2nd Relapse Research Articles

MO20-4 Extranodal lesions of DLBCL at the 1st relapse might predict CNS lesions in the 2nd relapse

MO20-4 Extranodal lesions of DLBCL at the 1st relapse might predict CNS lesions in the 2nd relapse

Immunotherapy for children with malignant brain tumors

The incidence of high-grade malignant gliomas (MG) ranges from 35 to 46% of all central nervous system tumors. Despite combined therapy including surgery, radiation treatment and chemotherapy, overall five-year survival does not exceed 10%. The advent of novel immunotherapeutic strategies has promoted a renewed hopes for the treatment of MG. The aim of the present study was to improve the survival rates of glioma patients. Our study included 5 pediatric patients at the median age of 7.6 years (2-16). Three pts had anaplastic astrocytoma (AA) (1st relapse, 1 pt; 2nd relapse, in 2 pts), One patient was diagnosed with glioblastoma multiforme (GBM) (3rd recurrence), and 1 child had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), the second relapse occurred at a median of 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogeneic immunocompetent cells (alloIC) for at least 2 years. Two of 3 pts with AA experienced a progression-free interval of 67 and 71 months. One patient with 3rd GBM relapse is alive without any treatment for 13.3 years after starting the immunotherapy. The median time of follow-up was 67 months, with the 2-year overall survival rate of 58%. Two pts died from the disease progression within 6 and 7 months from the beginning of immunotherapy. Over the period of treatment, the patients received a median of 20 alloIC injections (8 to 60), and 18 DV administrations (8 to 44). No serious side-effects were observed. Immunotherapy could be an promising option for treating patients with high-grade malignant gliomas refractory to conventional therapy and, therefore, deserves further investigations.

Phase 2 study of bizaxofusp, an IL-4R targeted toxin payload, in nonresectable recurrent GBM: Comparison of overall survival with contemporaneous eligibility-matched and propensity score balanced external control arm.

2079 Background: Bizaxofusp (MDNA55) is designed to selectively deliver a potent toxin payload to tumor cells by targeting the IL-4 receptor (IL-4R) overexpressed by GBM, but not normal brain. Localized delivery of bizaxofusp minimizes risk of off-target toxicities and systemic exposure while eliciting effective tumor cell killing. Bizaxofusp was evaluated using convection-enhanced delivery in MDNA55-05 (NCT02858895), a single-arm, open-label, multi-center Ph2 study in nonresectable recurrent GBM (rGBM). Methods: The study population comprised of de novo IDH wild-type GBM patients with 1st or 2nd relapse that were non-resectable. Forty-four patients were administered a single treatment of bizaxofusp (range: 18-240 μg). The primary endpoint was OS; secondary endpoints were safety and tumor response. IL-4R expression in tumor biopsies was determined using a validated assay. OS was compared to an eligibility matched external control arm (emECA) of 81 contemporaneous rGBM subjects receiving standard of care. The emECA was further refined by propensity-score balancing (pbECA) to the bizaxofusp arm based on known prognostic factors, resulting in a weighted sample size of 40.8. OS was defined as time from relapse (to unify index date in both arms) or treatment start (for analysis of tumor response) to death/censor. Tumor response was assessed following RANO and mRANO criteria. Results: Bizaxofusp showed an acceptable safety profile at doses up to 240 μg. TRAEs were primarily neurological or aggravation of pre-existing neurological deficits associated with GBM and were manageable with standard measures. Results showed that IL-4R expression did not impact mOS except in patients receiving low doses of bizaxofusp. The bizaxofusp arm had significantly longer median OS (mOS) than contemporaneous emECA (12.4 vs 7.7 months; HR: 0.64, 95% CI 0.46-0.93; p = 0.02). Survival benefit was also evident when compared to the pbECA: (12.4 vs 7.2 months; HR: 0.72, 95% CI 0.46-1.1; p = 0.27). Patients with tumor control (SD or PR/CR, n=21) had significantly longer mOS than patients with tumor progression (n=23) (16.7 vs 8.5 months; HR = 0.5, 95% CI 0.27-0.9; p = 0.01). Among patients with tumor control who had pseudoprogression (PsP) per mRANO, mOS (22.8 months) was significantly longer than patients with tumor progression (HR: 0.49, 95% CI 0.25-0.98; p = 0.049). Conclusions: Bizaxofusp achieved significant OS benefit in patients with nonresectable rGBM compared to contemporaneous emECA. Patients who experienced tumor control, including those with PsP, showed significantly longer survival than patients with tumor progression. Phase 3 ready registrational trial will comprise a high dose bizaxofusp arm and a hybrid control arm with 1/3 randomized subjects and 2/3 pmECA. Clinical trial information: NCT02858895 .

Abstract PO5-20-02: Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET)

Abstract Background: Despite treatment with trastuzumab-based therapy, up to half of patients with HER2+ advanced/metastatic breast cancer (MBC) will develop brain metastases (BrM). First-line therapy for advanced HER2+ MBC remains a taxane, trastuzumab, pertuzumab (TP) which demonstrates poor brain permeability. Isolated brain relapse with stable or absent extracranial disease remains a clinical problem in both the adjuvant (Untch et al., ESMO 2019 Congress) and metastatic settings (Noteware et al., Breast Cancer Res Treat. 2023). Current guidelines recommend continuing current systemic therapy in the setting of first isolated brain relapse following local therapy. Tucatinib, a brain-penetrable HER2-targeting tyrosine kinase inhibitor, when added to trastuzumab and capecitabine improves intracranial progression free survival (PFS) and overall survival (OS) in patients with stable or active HER2+ BrMs. We hypothesize that adding tucatinib to TP or T-DM1 in patients with HER2+ MBC with isolated brain relapse or progression could delay or prevent the development of further intracranial lesions and improve OS. Methods: BRIDGET (NCT05323955) is a single arm, phase II, multicenter study of tucatinib added to TP or T-DM1 after local therapy in patients with isolated brain relapse or progression. A total of 48 patients at 9 U.S. sites as part of the Hoosier Cancer Research Network (HCRN) with metastatic HER2+ breast cancer will be enrolled after 1st or 2nd BrM relapse or progression within 8 weeks of local therapy. Patients must currently be receiving standard of care treatment with TP or T-DM1 in the metastatic setting, or adjuvant trastuzumab-based or T-DM1 therapy with isolated brain recurrence. Extracranial disease must be stable per RECISTv1.1 or absent. Patients may not have leptomeningeal disease or untreated brain lesions over 5 mm. Patients will receive continuous tucatinib added to their current therapy (TP or T-DM1). The primary objective is intracranial PFS compared to a historical control (H0: PFS < 5 months (mos), HA: PFS > 8 mos) of the HER2CLIMB clinical trial where patients could continue on trial with isolated brain progression. In these patients, median time from brain progression to second progression or death was 7.6 mos (95% CI, 3.9 to 11.3 mos) in the tucatinib arm versus 3.1 mos (95% CI, 1.2 to 4.1 mos) in the control arm (Lin et al., J Clin Onc 2020). Secondary endpoints include PFS by RECISTv1.1, PFS of extracranial disease, locally treated versus new distant intracranial metastasis PFS, site of first progression (brain versus non-brain), OS, and toxicity in patients with BrM. Collection of correlative specimens including archival tissue, cerebrospinal fluid (optional), whole blood for ctDNA are planned. Patient-reported outcomes surveyed utilizing the FACT-BR and FACIT-Fatigue questionnaires are also included for future analyses. As of 7/06/23, accrual is 5 patients of the anticipated 48 patients overall, across 5 sites (Duke University, Dana Farber Cancer Institute, Ohio State University, Providence Portland Medical Center, and Washington University in St. Louis) currently open. An additional 4 sites are pending opening. Those interested in this trial can reach out to the study Principal Investigators, Carey Anders, MD (carey.anders@duke.edu) or Sarah Sammons, MD (sarahl_sammons@dfci.harvard.edu). Citation Format: Sarah Sammons, Amanda Van Swearingen, Laura Noteware, Nusayba Bagegni, Kelly Moulton, Stevie Threatt, Denise Jaggers, Shannon Shea, Eric Lipp, Erin Riley, Sin-Ho Jung, Gloria Broadwater, Masey Ross, Kimberly Strickland, Sasha Beyer, Alison Conlin, Aki Morikawa, Rashmi Murthy, Carey Anders. Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-02.

Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns

Tisagenlecleucel was approved by the Food and Drug Administration (FDA) in 2017 for refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-ALL in ≥2nd relapse. Outcomes of patients receiving commercial tisagenlecleucel upon 1st relapse have yet to be established. We aimed to report real-world tisagenlecleucel utilisation patterns and outcomes across indications, specifically including patients treated in 1st relapse, an indication omitted from formal FDA approval. We conducted a retrospective analysis of real-world tisagenlecleucel utilisation patterns across 185 children and young adults treated between August 30, 2017 and March 6, 2020 from centres participating in the Pediatric Real-World CAR Consortium (PRWCC), within the United States. We described definitions of refractory B-ALL used in the real-world setting and categorised patients by reported Chimeric Antigen Receptor (CAR) T-cell indication, including refractory, 1st relapse and ≥2nd relapse B-ALL. We analysed baseline patient characteristics and post-tisagenlecleucel outcomes across defined cohorts. Thirty-six percent (n=67) of our cohort received tisagenlecleucel following 1st relapse. Of 66 evaluable patients, 56 (85%, 95% CI 74-92%) achieved morphologic complete response. Overall-survival (OS) and event-free survival (EFS) at 1-year were 69%, (95% CI 58-82%) and 49%, (95% CI 37-64%), respectively, with survival outcomes statistically comparable to remaining patients (OS; p=0.14, EFS; p=0.39). Notably, toxicity was increased in this cohort, warranting further study. Interestingly, of 30 patients treated for upfront refractory disease, 23 (77%, 95% CI 58-90%) had flow cytometry and/or next-generation sequencing (NGS) minimum residual disease (MRD)-only disease at the end of induction, not meeting the historic morphologic definition of refractory. Our findings suggested that tisagenlecleucel response and survival rates overlap across patients treated with upfront refractory B-ALL, B-ALL ≥2nd relapse and B-ALL in 1st relapse. We additionally highlighted that definitions of refractory B-ALL are evolving beyond morphologic measures of residual disease. St. Baldrick's/Stand Up 2 Cancer, Parker Institute for Cancer Immunotherapy, Virginia and D.K. Ludwig Fund for Cancer Research.

Real-world use of tisagenlecleucel in children and young adults with relapsed or refractory B-cell lymphomas.

10031 Background: Survival for pediatric B-cell lymphomas (BCL) exceeds 90% with modern regimens, however outcomes remain poor for patients with relapsed or refractory (R/R) disease. Tisagenlecleucel is a CD19-directed CAR T-cell therapy (CART) that is FDA approved for adults with R/R BCL. No data exists for use of tisagenlecleucel in R/R pediatric BCL. Methods: We surveyed 48 sites in the Pediatric Real-World CAR Consortium to retrospectively describe use and outcomes of tisagenlecleucel for pediatric patients with R/R BCL. This cohort included 10 patients from 7 centers aged ≤25 years who were infused between 2019-2022 and were ≥3 months from CART. We aimed to describe response rates, as determined by each institution based on positron emission tomography, bone marrow evaluation, and/or cerebrospinal fluid (CSF) studies, along with toxicity and outcomes in this population. Results: Ten patients received CART with a median age at infusion of 19 (range, 7-24) years. Five patients had B-lymphoblastic lymphoma (B-LLy), 2 had primary mediastinal BCL, and 1 each had Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder related DLBCL. Five patients had primary refractory disease, and 5 were in ≥2nd relapse. Three had received prior hematopoietic stem cell transplant (HSCT). Two had CSF involvement, and 1 had central nervous system parenchymal disease at time of infusion. CART was well tolerated with 1 patient experiencing grade 3 cytokine release syndrome and 2 patients experiencing neurotoxicity (grade 2 n = 1, grade 3 n = 1), both of whom had CSF involvement at time of CART infusion. Best overall response was complete response (CR) for 6, partial response (PR) for 2, and refractory disease for 2. Two patients, both with B-LLy, underwent allogeneic HSCT while in CART-mediated CR with B-cell aplasia. Both patients with PR (1 DLBCL, 1 Burkitt) subsequently relapsed with CD19-negative disease; the patient with DLBCL subsequently achieved CR with salvage immuno-chemotherapy and HSCT. All 6 CR patients remain in remission at a median time to follow-up of 31 (range, 14-47) months. Conclusions: This multicenter case series of CD19-directed CART for R/R pediatric BCL suggests that tisagenlecleucel may be safe and active in this population with all CR patients currently in sustained remission. Larger studies are needed to understand how best to incorporate CART into treatment for R/R pediatric BCL. [Table: see text]

Favorable Overall Survival Following First and Second Relapse of MCL with Availability of Novel Therapies: Results from the Lion Prospective Observational Registry

Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma (NHL) associated with a high rate of relapse following frontline treatment, but with expanding treatment options for relapsed/refractory (RR) disease. Historically, outcomes for RR MCL have been unfavorable compared with indolent NHL subtypes, however survival data with more recently approved therapies is less well characterized. We report survival data following 2nd and 3rd line therapy for RR MCL in a large contemporary prospective cohort. Methods: We included patients (pts) with RR MCL enrolled in the Lymphoma Innovations ORIEN Network (LION) prospective observational registry at one of seven participating centers. The LION Cohort is a 7-center cohort project which enrolls patients with relapsed/refractory NHL. All patients signed written consent. Clinical data were abstracted from medical records using a standardized protocol. Event free survival was estimated using the method of Kaplan-Meier and defined as time from start of 2nd (EFS2) or 3rd (EFS3) line treatment until progression, subsequent treatment, or death censoring pts alive and without further treatment or relapse at last follow-up. Overall survival was estimated using Kaplan-Meier and defined as time from start of 2nd (OS2) or 3rd (OS3) line treatment until death, censoring pts alive at last follow-up. Comparisons of EFS and OS were performed using the log-rank test. Results: A total of 128 eligible pts with RR MCL consented between 2/5/2020 and 7/8/2022. Pts received 2nd line treatment between 2002- 2021; 84% (107/128) after November 2013. Baseline characteristics included male sex in 95 pts (77%), stage III/IV disease in 110 pts (91%), progression within 24 months (mo) of initial treatment (POD24) in 43 pts (34%). Median age at first relapse was 65 years. Second line treatments included BTK inhibitors (BTKi) in 61 pts (50%), bendamustine based therapy in 14 pts (12%), lenalidomide and/or bortezomib based therapy in 14 pts (12%), venetoclax in 3 pts (3%), and other classes of treatment in 30 pts (25%). After a median follow-up of 45 mo, the estimated median EFS2 was 26 mo (95% confidence interval [CI] 15-38), with a 24-month estimated EFS2 of 51% (95% CI 41-60) and 5-year estimated EFS2 of 24% (95% CI 14-34). The estimated 24-month OS2 was 91% (95% CI 84-96) and 5-year estimated OS2 was 84% (95% CI 74-90). Third line treatments included BTKi in 36 pts (47%), chimeric antigen receptor T-cell (CAR-T) in 10 pts (13%), bendamustine based therapy in 5 (7%), venetoclax in 3 (4%), lenalidomide and/or bortezomib in 3 (4%), and other treatments in 20 (26%). After a median follow-up of 34 mo from 2nd relapse, the estimated median EFS3 was 19 mo (95% CI 12-49), with a 24-month EFS3 of 47% (95% CI 34-58) and 5-year EFS3 of 29% (95% CI 16-43). The estimated 24-mo OS3 was 84% (95% CI 72-91) and 5-year estimated OS3 of 73% (95% CI 57-84). POD24 was associated with inferior EFS2, with estimated median EFS2 9.7 mo (95% CI 5.1-23.6) vs 34.4 mo (95% CI 18.4-45.9) for non-POD24 pts (p=0.0025). POD24 from frontline treatment was also associated with inferior EFS3 among pts with indexed third line therapy with median EFS3 15.6 mo (95% CI 8-37) for POD24 and 49.1 mo (95% CI 11-84) for non-POD24 pts (p=0.04). No significant differences were observed in EFS2 between pts treated with BTKi, with median EFS2 21 mo (95% CI 10-34), compared with other classes of second-line treatment with median EFS2 of 35 mo (95% CI 14-46, p=0.37). Likewise, EFS3 was not significantly different between patients treated with third-line BTKi with estimated median EFS3 of 54 mo (95% CI 11-not reached) compared to CAR-T with estimated median EFS3 of 9 mo (95% CI 3-19), compared to other third line treatments with median EFS3 of 20 mo (95% CI 10-49, p=0.4). Conclusions: We observed a median EFS2 of 26 mo and median EFS3 of 19 mo in a contemporary prospective cohort of pts with RR MCL. We did not observe an association between class of treatment received and EFS2 or EFS3, but observed inferior EFS2 and EFS3 for patients with POD24 following frontline therapy compared with patients with later first relapse highlighting the higher risk nature of this population. The observed OS2 and OS3 outcomes in this prospective cohort exceed historical estimates for relapsed MCL prior to availability of newer therapies, provide context for interpreting single arm trial results, and may inform future clinical trial design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Subclinical Minute FLT3-ITD Clone Can be Detected in Clinically FLT3-ITD-Negative Acute Myeloid Leukemia

Introduction The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is the most common recurrent mutation in acute myeloid leukemia (AML). FLT3-ITDs are predominately located in exons 14 and 15 and affect the juxtamembrane domain (JM) of the membranous tyrosine kinase receptor. Oligoclonal FLT3-ITD clone could be detected in single patient. In patients with FLT3-ITD-positive AML, the FLT3-ITD clone could disappear in relapsed AML, the whereas some cases acquired FLT3-ITD in relapsed sample despite the fact that FLT3-ITD was absent in initial AML samples. Clinically, FLT3-ITD was detected by agarose gel or capillary electrophoresis of the polymerase chain reaction (PCR) product. The detection sensitivity of these methods is about 1-5% variant allele frequency (VAF). PCR amplicon sequence using next-generation sequencing (NGS) enabled us to detect dynamics of subclinical minute FLT3-ITD clones. We hypothesized that subclinical minute FLT3-ITD could be detected in clinically FLT3-ITD-negative AML and that the clone might contribute to the emergence of FLT3-ITD on relapse. Patients and Methods Hokkaido Leukemia Net (HLN) is prospective cohort study collecting acute leukemia samples from affiliated hospitals covering Hokkaido. In this study, we focused on cytogenetically normal (CN) AML without FLT3-ITD diagnosed by electrophoresis. Initial diagnostic samples and relapsed samples were analyzed by the NGS assay to determine whether they had minute FLT3-ITD clones. FLT3 exons 14 and 15 were PCR-amplified and deep-sequenced by Miseq (>20,000 reads). Using an FLT3-ITD-positive AML cell line (MOLM14), the limit of quantitative detection of minute FLT3-ITD was 0.0067%. We defined "minute FLT3-ITD” as one that was not detected by gel electrophoresis but was detected by NGS with VAF of more than 0.0067%. This study was conducted in accordance with the Helsinki Declaration and was approved by the institutional review boards. Results A total of 74 FLT3-ITD-negative cases were identified in 112 CN-AML cases registered in HLN from 2017 to 2019 (age range 21-93 years (median 68); 36 males and 38 females). Initial diagnostic samples were analyzed for FLT3-ITD by NGS and 28 independent minute FLT3-ITDs (VAF range: 0.0077-5.4%, median VAF:0.16%) were detected in 19 cases (25.7%). ITD lengths were 18-93 bp (median length: 44 bp), and all minute FLT3-ITDs were in-frame mutations. In 5 of the 19 cases, more than two independent minute FLT3-ITDs were detected. The number of independent ITDs ranged from 1-5 (median number:1) per patient. We compared characteristics of the patients with and those without minute FLT3-ITD. The proportion of BM specimens (89.5% vs 87.3%, P=1.0), white blood cells [23,100 (460-250,900) vs 10,700 (800-174,000), P=0.138], NPM1 mutation positivity (52.6% vs 29.1%, P=0.094), percentage of patients with primary induction failure (47.4% vs 41.8%, P=0.44), and percentage of patients who received allogenic stem cell transplantation (21.1% vs 27.3%, P=0.76) were not significantly different between the minute FLT3-ITD-positive group and the minute FLT3-ITD-negative group. On the other hand, blast percentage (83.0% vs 66.0%, P=0.033) and the rate of relapse within 1 year (36.8% vs 10.9%, P=0.031) were significantly higher in minute the FLT3-ITD-positive group, whereas overall survival rate were not different in the two groups (P=0.78). In a median period of 25 months after initial diagnosis, 22 patients relapsed [7 (36.8%) of 19 minute FLT3-ITD-positive patients and 15 (27.3%) of 55 minutes FLT3-ITD-negative patients]. Of those 22 cases, we collected 23 relapse specimens of 18 cases [1st relapse (rel1), 18; 2nd relapse, (rel2), 5]. FLT3-ITD became clinically positive in 2 cases in rel1 and in 2 cases in rel2 (Figure, red lines). Regarding rel1, 2 of 3 cases in the initial minute FLT3-ITD-positive group developed clinically relevant FLT3-ITD, while none of the 15 cases in the minute FLT3-ITD-negative group developed clinically relevant FLT3-ITD (P=0.020). In both rel1 and rel2, cases that developed clinically positive FLT3-ITD (filled circle) were positive for minute FLT3-ITD at the preceding time point (empty circle). Conclusion This is the first study clarifying the clonal dynamics of minute FLT3-ITD in clinically FLT3-ITD-negative AML. The clinical significance of an FLT3 inhibitor for patients with minute FLT3-ITD needs to be clarified in the future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CRC-403: A Phase 1/2 Study of bbT369, a Dual CD79a and CD20 Targeting CAR T Cell Drug Product with a Gene Edit, in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)

