDd and 19 in XCd), XDd arm has completed recruitment. Of these, 23 patients were male and 21 were female. The median age was 60 years (range: 29-74years). The median time since initial diagnosis was 4.0 years (range: 0.5-15.5years). The median number of prior treatments was 3 (range: 1- 10). There were 13 patients (29.5%) with high-risk cytogenetic abnormalities, 8 patients (18.2%) with extramedullary disease (EMD). Eight patients (18.2%) received prior autologous stem cell transplantation and 7 patients (15.9%) received CAR-T therapy. Forty-two patients (95.5%) were exposed to bortezomib, 35 patients (79.5%) were exposed to lenalidomide, 18 patients (40.9%) exposed to pomalidomide, and 10 patients (22.7%) exposed to daratumumab. The median treatment duration of all patients was 13 weeks (range: 1- 48). Thirteen patients remained on treatment. Based on the 35 patients evaluated for efficacy, the ORR was 48.6% (52.4% in XDd arm, n=21; and 42.9% in XCd arm, n=14) including 1 CR, 1 VGPR and 15 PRs. Three patients achieved MR and 12 patients had stable disease. The most common hematological adverse events (AEs) (All Grades, Grade ≥3) were thrombocytopenia (61.4%, 27.3%), leukopenia (54.5%, 34.1%), and anemia (45.5%, 29.5%). The most common non-hematological AEs (All Grades, Grade ≥3) were fatigue (47.7%, 2.3%) nausea (45.5%, 2.3%) and vomiting (31.8%, 4.5%). Most treatment related adverse events occurred in the first 8 weeks and were alleviated over time. Conclusion: Once weekly selinexor and dexamethasone (Xd) combined with cyclophosphamide or liposome doxorubicin showed encouraging efficacy and manageable safety in treatment for RRMM. This enrollment is still ongoing and data on all participants will be reported in due course.