Refractory Setting Research Articles

‘Fast but not so Furious’: Short observation time after subcutaneous Daratumumab administration is both a safe and cost-effective strategy

BackgroundDaratumumab, an anti-CD38 monoclonal antibody, is a key component in the treatment paradigms of multiple myeloma and AL amyloidosis in both the newly diagnosed and relapsed and/or refractory setting. Intravenous (IV) daratumumab administration requires extended infusion times and is associated with higher rates of infusion related reactions (IRRs) when compared to the subcutaneous (SC) formulation. We report real world safety outcomes and infusion chair time savings associated with SC administration in daratumumab naïve patients. MethodsWe retrospectively analyzed medical records at our institution for the incidence and severity of IRRs following differing observation periods post SC daratumumab administration. Infusion chair time was calculated to quantify chair time savings with SC administration. ResultsSixty-six daratumumab naïve patients were included. Nine percent of patients developed IRRs with SC daratumumab with all reactions occurring within six hours of the first dose. All reactions were grade ≤ 2 in severity and were reversible with supportive care. Over the 18 month study period, a total of 904 SC doses were administered, amounting to a potential 1785 hours of infusion chair time savings when compared to IV administration. ConclusionSC daratumumab may be given safely with a short initial observation period and without observation for subsequent doses, resulting in reduced infusion chair time as well as administration related cost and resources.

Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond.

Simple SummaryGastric and gastro-oesophageal junction cancers (GC) are the fourth cause of cancer-related deaths, representing an international problem which needs a proper assessment. Beyond being an aggressive disease, which rapidly progress to different lines of treatment, patients suffering GC normally present a non-depreciable number of symptoms that make them especially fragile. In this context, sequential treatment lines with few toxic adverse events have been associated to an increased survival. A satisfactory GC therapy comprise at least three lines of treatment including chemotherapy and immunotherapy and/or targeted agents when indicated.Gastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC.

Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell-Mediated Antitumor Immune Responses.

Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I PRMTs remains uncharacterized. Here, our The Cancer Genome Atlas dataset analysis revealed that expression of type I PRMTs associated with poor clinical response and decreased immune infiltration in patients with melanoma. In cancer cell lines, inhibition of type I PRMTs induced an IFN gene signature, amplified responses to IFN and innate immune signaling, and decreased expression of the immunosuppressive cytokine VEGF. In immunocompetent mouse tumor models, including a model of T-cell exclusion that represents a common mechanism of anti-programmed cell death protein 1 (PD-1) resistance in humans, type I PRMT inhibition increased T-cell infiltration, produced durable responses dependent on CD8+ T cells, and enhanced efficacy of anti-PD-1 therapy. These data indicate that type I PRMT inhibition exhibits immunomodulatory properties and synergizes with immune checkpoint blockade (ICB) to induce durable antitumor responses in a T cell-dependent manner, suggesting that type I PRMT inhibition can potentiate an antitumor immunity in refractory settings.

Advances and Personalized Approaches in the Frontline Treatment of T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogenous subset of non-Hodgkin lymphoma characterized by an aggressive clinical course. Historically, the treatment of PTCLs have been analogous to that of aggressive B-cell lymphomas; however, it has been well-established that overall responses and complete remission rates are far inferior using near-identical chemotherapy strategies. Recently, there has been a plethora of newer agents designed to target distinguishing cellular and molecular features of specific PTCL subtypes. These agents have been proven to yield superior anti-lymphoma responses and, in some cases, overall survival in the relapsed, refractory, and frontline treatment setting. In this review, we will summarize and highlight the most influential clinical trials leading to the Food and Drug Administration (FDA) approval of several novel therapeutic agents against PTCL, with an emphasis on emerging studies and strategies to expand their potential use in the frontline treatment setting.

Follicular Lymphoma: a Focus on Current and Emerging Therapies

Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

Comparative analysis of overall survival in patients with HER2-amplified treatment-refractory metastatic colorectal cancer treated with pertuzumab plus trastuzumab in Mypathway and patients treated in the real-world.