BACKGROUND: Currently approved CD19 directed CAR T cell therapies have improved outcomes for non-Hodgkin lymphoma (NHL) patients, however only 30-40% of patients treated at 2nd relapse or later obtain long term remission after this treatment (Neelapu et al. 2017; Schuster et al. 2019). A next generation autologous CAR T cell, bbT369, has been devised specifically to address and overcome hypothesized mechanisms of CD19 CAR T cell treatment failure including loss/downregulation of target antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR T cells, and CAR T cell dysfunction due to an immunosuppressive microenvironment (Shah and Fry 2019). bbT369 is a dual targeting (CD79a/CD20) CAR T cell that uses an OR gated design (encounter with either antigen activates the CAR T cell) to limit antigen escape. The construct contains split costimulatory domains (CD28 and 41BB) to enhance T cell activation and a gene edit knocking-out CBLB function intended to enhance potency and reduce T cell exhaustion. Studies have demonstrated CD79a and CD20 may be ideal targets in B cell lymphoma, with high tissue restricted expression. In Daudi cell and mouse models, bbT369 outperformed CD19 directed CAR T cells demonstrating increased IL-2 secretion and longer durations of tumor control (Certo et al, 2022). METHODS: CRC-403 (NCT05169489) is a non-randomized, open label, multi-site Phase 1/2 study enrolling relapsed and/or refractory B Cell Non-Hodgkin's Lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), primary mediastinal (thymic) large B cell lymphoma (PMBCL), follicular lymphoma (FL) 3b, and DLBCL transformed from FL (tFL). Patients must have relapsed after ASCT or after at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody and an anthracycline containing chemotherapy regimen. Patients with tFL must be relapsed after receipt of ASCT or at least 2 prior therapies after documentation of transformation. In addition to patients naïve to CAR T cell therapy, patients with prior exposure to non-investigational CD19 CAR T cell therapy are eligible for enrollment if they did not experience disease progression within 6 weeks of initial CAR T cell infusion. Approximately 50 patients will be enrolled during the dose escalation phase to ensure a maximum of 36 subjects will be treated with bbT369. The primary endpoint of the phase 1 portion of this study is incidence of safety events, including adverse event, adverse events of special interest and dose limiting toxicities. Secondary endpoints include investigator assessed overall response rate including complete response rate, time to response, time to complete response and time to next therapy for B-NHL. Exploratory endpoints include OS, DOR, PFS, bbT369 expansion kinetics including expansion and persistence, immunophenotype in peripheral blood and tumor biopsy tissue with the objective of correlating findings with clinical response. The starting dose of bbT369 is 50x106 CAR+ T cells and a BOIN design is being used for dose escalation/de-escalation decisions during the study. Upon establishment of the RP2D, the phase 2 portion will begin enrollment.

Outcomes Following Hypomethylating Agent / Venetoclax Combination-Therapy for MDS or AML Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the consolidation therapy with the highest chance of sustained remission for most patients (pts) with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse occurs in up to 40% of pts and adversely affects prognosis. Currently, post-HSCT relapse strategies include intensive chemotherapy, hypomethylating agents (HMA), as well as targeted therapy, e.g. FLT3-inhibitors frequently combined with donor lymphocyte infusions (DLIs). Here we investigated combinations of HMA and venetoclax (VEN) as salvage options for relapse after alloHSCT. Methods: 2 MDS and 24 AML pts (median age 60 [range 38-73] years) relapsed after a median of 6.2 (range 1.6-55.5) months (mo) after 1st (n=22) or 2nd (n=4) HSCT. Conditioning regimens were myeloablative (n=5) or non-myeloablative (n=21). Remission status at HSCT was composite complete remission (CRc; including CR, CR with incomplete recovery [CRi] and morphologic leukemia free state [MLFS]; 50%), partial remission or stable disease (12%), and refractory (38%). While 22 pts had hematological relapse, 4 pts showed either combined (n=3) or sole (n=1) extramedullary disease. All pts subsequently received HMA/VEN-based therapies (azacitidine/venetoclax [n=22], azacitidne/venetoclax/gilteritinib [n=3] or decitabine/venetoclax [n=1]) with concomitant DLI in 13 pts. Prior to HMA/VEN, 13 pts received a different relapse therapy including azacitidine [n=7], gilteritinib [n=2], radiation [n=1], an investigational therapy with an IRAK4 inhibitor [n=1], or a combination therapy with azacitidine and pevonedistat [n=1] or tagraxofusp [n=1]. European LeukemiaNET 2022 risk at the timepoint of relapse was favorable (n=2), intermediate (n=4) or adverse (n=20). Median follow-up since HMA/VEN start was 6.4 mo. Results: HMA/VEN was well tolerated and administered in an outpatient setting in 20/26 pts (77%). The most common adverse effects were expected and included neutropenia CTCAE 3/4° in 25/26 pts (96%) and thrombocytopenia CTCAE 3/4° in 22/26 pts (85%). Eight pts (31%) developed at least one episode of febrile neutropenia. Four pts (15%) showed signs of afebrile infections and were hospitalized. Thirteen pts (50%) achieved a CRc (CR [n=3], CRi [n=8], MLFS [n=2]) under HMA/VEN therapy (Figure 1A), with a median time to 1st and best morphological response of 1.0 and 2.1 mo, respectively. Later relapse (>12 mo after HSCT) and a lower number of prior therapies before HMA/VEN (≤2 vs. >2 lines) associated with improved outcomes (cumulative incidence of achieving a CRc: P=.004 and P=.04, and OS: P=.02 and P=.02, respectively). Six of 13 pts (46%), who received a prior non-HMA/VEN therapy for the current relapse achieved a CRc after switching to HMA/VEN. Pts achieving a CRc had a significantly longer OS compared to pts with no CRc (P=.002; Figure 1B). Of the pts with CRc, 7 continued HMA/VEN with a median response duration of 7.2 mo (6/7 pts are still on treatment at last follow-up), 5 received a 2nd HSCT and 1 an experimental CART-therapy. For those that could be bridged to a 2nd HSCT outcomes were beneficial with 4/5 pts (80%) alive and disease-free (median follow-up since 2nd HSCT: 4.3 months). One patient with CART-therapy suffered from a 2nd relapse 1.7 months after treatment and is currently again salvaged with HMA/VEN. Two of 13 pts (15%) died after initial CRc, 1 due to non-relapse mortality of a 2nd HSCT and 1 by losing treatment response. Of the 13 pts who did not achieve a CRc, 1 patient could be bridged to 2nd HSCT with a post-HSCT relapse free survival of 12 mo. In the remaining 12 non-CRc pts median OS since start of HMA/VEN was 2.9 mo (range 0.7-6.5 mo) and 9/12 pts (75%) died due to progressive disease. Regarding the molecular risk profile, none of the TP53 mutated pts (n=3) responded, whereas pts with IDH1/2, NPM1, or myelodysplasia-related gene mutations, i.e.ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2, had mixed responses (2/5 pts [40%], 1/3 pts [33%], and 8/15 pts [53%], respectively). Conclusion: HMA/VEN is a promising and well tolerated treatment strategy for MDS and AML pts relapsing after HSCT with a CRc of 50% and potential long-term survival. Especially pts that could be bridged to a 2nd HSCT benefited from the treatment. However, in pts with a disease resistant to HMA/VEN, outcome was very poor with a median OS of only 2.9 mo. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of Patients with Treatment-Free Remission in Chronic Myeloid Leukemia

Background: Chronic myeloid leukemia (CML) is a relatively common BCR-ABL-positive chronic myeloproliferative neoplasm within the structure of morbidity by hematological malignancies with primary bone marrow (BM) involvement, being characterized in the advanced phases by a relapsing evolution, sizable disease burden, unfavorable socio-economic impact and poor prognosis. Tyrosine kinase inhibitors (TKIs) have improved fundamentally the treatment outcomes in CML, bringing the patients' life expectancy closer to that of the general population. Nevertheless, TKI discontinuation studies indicate discordance in the incidence of hematological and molecular relapses. Objectives: The aim of the study was to evaluate the short- and long-term outcomes of treatment discontinuation in CML patients with complete molecular response (CMR). Material and methods: This prospective study included 22 patients with chronic phase of CML, treated and followed up at the Oncologic Institute from Moldova between 2017-2022. The age range was 29-73 years (average age - 45.8 years). The male/female ratio was 1:1.2. The quantitative reverse transcription polymerase chain reaction (PCR) was performed in order to determine the expression of the BCR-ABL p210 and p190 transcripts. Five transcription products (b2a2, b3a2, b2a3, b3a3 si e1a2) were analyzed by the usage of the PCR test. The real-time quantitative PCR revealed the wide range of BCR-ABL p210 transcript: 21.84-100% IS. In 7 (31.8%) cases the initial rate of BCR-ABL p210-positive cells was less than 50%. Only 2 (9.0%) patients also proved to be positive for BCR-ABL p190 transcript. Results: CMR was obtained in 15 (68.2%) patients after imatinib therapy and in 7 (31.8%) patients after therapy with 2nd TKIs generation. The therapy with TKIs was stopped due to the different reasons in all patients after the achievement of CMR. Two (9.1%) patients discontinued the TKIs treatment due to the pregnancy. The molecular relapse occurred in 6 (27.3%) pts, including one pregnant female. There were no subsequent hematological relapses. All patients with molecular relapse had the initial BCR-ABL p210 transcript expression > 50%. One (4.5%) of them was positive for BCR-ABL p190 transcript at diagnosis. The CMR span ranged between 2.5-26 months in relapsed patients. The range of BCR-ABL p210 transcript in the relapsed cases was 0.002-0.56%. These patients attained the 2nd CMR after resuming the treatment with the same or higher TKIs generation. In 2 (9.0%) pregnant females the pregnancy resulted in the healthy newborns. One (4.5%) female with a history of lymphoblastic type of acute phase experienced the minor molecular relapse (BCR-ABL p210 transcript - 0.56%), and reobtained the CMR after restarting imatinib mesylate. The relapsed patients did not develop the 2nd molecular relapse. All patients are alive, with the ECOG-WHO score of 0-1. Conclusions: TKIs stopping proved to be a reliable management option in CML patients with chronic phase, CMR and low BCR-ABL p210 transcript expression at diagnosis. The stable 2nd CMR may be achieved after resuming the TKIs treatment at a higher dosage or generation in patients with minor molecular relapse. Pregnancy may not influence the molecular relapse rate after TKIs discontinuation and its curability.

Abrogation of Immune Effector Cell Neurotoxicity Syndrome (ICANS) By Rimiducid (RIM) in Patients Treated with CD19-Specific Chimeric Antigen Receptor Modified T-Cells (CAR-T) Engineered with an Inducible Caspase 9 (iC9 CAR.19)-Clinical and Pharmacodynamic Correlates

Introduction: CD19-targeted CAR-T cells are highly active in B-cell malignancies. While early use of corticosteroids (CS) and tocilizumab have improved the management of cytokine release syndrome (CRS), CS are the mainstay of ICANS management. Though patients with low-grade ICANS often do not require therapy, severe ICANS that does not respond to CS is life-threatening. Rimiducid (RIM) is a dimerizing drug that induces apoptosis in cells engineered with an inducible caspase-9 switch. We reported the first case of the administration of a potentially ablative dose of RIM (0.4 mg/kg) to a patient with B-lymphoblastic leukemia (B-ALL) with severe, prolonged ICANS (Foster MC et al. Blood 2021 Jun 10;137(23):3306-3309). Given this patient's rapid resolution of steroid-nonresponsive ICANS and reduction in iC9 CAR.19 numbers, we sought to explore the effects of lower, potentially non-ablative doses of RIM in patients with CS-nonresponsive ICANS before the development of life threatening complications, with a goal of clinical resolution of ICANS without ablation of CAR T cells. Here, we report the clinical and pharmacodynamic courses of ICANS for the four patients treated with RIM for ICANS to date, in an ongoing expansion cohort of a phase I/II study of iC9 CAR.19 cells in patients with B-ALL. Methods: Adults with B-ALL in 2nd or greater bone marrow (BM) relapse, relapse >100 days after allogeneic stem cell transplant, disease refractory to ≥2 induction therapies, or with measurable residual disease (MRD) persistence/recurrence were enrolled. T-lymphocytes were collected from the subjects, and CAR-T cell products generated by gene modification with a g-retroviral vector encoding for iC9, ΔNGFR (for selection and tracking purposes) and CAR.CD19 (encoding 4-1BB) genes (Diaconu I et al Mol Ther 2017; 25:580). Subjects underwent lymphodepletion with fludarabine and cyclophosphamide followed by infusion of iC9 CAR.19 cells at one of two dose levels (DL1: 5 x 105 CAR-T cells/kg; DL2: 1 x 106 CAR-T cells/kg). Toxicities were graded by CTCAE v5 or ASBMT consensus grading for CRS and ICANS. CAR-T cell expansion in peripheral blood (PB) was measured by flow cytometry (FC) and droplet digital PCR (ddPCR). Cytokines were measured by commercially available multiplex (Luminex®) cytokine assays. Leukemia response was determined by NCCN criteria. Subjects who experienced grade 3-4 ICANS despite CS for >72 hours received RIM 0.4 mg/kg IV over 2 hours. After protocol amendment, subjects with ≥ grade 2 ICANS for >24 hours despite CS received RIM 0.1 mg/kg IV over 2 hours. FC, ddPCR and cytokine levels were measured prior to RIM, at 4 hours after the end of RIM infusion and daily until ICANS resolution. Results: 13 subjects were treated, 3 on DL1 and 10 on DL2, which was the expansion cohort cell dose. Median age was 31 years (range 21-69). CRS developed in 11, with median duration of 5 days (range 1-8). Maximum CRS grade was 2 in 5 and 1 in 6. ICANS developed in 5 subjects, with maximum grade 4 in 2, and grade 3 in 3. One patient with CS-responsive grade 3 ICANS did not meet criteria for RIM. Two subjects with grade 3-4 ICANS for >72 hours received RIM 0.4 mg/kg, both achieving improvement by at least 1 grade within 12 hours and with resolution within 5 days (FIGURE 1). ddPCR for ΔNGFR showed reduction in transcripts by 4 hours after the end of RIM infusion (by 83.6% and 98.6% respectively, FIGURE 2). In two subjects with grade 3 ICANS for 24 hours treated with RIM 0.1 mg/kg, ICANS improved to grade 1 in 24 hours and grade 0 in 48 hours (FIGURE 1). In these subjects, ddPCR for ΔNGFR showed reduction in transcripts at 4 hours after end of RIM infusion by 88.6% and 88.1% respectively (FIGURE 2). Rates of overall response (CR+CRi+MLFS at 4 weeks) were 3/4 RIM subjects versus 9/9 in other subjects. The subject with grade 3 ICANS who did not receive RIM demonstrated peak ΔNGFR transcripts, IL-6, TNF-α and IFNγ two weeks after iC9 CAR.19 infusion, whereas peak transcripts and cytokine levels occurred at one week, and prior to RIM for RIM-treated subjects. Conclusion: RIM administration to patients with ICANS is associated with abrupt reduction of circulating iC9 CAR.19 cells and ICANS grade. Despite detection of CAR-T cells at 3 weeks post infusion and the observance of remissions after treatment with RIM, further investigation of the effects of RIM on iC9 CAR.19 persistence and antileukemic activity is warranted. Lower, potentially less ablative doses of RIM are being explored. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CD19-CAR-T Cells Are Effective and Safe Treatment of Post-Transplant Relapse in Pediatric and Young Adult Patients with B-Lineage ALL: Real-World Data from Germany