36 Background: ML28897 (MyPathway) is a multi-basket trial evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. In MyPathway, patients with treatment-refractory HER2-amplified metastatic colorectal cancer (mCRC) were enrolled and received pertuzumab plus trastuzumab. In order to facilitate contextualization of the outcome of pertuzumab plus trastuzumab in MyPathway, we conducted a retrospective study to compare with the outcome in real-world HER2-amplified mCRC patients. Methods: Overall survival (OS) was used as the endpoint to compare outcomes from MyPathway (PER/HER arm) and the external control of HER2-amplified mCRC patients treated with any therapy except anti-HER2 therapy in the refractory setting (EC arm) from the US-based de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). The de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). OS was defined as time from first treatment to death in the PER/HER arm and from index date (initiation of treatment in the refractory setting) to death in the EC arm. For patients in the CGDB who had met study eligibility criteria at multiple index dates, all eligible index dates were used for the analysis. Standardized mortality ratio weighting based on propensity score was used for deriving the pseudo-population (post-weighting population). In the post-weighting population, multivariate Cox regression models and Kaplan-Meier analyses were used to compare between the arms. A series of sensitivity analyses were conducted to investigate the robustness and consistency of the primary analysis results. Results: The PER/HER arm consisted of 57 patients who had treatment-refractory mCRC with HER2 amplification and enrolled in the MyPathway by August 1, 2017 data cutoff. For the EC arm, 64 HER2-amplified mCRC patients were selected from CGDB collected between January 1, 2011 and December 31, 2019. After applying the predefined inclusion/exclusion criteria set to be similar to those in the MyPathway, 27 eligible index dates were selected from 18 eligible patients and used for primary analysis. In the post-weighting population, the hazard ratio (HR) for OS estimated by multivariate Cox regression model was 0.729 (95% CI: 0.184-3.900) and median survival in the PER/HER arm and the EC arm were 11.47 months (95% CI: 7.72-22.11) and 9.72 months (95% CI: 7.43-22.21), respectively. The results of the all sensitivity analyses were consistent with those in the primary analysis in terms of the point estimate of HR. Conclusions: Despite a small sample size, the totality of findings suggests that the combination of pertuzumab and trastuzumab could have a potential benefit in OS for this population.

Targeted Therapy for Relapsed/Refractory Follicular Lymphoma: Focus on Clinical Utility of Tazemetostat.

The management of follicular lymphoma (FL) in the relapsed and refractory setting is challenging and an area of ongoing investigation. Epigenetic dysregulation has recently been shown to be a hallmark of FL. Mutations in histone-modifying genes are likely early, driver events in FL pathogenesis, and so are attractive targets to drug. Gain-of-function mutations in the histone methyltransferase EZH2 are common in FL and maintained through disease evolution. With mounting data supporting a critical role for EZH2 as an oncogenic driver for FL, the small molecule inhibitor, tazemetostat, was developed. Tazemetostat has shown promising activity in preclinical models and early phase trials. Importantly, responses were seen in patients with high-risk features. Based on these data, tazemetostat was approved in the US in 2020 for EZH2mut patients with FL who had received at least two prior lines of systemic therapy, or for EZH2wt patients without alternative treatment options. Here, we will review the biology of FL as it pertains to tazemetostat, the available clinical trial data, and future directions for this new therapy.

Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia

BackgroundDiagnosis of acute myeloid leukemia (AML) is associated with poor outcome in elderly and unfit patients. Recently, approval of the BCL-2 inhibitor venetoclax (VEN) in combination with hypo-methylating agents (HMA) led to a significant improvement of response rates and survival. Further, application in the relapsed or refractory (r/r) AML setting or in context of allogeneic stem cell transplantation (alloHSCT) seems feasible.Methods and patientsFifty-six consecutive adult AML patients on VEN from January 2019 to June 2021 were analyzed retrospectively. Patients received VEN either as first-line treatment, as subsequent therapy (r/r AML excluding prior alloHSCT), or at relapse after alloHSCT. VEN was administered orally in 28-day cycles either combined with HMA or low-dose cytarabine (LDAC).ResultsAfter a median follow-up of 11.5 (range 6.1–22.3) months, median overall survival (OS) from start of VEN treatment was 13.3 (2.2–20.5) months, 5.0 (0.8–24.3) months and 4.0 (1.5–22.1) months for first-line, subsequent line treatment and at relapse post-alloHSCT, respectively. Median OS was 11.5 (10–22.3) months from start of VEN when subsequent alloHSCT was carried out. Relapse-free survival (RFS) for the total cohort was 10.2 (2.2 – 24.3) months. Overall response rate (composite complete remission + partial remission) was 51.8% for the total cohort (61.1% for VEN first-line treatment, 52.2% for subsequent line and 42.8% at relapse post-alloHSCT). Subgroup analysis revealed a significantly reduced median OS in FLT3-ITD mutated AML with 3.4 (1.9–4.9) months versus 10.4 (0.8–24.3) months for non-mutated cases, (HR 4.45, 95% CI 0.89–22.13, p = 0.0002). Patients harboring NPM1 or IDH1/2 mutations lacking co-occurrence of FLT3-ITD showed a survival advantage over patients without those mutations (11.2 (5–24.3) months versus 5.0 (0.8–22.1) months, respectively, (HR 0.53, 95% CI 0.23 – 1.21, p = 0.131). Multivariate analysis revealed mutated NPM1 as a significant prognostic variable for achieving complete remission (CR) (HR 19.14, 95% CI 2.30 – 436.2, p < 0.05). The most common adverse events were hematological, with grade 3 and 4 neutropenia and thrombocytopenia reported in 44.6% and 14.5% of patients, respectively.ConclusionDetailed analyses on efficacy for common clinical scenarios, such as first-line treatment, subsequent therapy (r/r AML), and application prior to and post-alloHSCT, are presented. The findings suggest VEN treatment combinations efficacious not only in first-line setting but also in r/r AML. Furthermore, VEN might play a role in a subgroup of patients with failure to conventional chemotherapy as a salvage regimen aiming for potential curative alloHSCT.

Relapsed Refractory Hodgkin Lymphoma and Brentuximab Vedotin-Bendamustine Combination Therapy as a Bridge to Transplantation: Real-World Evidence From a Middle-Income Setting and Literature Review

IntroductionDespite high cure rates with standard treatment, 30% patients with Hodgkin lymphoma develop relapsed or refractory (R/R) disease. Salvage therapy followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care. Brentuximab Vedotin (Bv) in combination with Bendamustine (B) has been tested in the salvage setting with promising results.Materials and MethodologyWe conducted a single centre retrospective chart review of patients who received BBv salvage therapy to determine its activity and safety in patients with R/R classical Hodgkin lymphoma (HL). Between May 2011- December 2019, 179 patients were diagnosed with R/R HL.ResultsThirty patients received BBv [median age: 30 (15-59) years, females (n=15)]. Primary refractory disease in 19 patients (63%), and 26 patients (87%) had advanced stage at treatment. Most patients received BBv after 2 prior lines of therapy [n=16 (53%)]. The median number of cycles of BBv were 3 (1-6). The number of BBv cycles delivered as outpatient was 63%. The most common Grade III/IV hematological adverse event was neutropenia [n=21, (70%)], while grade III/IV non-hematological toxicities included infections in 4 (13%), neuropathy in 4(13%), skin rash in 2 (7%), GI toxicities in 3 (10%) and liver dysfunction in 2 (7%) patients. The ORR and CR rates were 79% and 62%, respectively. Seventeen patients (57%) underwent an autologous HCT and 8 (26%) underwent an Allogeneic HCT (all haploidentical). The median follow up time from BBv administration was 12 months. Six patients died: 2 = disease progression, and 4 = non-relapse causes (Infection and sepsis = 2, GVHD=2). In addition to this, one patient progressed soon after HCT and another patient relapsed 22 months post HCT. Three year Overall survival (OS) and Event free survival (EFS) probability post-BBv treatment was 75% and 58%, respectively. OS and EFS analysis based on response (viz., CMR) to BBv demonstrated that patients in CMR had better survival probability [93% (p=0.0022) 3yr-OS and 72% (p=0.038) 3yr-EFS probability].ConclusionsBBv is an active and well-tolerated salvage treatment for patients with R/R HL, even in refractory and advanced settings. In middle-income settings, cost constraints and access determine patient uptake of this regimen.