Introduction: Patients with precursor-B acute lymphoblastic leukemia (pre-B ALL) which have relapsed subsequent to allogeneic hematopoietic stem cell transplantation (HSCT), have relapsed twice, or were resistant to upfront therapy have a dismal prognosis. CD19-directed chimeric antigen receptor (CAR) T cells have evolved as potent immune therapy for such patients. Tisagenlecleucel (Tisa-cel) is a commercial CD19-directed autologous CAR-T cell product. The CAR contains the co-stimulatory element 4-1BB to promote in vivo persistence and proliferation. Thus this therapy is in principle competent to serve as a stand-alone therapy. Based on the results of the ELIANA trial (Maude et al. NEJM 2017), Tisa-cel was approved by FDA and EMA for pediatric/young adult B-ALL in 2017 and 2018. In clinical trials, stringent inclusion criteria narrow down the risk profiles of trial subjects. Treatment in clinical trials provides close guidance to physicians and patients during the trial. However, post approval reality leads to treatment of patients with higher and more variable risk profiles treated in many centers. With approval by the local ethics committees, we performed a retrospective study asking all CAR T cell centers in Germany approved for treatment with Tisa-cel (Kymriah®) to provide treatment data reflecting post approval reality, in order to identify patients who might most benefit from this novel, complex and expensive treatment. Patients: Twenty-one centers included all pediatric and young adult patients with pre-B ALL (n=81) who had received Tisa-cel between 8/2018-1/2022, allowing for a minimal follow-up of 5 months of surviving patients. Median age was 11.5 years (range: 1.0-25.0 years), 53 (65.4%) were male and 28 (34.6%) female, median body weight was 41.6 kg (range: 8.0 kg-135 kg). 65 patients (80.2%) had relapsed after HSCT, 15 (18.5%) had suffered a 2nd relapse without HSCT and 1 had primary refractory disease. For bridging therapy, 3 patients (3.7%) received Blinatumomab, 4 (4.9%) inotuzumab, 72 (88.9%) received low-dose chemotherapy. One patient was bridged with a high-dose chemotherapy; 1 patient with extra-medullary disease did not receive any bridging therapy. Results: Cytokine release syndrome (CRS) was observed in 55 (67.9%) patients (grade I-II: n=50, Grade III-IV: n=4 and grade V: n=1); immune cell-associated neurological syndrome (ICANS) was seen in 6 (7.4%) patients (grade I: n=2, grade III-IV: n=4). At day 28, 72 patients (88.9%) were in CR, 8 (9.9%) in NR. One patient (1.2%) succumbed to CRS. At last follow-up, 42 patients (60%) remained in remission, 34 patients had relapsed, 1 died of TRM, 3 of NRM, 1 had developed secondary MDS. This translated into an event-free survival probability (pEFS) of 43.9% (±6.5), an of overall survival (pOS) of 52.9% (±7.0), and a cumulative incidence of relapse (CIR) of 48.8% (±6.4) at 2 years post CAR T cell transfusion. CIR CD19 neg. was 33.8% (±6.1%) and CIR CD19 pos. was 15% (±4.2%). Interestingly, there was no difference between children and adult patients with regard to pEFS and pOS. A trend towards a higher pEFS (n=16, 55.0±12.7%) compared to patients receiving CAR-T for relapse after alloHSCT (n=65, 41.8±7.2%) was observed (p=0.630). Time to relapse after HSCT was a strong predictor for outcome. Patients relapsing within 6 months of HSCT had a pEFS (pOS) of 17.2±9.6% (15.6±9.6%), pEFS (pOS) for those relapsing later was 53.8±9.0% (74.5±8.0%) p=0.001), Figure 1. Risk factors: For the subgroup with post HSCT relapse, multivariable Cox-regression analysis considering age, time from HSCT to relapse, extra-medullary relapse, remission status at start of lymphodepleting chemotherapy (LDC) and LDC dosing revealed that time from HSCT to relapse >6 months’ post HSCT as a single factor reduced the risk to 0.381 and 0.221, respectively (p=0.001 and p=0.003), Table 1. Conclusion: In our analysis providing the first real-world experience in a patient cohort highly enriched for patients with post HSCT relapse, 40% of ALL patients with poor prognosis were rescued with a single dose of Tisa-cel. Our novel finding that patients post HSCT had a far better EFS if relapse occurred beyond 6 months might be attributable to more competent T-cell system with more native T-cells with higher plasticity for proliferation, expansion and persistence. This is currently a matter of investigation and may in future allow to implement strategies to optimize CAR T cell therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CD20 and CD19 expression loss in relapsed or refractory b-cell non-Hodgkin lymphoma: A retrospective cohort.