European-Australasian consensus on the management of advanced gastric and gastro-oesophageal junction cancer: current practice and new directions.

Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2-targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making.

Follicular Lymphoma: a Focus on Current and Emerging Therapies

Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

Emerging mechanisms of immunotherapy resistance in sarcomas.

Sarcomas are a heterogeneous group of over 150 mesenchymal neoplasms of bone and soft tissue. Clinical prognosis remains poor in the metastatic and refractory setting, despite treatment with traditional chemotherapies. A subset of sarcoma patients can exhibit remarkable responses to novel immune therapies; however, most patients will not respond. Emerging data from genetic and transcriptomic datasets suggests that patients who are resistant to checkpoint inhibitor monotherapy may have low expression of immune-related genes, suggesting that the sarcoma was not sufficiently immunogenic to trigger or maintain an immune response to generate tumor-specific immune effector cells. In this review, we discuss the emerging data surrounding potential mechanisms of resistance, including various biomarkers explored in clinical trials of immune therapy for sarcomas. We also review future directions in clinical trials that are focused on boosting tumor immunogenicity to improve the activity of checkpoint inhibitors, as well as adoptive cellular therapy approaches to bypass deficiencies in neoantigens or antigen presentation.

Current and Future Therapies for Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) is an indolent non-Hodgkin lymphoma with three subtypes: nodal, extranodal and splenic. Initial therapies can vary based on the subtype of MZL, location of disease and stage of disease. Treatment of MZL in the relapsed refractory (R/R) setting has evolved in recent years with the approvals of Bruton's tyrosine kinase inhibitors, phosphoinositide 3-kinase inhibitors and an immune modulatory drug, lenalidomide. Questions remain as to how best to use these agents to maximize efficacy and minimize toxicity. In this article, we focus on the management of MZL with currently available agents, particularly in the R/R setting. We also examine the therapies that may further change the treatment paradigm for MZL. Specifically, we discuss the available data for chimeric antigen receptor T-cell therapies and CD20–CD3 bispecific antibodies, and consider the limitations and potential benefits of these approaches.

MicroRNA Content of Ewing Sarcoma Derived Extracellular Vesicles Leads to Biomarker Potential and Identification of a Previously Undocumented EWS-FLI1 Translocation.

Objective: Ewing Sarcoma Family of Tumors (ESFT) are a highly aggressive pediatric bone and soft tissue malignancy with poor outcomes in the refractory and recurrent setting. Over 90% of Ewing Sarcoma (ES) tumors are driven by the pathognomonic EWS-ETS chimeric transcripts and their corresponding oncoproteins. It has been suggested that the EWS-ETS oncogenic action can mediate microRNA (miRNA) processing. Importantly, small extracellular vesicles (sEVs), including those frequently referred to as exosomes have been shown to be highly enriched with tumor-derived small RNAs such as miRNAs. We hypothesized that ESFT-specific sEVs are enriched with certain miRNAs which could be utilized toward an exo-miRNA biomarker signature specific to this disease. Methods: We performed miRNAseq to compare both the exo-derived and cell-derived miRNA content from 8 ESFT, 2 osteosarcoma, 2 non-cancerous cell lines, and pediatric plasma samples. Results: We found that sEVs derived from ESFT cells contained nearly 2-fold more number of unique individual miRNAs as compared to non-ESFT samples. Quantitative analysis of the differential enrichment of sEV miRNAs resulted in the identification of 62 sEV-miRNAs (exo-miRNAs) with significant (P < .05) enrichment variation between ESFT and non-ESFT sEV samples. To determine if we could utilize this miRNA signature to diagnose ESFT patients via a liquid biopsy, we analyzed the RNA content of total circulating sEVs isolated from 500 µL plasma from 5 pediatric ESFT patients, 2 pediatric osteosarcoma patients, 2 pediatric rhabdomyosarcoma patients, and 4 non-cancer pediatric controls. Pearson's clustering of 60 of the 62 candidate exo-miRNAs correctly identified 80% (4 of 5) of pathology confirmed ESFT patients. Importantly, RNAseq analysis of tumor tissue from the 1 outlier, revealed a previously uncharacterized EWS-FLI1 translocation.Conclusions: Taken together, these findings support the development and validation of an exo-miRNA-based liquid biopsy to aid in the diagnosis and monitoring of ESFT.