e19537 Background: CD20-targeted therapies such as rituximab are widely used in the management of B-cell non-Hodgkin lymphoma (NHL). Re-treatment with anti-CD20 agents is common, however previous research has demonstrated loss of CD20 expression at time of relapse or refractory disease in a subset of patients. There is also amplified interest in alternative targets, specifically CD19, in the relapsed or refractory setting. Incidence of CD19 loss has been explored in post-CAR T cell therapy patients but not described elsewhere. We hypothesized that CD marker loss may be higher than previous reports due to expanded use of CD20- and CD19-targeted therapy. Methods: The present study is a retrospective cohort analysis of 229 patients with B-cell NHL from Harbor-UCLA Medical Center in Los Angeles, CA from 2006 to 2022. Charts were retrospectively reviewed for cases of B-cell NHL, and data was collected about demographics, diagnosis, treatment, and relapses. CD20 and CD19 expression analysis was performed by immunohistochemistry and / or flow cytometry at diagnosis and at each relapse whenever possible. The primary endpoint of the study was the rate of CD marker expression loss at time of relapse. Results: The cohort of 229 patients was composed of 54.1% diffuse large B-cell lymphoma (DLBCL), 14.4% follicular lymphoma (FL), 8.3% high-grade B-cell lymphoma (HGBCL), 7.0% marginal zone lymphoma (MZL), 4.8% mantle cell lymphoma (MCL), and 11.2% other. Overall, 28.8% (66/229) patients had relapsed or refractory disease. The rate of CD20 expression loss was 7.9% (5/63) across all relapses with two patients converting at first relapse (1 FL relapsing as HGBCL, 1 MZL), two patients at 2nd relapse (1 FL relapsing as DLBCL, 1 MZL relapsing as DLBCL), and one patient at 5th relapse (1 MZL). All five patients with CD20 phenotypic conversion received rituximab, and three patients received two or more rounds of anti-CD20 therapy. The median OS after CD20 expression loss was 4 months (95% CI 3.3 – 4.7 months). All patients (14/14) who had CD19 testing performed at relapse maintained CD19 positivity. Conclusions: This retrospective study demonstrates a rate of CD20 expression loss at relapse of 7.9%, which is less than previously reported rates ranging between 11-60%. CD20 expression loss seems to be associated with transformation to high-grade lymphoma, poor overall survival, and marginal zone histology. The conservation of CD19 expression across relapses supports the use of novel anti-CD19 targeted therapy in the relapsed or refractory setting. Whenever possible, repeat biopsy should be done at time of relapse prior to treatment with CD-targeted therapy. This study is of notable clinical relevance with expanded use of anti-CD20 agents and novel CD19-targeted therapies in the management of B-cell NHL.

AGO-OVAR 2.29 (ENGOT-ov34): Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer (ROC).

TPS5611 Background: Paclitaxel or pegylated liposomal doxorubicin in combination with bevacizumab constitutes a standard treatment option in patients with relapsed ovarian cancer who are not considered candidate for platinum, but responses are short-lived. Immune checkpoint inhibitors like atezolizumab as single agents have limited activity in ovarian cancer. There is a biologic rationale to combine checkpoint inhibitors with chemotherapy and bevacizumab, however, the role of such combination for the management of ovarian cancer is so far undefined. Because of the intimate relationship between angiogenesis and immunosuppression, it is expected that the inhibition of both pathways could lead to synergism and more durable clinical benefit. The addition of a chemotherapeutic agent is expected to lead to the release of tumor antigens and enhance the efficacy of immunotherapy in turn. Therefore, we aim to test the efficacy of atezolizumab in combination with non-platinum-based chemotherapy and bevacizumab vs the combination of a non-platinum-based chemotherapy and bevacizumab alone. Methods: AGO-OVAR 2.29 is a randomized (1:1), double blinded, phase III trial evaluating the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy (weekly paclitaxel or pegylated liposomal doxorubicin) compared with placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after completing platinum-based chemotherapy or 3rd relapse. A de novo tumor biopsy to determine the PD-L1 expression status prior to randomization for stratification is mandatory. Patients are treated with chemotherapy plus bevacizumab + atezolizumab/placebo until progression or unacceptable toxicity. Co-primary endpoints are overall survival and progression-free survival. It is planned to randomize approximately 664 patients. Safety interim analyses were performed after inclusion of 24 and an additional 60 and 120 patients who had completed at least one treatment cycle. As of 09th February 2022, 461 patients have been randomized. Clinical trial information: NCT03353831.

Immunotherapy by anti-GD2 antibodies in patients with primary high-risk neuroblastoma, primary resistant and relapsed disease: Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg experience

Introduction. The long-term event-free survival of patients with high-risk neuroblastoma (NB) receiving intensive complex therapy according to current russian standard do not exceed 40 %. Also, there is no standard tactics in patients with primary resistant and relapsed disease, most of them die due to disease progression. While, anti-GD2 immunotherapy (IT) proved to be effective in patients with high-risk NB, in Russian Federation this method is not generally available. There are currently two pilot studies ongoing in Raisa Gorbacheva Memorial Institute aimed to evaluate the effectiveness of anti-GD2 antibodies in high-risk NB patients.Aim of the study – describing a single-center experience of anti-GD2 IT in primary high-risk NB patients and patients with primary resistant and relapsed disease.Materials and methods. A total of 20 patients received anti-GD2 antibodies, 16 of them were included into pilot trials. The median age at IT initiation was 5 (3–17) years. In 13 cases the therapy was initiated in patients with high-risk disease after auto-HSCT, in 3 cases – in patients with 1st systemic relapse of primary resistant disease after 2nd-line therapy and haplo-HSCT, in 1 case – in patient with 2nd chemosensitive relapse after haplo-HSCT. Also, 3 patients with progressive chemoresistant disease received anti-GD2 antibodies as monotherapy (n = 1) or in combination with chemotherapy (n = 2) as salvage regimen.Results. Patients receiving anti-GD2 antibodies after auto-HSCT retain response to therapy in 11 of 13 cases with a median follow-up period of 15 (6–27) months, in 2 cases there was disease progression during or immediately after IT cessation. Both patients with disease progression responded well to salvage therapy. Two of 3 haplo-HSCT recipients with prior good response to 2nd-line therapy are currently in remission 16 and 36 months past haplo-HSCT, one patient progressed 55 months after transplantation. A patient with 2nd late relapse after haplo-HSCT currently maintains remission on IT. Both patients with chemorefractory progressive disease did not respond to IT and died due to disease progression. IT was characterized by acceptable toxicity. In most cases it was complicated by Gr 1–2 fever, rash or neuropathic pain effectively controlled by supportive therapy. However, three patients had signs of neurotoxicity requiring therapy termination in one case.Conclusion. Dinutuximab beta IT is characterized by acceptable toxicity. With a median follow-up of 18 (6–59) months the majority (14 of 17) patients receiving anti-GD2 antibodies as maintenance therapy after auto- or allogeneic HSCT retain response. However, we did not observe any response in patients with progressive chemorefractory disease.