Differential Outcomes of Salvage with FLAG-IDA and Venetoclax-Based Regimens in Relapsed and Refractory Acute Myeloid Leukemia

Background: Sequencing and selection of salvage regimens for acute myeloid leukemia (AML) remains unclear. Venetoclax augmentation of a hypomethylating agent (HMA) backbone has joined the salvage armamentarium following impressive performance in the front-line setting. However, little is known about the outcomes with venetoclax in relapsed and refractory (R/R) AML. Survival and toxicity data remain scarce for venetoclax-based salvage, particularly when compared to intensive reinduction. This study characterizes outcomes between venetoclax-based salvage regimens and FLAG-IDA in the R/R setting.Patients & Methods: We retrospectively analyzed all patients with AML treated at Massey Cancer Center younger than 65 in the R/R setting with either FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) or venetoclax in combination with decitabine, azacitidine, or low-dose cytarabine from June 2018 to December 2020. Baseline patient demographics and disease characteristics were obtained and recorded in RedCap. Statistical analyses using unpaired t-test with Welch's correction or the Mann-Whitney test, Fischer's exact test, and Kaplan-Meier survival analyses were computed and compared with log-rank tests using GraphPad Prism. The event for calculating the overall survival was the date of death with patients otherwise censored at the date of last contact.Results: Twenty-eight patients were identified meeting inclusion criteria: 19 underwent salvage with venetoclax-based regimens and 9 patients were treated with FLAG-IDA. Five patients (55.6%) in the FLAG-IDA cohort underwent salvage for refractory disease (primary induction failure), compared to only two (10.5%) in the venetoclax group, which was statistically significant (p = 0.019). The remaining patients in both cohorts were treated in the relapsed setting. There was no significant difference in sex (p = >0.999), ECOG performance status at diagnosis (p = 0.083), or Charlson Comorbidity Index (CCI) scores (p = 0.128). The median age of patients treated with FLAG-IDA was 39 (range: 24 - 62), the four most common molecular mutations in the FLAG-IDA cohort occurred at a frequency of 22.2% each: FLT3-ITD, NPM1, WT1, and biallelic CEBPA. Two patients (22.2%) had favorable cytogenetics at diagnosis, one (11.1%) had intermediate cytogenetics, five (55.6%) had adverse cytogenetics, and one was unknown. All were initially treated with a 7+3 backbone. The most common non-hematological toxicities were neutropenic fever (55.6%) and acute kidney injury (22.2%). Five (55.6%) achieved CR and one (11.1%) achieved CRi for an ORR of 66.7%. There were no deaths within 60 days of salvage. Five (55.6%) patients went on to receive allogeneic SCT. Median survival was not reached at a median follow-up of 430 days (14.1 months).In the venetoclax-based cohort of 19 patients, the median age was 58 (range: 23 - 65), At the time of initial diagnosis, the most common molecular aberrations were TP53 (26.3%), NPM1 (15.7%), followed by FLT3-TKD, RUNX1, and TET2 (10.5% each). Two (10.5%) patients had favorable cytogenetics at initial diagnosis, two (10.5%) had intermediate, 14 (73.7%) had adverse cytogenetics, and one patient had unknown cytogenetics. Seventeen (89.5%) patients were initially treated with 7+3, one (5.3%) was treated with azacitidine, and one (5.3%) was treated with CPX-351. The most common non-hematological toxicities were infection (42.1%), neutropenic fever (31.6%), and GI toxicity (15.8%). Two (10.5%) patients achieved CR and four (21.1%) achieved CRi for an ORR of 31.6%. There were 3 deaths in 30 days and 1 death within 60 days. Four (21.1%) went on to receive allogeneic SCT after venetoclax-based salvage. The median survival was 268 days (8.81 months) and was statistically significant from the FLAG-IDA cohort (p = 0.0029).Conclusion: Our results suggest the efficacy of FLAG-IDA compared to venetoclax-based regimens with respect to ORR, survival, toxicity, and progression to transplant in the R/R setting for presumable intensive induction candidates, as evidenced retrospectively by prior receipt of such regimens. These differences may be impacted by changes to disease biology between the relapsed and refractory settings and TP53 status. Larger prospective studies with separate analyses between the relapsed and refractory settings are needed to confirm these findings. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Venetoclax-Azacitidine As Salvage Therapy and Bridge to Allogeneic Cell Transplantation in Relapsed/Refractory AML Compared to Historical Data of the SAL Registry Study