P-115: Renal response to rescue treatments in Relapsed Refractory Multiple Myeloma (RRMM) patients with renal impairment: final data of a large, observational, prospective study (MIR50)

P-115: Renal response to rescue treatments in Relapsed Refractory Multiple Myeloma (RRMM) patients with renal impairment: final data of a large, observational, prospective study (MIR50)

Malignant perivascular epithelioid cell neoplasm in the liver: report of a pediatric case

BackgroundPerivascular epithelioid cell neoplasm (PEComa) in a child is very rare. We herein report the first malignant case of PEComa developing in the liver of a pediatric patient.Case presentationA 10-year-old boy visited a private clinic with prolonged fever of unknown etiology. Abdominal ultrasonography was performed to evaluate the fever’s origin, revealing a large tumor in the liver. He was thus referred to a nearby hospital to investigate the tumor further. Enhanced computed tomography (CT) showed a 6.8 × 5.9 × 10.5-cm solid lesion on S4 and S5. On magnetic resonance imaging (MRI), the tumor had a low signal intensity on T1 imaging and high signal intensity on T2 imaging, with partial diffusion restriction. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed a marked uptake in the mass lesion with no evidence of metastasis. The patient was negative for all tumor markers, including AFP, CEA and PIVKA-II. The results of a needle biopsy suggested hepatocellular carcinoma. The tumor’s rapid growth suggested malignancy. Hepatic segmentectomy (S4 + S5 + S8) was performed. The tumor was resected en bloc with a margin. Microscopically, the tumor showed atypical spindle, polygonal or oval-shaped cells with a high nuclear grade, and vascular invasion. Immunohistochemistry was positive for alpha-smooth muscle antigen (α-SMA), human melanin black-45 (HMB-45) and melan A. The pathological diagnosis was malignant PEComa. In the 6 months after surgery, the patient complained of shoulder pain. MRI showed a dumbbell-shaped tumor at the 2nd thoracic vertebrae, which was confirmed to be bone metastasis of PEComa. After chemotherapy, including ifosfamide and doxorubicin, vertebrectomy was performed. Two years later, thoracoabdominal CT showed a 10-cm solid mass occupying the pelvis and a 15-mm nodule in the middle lobe of the right lung. Under a diagnosis of peritoneal and lung metastases, they were surgically removed and metastasis of PEComa was pathologically confirmed. Four months after the 2nd relapse, pelvic metastasis appeared again and mTOR (mammalian target of rapamycin) inhibitor was initiated. To our knowledge, this is the first report of malignant hepatic PEComa in a pediatric patient.ConclusionAlthough extremely rare, malignant hepatic PEComa can develop in a child.

Prolonged Arsenic Trioxide (ATO) and All- Trans Retinoic Acid (ATRA) Therapy for Relapsed Acute Promyelocytic Leukemia

▪Background.The recommended salvage treatment for patients with acute promyelocytic leukemia (APL) who relapse after front-line all-trans retinoic acid (ATRA) and chemotherapy is arsenic trioxide (ATO) combined to ATRA. However, the best consolidation strategy to be adopted after the achievement of a second remission is still a matter of debate. Currently, hematopoietic stem cell transplantation (HSCT, autologous or allogeneic) represents one of the preferred strategies but non-transplant based approaches may be taken into account in selected cases considering patient and disease-related factors. Prolonged therapy with ATRA-ATO without conventional chemotherapy was recently shown to be highly effective in front-line therapy of APL. However, only limited data is available on the efficacy of this protocol in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO at the time of disease relapse.Patients and methods. Twenty-two adult patients with APL undergoing disease relapse and treated between 2006-2017 in 2 hematology units located in Rome (Policlinico Tor Vergata and Policlinico Umberto I) were included in this study. All patients received for induction and consolidation ATO-ATRA as reported elsewhere (Lo-Coco et al, NEJM 2013) followed in 2 cases by transplant procedures. For 9 patients who were included in a previous report (Breccia et al, Haematologica 2011) we provide here an updated follow-up. All 22 patients signed an informed consent prior to treatment and the study was approved from the local IRBs. Molecular and haematologic relapse was in all cases confirmed by quantitative reverse-transcript PCR (RQ-PCR) according to standardized procedures. The RQ-PCR analysis for PML/RARA monitoring was repeated after the second ATRA-ATO cycle and at the end of therapy in all cases and at 3 months intervals during follow-up.Results. The main patient characteristics, treatment response and outcome are summarized in Table 1. Median age at the time of relapse was 45.5 years (range: 20-81 years). Eighteen patients were treated in 1st relapse, 3 in 2nd relapse and 1 in 4th relapse after allogeneic HSCT. All patients received first line therapy according to AIDA protocols. Details of successive treatments for patients receiving ATRA-ATO in ≥2 relapse are reported in Table 1. Of the 22 patients receiving ATRA-ATO, 7 were treated for hematologic recurrence, 14 for molecular relapse (with concomitant extramedullary disease in 3 cases) and 1 for isolated extramedullary relapse in the form of a paravertebral mass. The median length of the CR preceding ATRA-ATO therapy was 29 months (range: 1-120); 16 patients had a CR1 ≥ 12 months. Twenty-two patients completed induction and proceeded to consolidation for a median of 5 ATRA-ATO cycles (range:2-5, see Table 1 for details). Twenty of 22 patients (91%) obtained a new molecular remission (CRm) after the 2nd ATO-ATRA cycle, while 2 patients showed molecular persistence of disease and discontinued therapy after the third consolidation course due to disease progression. One patient underwent allogeneic HSCT from an HLA-identical sibling donor and one received autologous HSCT after 3 ATRA-ATO cycles in both cases. The remaining 18 patients were treated with repeated ATRA-ATO due to physician choice (prolonged previous remission, 8 patients; age and/or unfitness for intensive chemotherapy, 5 patients), refusal of HSCT (3 patients) or lack of a suitable donor (2 patients). With a median follow-up of 58 months from the time of relapse (range: 21-128 months), 14 patients (63.6%) are alive in prolonged CRm, 2 showed progressive disease and 5 relapsed at a median of 19 months (range: 6-27). Of the relapsed/refractory patients, 4 (18%) died due to disease progression, while 3 patients (14%) were rescued with allogeneic HSCT (2 patients) or with other agents + donor lymphocytes infusion (1 patient) and are currently alive and in CRm. Overall, 17 patients are alive (77%) and 5 died of disease progression (4 patients) or unrelated causes while still in CRm (1 patient).Conclusions. Although based on a retrospective series, this study suggests a potentially curative effect of the prolonged ATRA-ATO regimen used as salvage therapy for APL patients relapsed after long CR1. Prospective studies are warranted to confirm these observations. [Display omitted] DisclosuresCicconi:TEVA: Speakers Bureau. Breccia:TEVA: Speakers Bureau. Foa:AbbVie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Lo Coco:TEVA: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Lundbeck: Honoraria, Speakers Bureau.

Indications for Hematopoietic Stem Cell Transplantation in Patients with Waldenstrom's Macroglobulinemia: A Consensus Project of the EBMT Lymphoma Working Party (LWP)/ European Consortium for Waldenstrom's Macroglobulinemia (ECWM)/International Waldenstrom's Macroglobulinemia Foundation (IWMF)

Indications for Hematopoietic Stem Cell Transplantation in Patients with Waldenstrom's Macroglobulinemia: A Consensus Project of the EBMT Lymphoma Working Party (LWP)/ European Consortium for Waldenstrom's Macroglobulinemia (ECWM)/International Waldenstrom's Macroglobulinemia Foundation (IWMF)