Venetoclax-Azacitidine As Salvage Therapy and Bridge to Allogeneic Cell Transplantation in Relapsed/Refractory AML Compared to Historical Data of the SAL Registry Study

The Impact of Molecular and Cytogenetic Clonal Evolution on Survival in Relapsed/Refractory AML

Background: Clonal diversity and evolution in acute myeloid leukemia (AML) are consequences of disease progression and play a pivotal role in the development of drug resistance and refractoriness to therapy. Much work has been done with characterizing clonal architecture in bulk tumors samples or single-cell DNA sequencing, but real-world data observing the impact of clonal evolution and responses to therapy remains scarce in the relapsed and refractory settings. Therefore, the purpose of this study was to analyze the impact of observed clonal evolution on survival.Patients & Methods: We retrospectively analyzed 81 patients with AML with relapsed or refractory disease from June 2018 to December 2020. Cytogenetic and molecular data were obtained at the time of diagnosis and the time of primary induction failure or relapse, when available. We identified a total of 24 patients that demonstrated evidence of clonal evolution following induction or salvage therapy. Baseline patient demographics were obtained, including cytogenetic risk and next-generation sequencing molecular profiling at diagnosis and throughout treatment alongside dates and types of induction regimens. We compared the survival of those with evidence of clonal evolution to matched groups without. The groups with and without clonal evolution were compared for baseline statistical differences using an unpaired t-test with Welch's correction and Kaplan-Meier survival analyses were computed and compared with log-rank tests using GraphPad Prism. The event for calculating the overall survival was the date of death with patients otherwise censored at the date of last contact.Results: Of the 24 patients with evidence of clonal evolution, we detected that evolution occurred in four (16.7%) patients at the time of primary induction failure (refractory to first induction), 19 (70.8%) at the time of first relapse, and 3 (12.5%) at the time of second relapse. The median age of patients with clonal evolution was 63 years (range: 23 - 74) with 17 (70.8%) males and 7 (29.2%) females. The most commonly occurring mutations were NPM1 (25.0%), FLT3-ITD (20.8%), and TP53 (20.8%). At the time of initial diagnosis, cytogenetic risk was favorable in one (4.2%), intermediate in 7 (29.2%), and adverse in 16 (66.7%). The majority (79.2%) of patients underwent first induction with 7+3 and 8 (33.3%) patients underwent allogenic SCT. At the time of clonal evolution and ignoring the adverse prognosis associated with relapse, one patient with favorable cytogenetics remained favorable, only one (14.3%) patient with intermediate cytogenetics shifted to adverse, and one (6.3%) patient in the adverse category shifted to intermediate by ELN criteria. Three (12.5%) patients out of 24 acquired FLT3-ITD and three (12.5%) acquired an additional cooperating mutation (NRAS, KRAS, or KIT) for a total of 25.0% acquiring a signaling pathway mutation. Out of 10 patients with either mutated TP53 or MLL, three (27.3%) acquired a cooperating mutation in FLT3 or RAS. We then compared the clonal evolution cohort with the 57 remaining relapsed/refractory patients without evidence of clonal evolution. There was no difference between the groups with respect to baseline characteristics, including age (p = 0.989), ECOG status at diagnosis (p = 0.4689), Charlson Comorbidity Index (CCI) score (p = 0.6454), or prior SCT (p = >0.999). The median overall survival (OS) of the clonal evolution group was 227 days and compared to 382 days in the non-evolution cohort (p = 0.843).Conclusion: We did not detect a significant OS difference between those with clonal evolution and those without. Independent of the adverse prognosis associated with relapsed or refractory disease, cytogenetic risk category appeared to remain the same with clonal evolution. Common trends during clonal evolution included acquisition of one or several cooperating mutations in FLT3 or RAS, both with and without the presence of mutated TP53 and MLL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Real World Experience of Combined Treatment with Romidepsin and Azacitidine in Patients with Peripheral T-Cell Lymphoma

BACKGROUNDPatients with peripheral T-cell lymphoma (PTCL) lack good treatment options, particularly in the relapsed and refractory setting (Mak V et al. J Clin Oncol 2013). The development of the targeted therapies in PTCL has been lagging behind those developed for B cell lymphomas. Our work suggested that combinations of epigenetic therapies can be a safe and effective approach for patients with PTCL, particularly those with T-cell lymphomas with a follicular helper phenotype (Marchi E et al. Br. J Haematol 2015; O'Connor O.A. et al; Blood 2019; Falchi L et al. Blood 2020). While the reason for this is not clear, it is thought recurrent mutations in epigenetic factors, including Ten-Eleven Translocation-2 (TET2), DNA methyl transferase-3A (DNMT3A) and isocitrate dehydrogenase-2 (IDH2) may contribute for their increased vulnerability (Couronné L. et al. N Eng J Med 2012; Lemonnier F et al. Blood 2012). Despite these presumptions, a direct explanation for the sensitivity to epigenetic based treatment remains to be established.OBJECTIVESTo evaluate the merits of romidepsin plus subcutaneous azacitidine in patients with PTCL when administered in a ‘real-world’ scenario.METHODSWe retrospectively identified PTCL patients that were treated with azacitidine and romidepsin outside of a clinical trial based upon queries regarding off study use. The study was reviewed and approved by each Medical Center Institutional Review Board. We have identified 13 patients world-wide whose pretreatment characteristics are shown in Table 1. These patients were treated using 3 different schedules: Schedule A: azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 14 mg/m2 on day 1, 8 and 15 of a 28 day cycle (total of 6 patients); Schedule B: azacitidine 75mg/m2 s.c. on days 1-5, romidepsin 14 mg/m2 on day 8, 15 and 22 of a 35 day cycle; and Schedule C (total of 2 patients): azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 12-14 mg/m2 on day 8, 15 and 22 of a 28 day cycle (total of 5 patients).RESULTSWe retrospectively identified 13 patients that were treated with romidepsin and azacitidine off study. Ten patients had angioimmunoblastic lymphoma (AITL), 2 had adult T-cell leukemia/lymphoma (ATLL) and 1 had PTCL-NOS. Eight of the 13 patients had next generation sequencing performed. Most common mutations found were those of TET2 (5 pts), RHOA (4pts), IDH2 (3pts) and DNMT3A (1 pt). One ATLL patient had mutations in TRAF3, FAT1 and MED12. Among these 13 patients, overall response rate (ORR) was 84% and the complete response rate (CR) was 61%. Median number of cycles was 3 (range 1-12). Treatment was well tolerated but notable adverse effects included nausea, fatigue, rash, neutropenia and thrombocytopenia. One patient experienced febrile neutropenia while another had pulmonary infiltrates (differential diagnosis included drug toxicity versus infection). Thrombocytopenia was the most common reason for dose reduction of romidepsin (to 12mg/m2) or its omission on day 8, 15 or 22. In 3 patients, azacitidine and romidepsin were used to achieve remission prior to allogeneic transplant (range of cycles 1-3), with all 3 patients were in CR at their last disease assessment. One patient died of transplant related mortality 8 months after his allogeneic stem cell transplant. There was 1 patient with AITL (treatment naïve) noted to have progression of disease at first imaging following 2 cycles of romidepsin and azacitidine. On the day of her PET/CT, she was however diagnosed with symptomatic Covid19 infection and was hospitalized. A repeat PET/CT 6 weeks later (without any additional lymphoma treatment) revealed PR.CONCLUSIONSSubcutaneous azacitidine and romidepsin administered in a ‘real-world’ situation is highly effective in patients with relapsed PTCL with tolerable toxicity, and can be used to successfully bridge patients to stem cell transplant. Notably, the efficacy was similar to the one reported on a clinical study with oral azacitidine and romidepsin. [Display omitted] DisclosuresKalac: Astra Zeneca: Consultancy; Kyowa Kirin: Consultancy; Gilead: Consultancy; Johnson and Johnson: Research Funding; Guidepoint: Consultancy; GLG: Consultancy. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Montanari: Seattle Genetics: Research Funding. O'Connor: Servier: Research Funding; Mundipharma: Honoraria; Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company. Marchi: BMS: Research Funding; Astex: Research Funding; Merck: Research Funding; Myeloid Therapeutics: Honoraria; Kyowa Kirin: Honoraria; Kymera Therapeutics: Other: Scientific Advisor.

Comparison of Salvage Intensive Chemotherapy Versus Venetoclax Combined Regimen in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

▪Introduction: Venetoclax (VEN) combined regimen received FDA approval for newly diagnosed elderly or unfit acute myeloid leukemia (AML) patients. Recently, with increasing use as off-label for relapsed or refractory setting in real practice, the evidence that the regimen is potentially effective in R/R AML is emerging. However, there is no answer to the question how VEN combined treatment compares to intensive chemotherapy (IC) in R/R AML when the patients were intended to be cured with bridging to stem cell transplantation (SCT) after either of these treatments.Methods: Adult AML patients (age ≥18 years) who were refractory to or relapsed after anthracycline plus cytarabine induction were subjected to this analysis. As a group of interest, R/R AML patients who received VEN combined regimen were screened first, and we found a total of 54 corresponding patients between Feb 2020 and Jan 2021. As a comparison, we searched historical controls who were treated with salvage IC during the past two years, revealing a total of 89 patients between Jan 2018 and Jan 2020. Patients analyzed here received VEN-combination or IC as their first or second-line salvage therapy.Results: Overall, the median age was 49 years (range, 18 to 72), and the patients of first line salvage (n=125, 87.4%) were more included. When comparing IC and VEN-combination groups, there were no differences in age, sex, ELN risk groups, cytogenetics, disease type or mutation status. However, more patients in VEN-combination group were in their second line salvage setting (IC vs VEN-combination; 5.6% vs 24.1%, p<0.001) and had received prior SCT (13.5% vs 38.5%, p<0.001). The percentage of patients who had CR, CRi and MLFS were 39.3%, 6.0%, and 0.0% in IC group, and were 40.7%, 11.1%, and 7.4% in VEN group, yielding an overall response rate of 45.2% and 59.3%, respectively (p=0.108). Regarding the bridging to SCT, patients who underwent allo-SCT after salvage therapy were 69.7% in IC and 68.5% in VEN-combination group (p=0.886), of whom 62.9% (IC) and 86.5% (VEN-combination) of patients achieved either CR, CRi or MLFS at SCT (p=0.012). Of note, the median time to SCT were shorter in patients who received VEN-combined regimen (median, 103 days) compared to patients receiving IC (median, 139 days) (p=0.012). The median OS without censoring at the time of SCT were 334 days (95% CI, 198-469) and 381 days (95% CI, 345-416) in IC and VEN-combination group, respectively (p=0.592), after a median follow up period of 685 days and 345 days. VEN-combined regimen was significantly superior to IC in achieving response (p=0.031, OR=2.980 [95% CI 1.105-8.033]) and showed trend towards better survival (p=0.059, HR=0.454 [95% CI 0.200-1.030]) among the patients of fist-line salvage setting only, although significant differences were not shown in overall patients.Conclusion: These findings suggest that VEN-combined treatment is a feasible option for R/R AML and could be chosen over salvage IC in R/R AML based on its anti-leukemic response, bridging to SCT with disease control and survival, which were comparable to IC in overall patients and were tended to be superior in patients of first salvage setting only. DisclosuresKim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:venetoclax use in R/R AML: off label use

Outcome with Hypomethylating Agent and Venetoclax Combination in Patients with Chronic Myelomonocytic Leukemia

Outcome with Hypomethylating Agent and Venetoclax Combination in Patients with Chronic Myelomonocytic Leukemia