Efficacy Of Novel Agents Research Articles

Developing Therapies for C3 Glomerulopathy: Report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials.

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM)

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

Colonization efficiency of multidrug-resistant Neisseria gonorrhoeae in a female mouse model.

The rapid occurrence of gonococcal resistance to all classes of antibiotics could lead to untreatable gonorrhea. Thus, development of novel anti-Neisseria gonorrhoeae drugs is urgently needed. N. gonorrhoeae FA1090 is the most used in gonococcal infection mouse models because of its natural resistance to streptomycin. Streptomycin inhibits the urogenital commensal flora that permits gonococcal colonization. However, this strain is drug-susceptible and cannot be used to investigate the efficacy of novel agents against multidrug-resistant N. gonorrhoeae. Hence, to test the in vivo efficacy of new therapeutics against N. gonorrhoeae resistant to the frontline antibiotics, azithromycin or ceftriaxone, we constructed streptomycin-resistant mutants of N. gonorrhoeae CDC-181 (azithromycin-resistant) and WHO-X (ceftriaxone-resistant). We identified the inoculum size needed to successfully colonize mice. Both mutants, CDC-181-rpsLA128G and WHO-X-rpsLA128G, colonized the genital tract of mice for 14 days with 100% colonization observed for at least 7 days. CDC-181-rpsLA128G demonstrated better colonization of the murine genital tract compared to WHO-X-rpsLA128G. Lower inoculum of WHO-X-rpsLA128G (105 and 106 CFU) colonized mice better than higher inoculum. Overall, our results indicate that CDC-181-rpsLA128G and WHO-X-rpsLA128G can colonize the lower genital tract of mice and are suitable to be used in mouse models to investigate the efficacy of anti-gonococcal agents.

Central nervous system status is prognostic in T-cell acute lymphoblastic leukemia: a Children’s Oncology Group report

AbstractTo determine the prognostic significance of central nervous system (CNS) leukemic involvement in newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL), outcomes on consecutive, phase 3 Children’s Oncology Group clinical trials were examined. AALL0434 and AALL1231 tested efficacy of novel agents within augmented-Berlin-Frankfurt-Münster (aBFM) therapy. In addition to testing study-specific chemotherapy through randomization, the AALL0434 regimen delivered cranial radiation therapy (CRT) to most participants (90.8%), whereas AALL1231 intensified chemotherapy to eliminate CRT in 88.2% of participants. In an analysis of 2164 patients with T-ALL (AALL0434, 1550; AALL1231, 614), 1564 had CNS-1 (72.3%), 441 CNS-2 (20.4%), and 159 CNS-3 (7.3%). The 4-year event-free-survival (EFS) was similar for CNS-1 (85.1% ± 1.0%) and CNS-2 (83.2% ± 2.0%), but lower for CNS-3 (71.8% ± 4.0%; P = .0004). Patients with CNS-1 and CNS-2 had similar 4-year overall survival (OS) (90.1% ± 0.8% and 90.5% ± 1.5%, respectively), with OS for CNS-3 being 82.7% ± 3.4% (P = .005). Despite therapeutic differences, outcomes for CNS-1 and CNS-2 were similar regardless of CRT, intensified corticosteroids, or novel agents. Except for significantly superior outcomes with nelarabine on AALL0434 (4-year disease-free survival, 93.1% ± 5.2%), EFS/OS was inferior with CNS-3 status, all of whom received CRT. Combined analyses of >2000 patients with T-ALL identified that CNS-1 and CNS-2 status at diagnosis had similar outcomes. Unlike B-ALL, CNS-2 status in T-ALL does not impact outcome with aBFM therapy, without additional intrathecal therapy, with or without CRT. Although nelarabine improved outcomes for those with CNS-3 status, novel approaches are needed. These trials were registered at www.clinicaltrials.gov as #NCT00408005 (AALL0434) and #NCT02112916 (AALL1231).

Neoadjuvant endocrine therapy in ER-positive breast cancer: evolution, indication, and tailored treatment strategy.

In recent years, endocrine therapy (ET), an effective systemic treatment for the management of estrogen receptor (ER)-positive breast cancers, has regained interest as a neoadjuvant therapy based on evidence that ET can fulfill the aim of neoadjuvant systemic treatment for tumor shrinkage as well as elucidate important clinical information on endocrine sensitivity that enables the prognostication of patients. Moreover, neoadjuvant endocrine therapy (NET) potentially provides an opportunity for early assessment of the clinical efficacy of novel agents. Furthermore, recently reported trials have generated evidence for a more tailored approach for perioperative management of ER-positive breast cancer using clinical and molecular biomarkers, and this has provided a rationale that enables the broadening of clinical indications for NET. This review discusses the current evidence for NET, the evolution of NET trials, clinical indications, and NET-based treatment strategies.

Changes in referral pathway and phenotypic status of patients diagnosed with ATTR cardiac amyloidosis during the past 20 years

Abstract Background Diagnostic and therapeutic advances have led to much increased awareness of transthyretin (ATTR) cardiac amyloidosis (CA). Purpose We sought to characterise the impact of this on referral practice, cardiac phenotype at diagnosis and specifically to determine whether patients are now being diagnosed at an earlier stage in their disease process. Methods We studied 1845 patients diagnosed with ATTR-CA at the National Amyloidosis Centre (NAC) from 2002–2021, all of whom underwent deep clinical phenotyping and follow-up. Results Analysis by 5-year quartiles revealed a substantial incremental increase in patients diagnosed with ATTR-CA (35 vs 260 vs 704 vs 846), which was associated with greater proportions of patients referred following advanced cardiac imaging (referrals following cardiac magnetic resonance and bone scintigraphy: 3% vs 44% vs 67% vs 76%; P<0.001). Over time, median duration of symptoms prior to diagnosis diminished from 36-months between 2002–2006 to 12-months between 2017–2021 (P<0.001) and a greater proportion of patients presented with milder disease across the 5-yearly quartiles (NAC stage 1: 40% vs 43% vs 44% vs 57%; P<0.001). The latter was associated with more favourable echocardiographic parameters of structure and function, including an incremental reduction in maximal left ventricular wall thickness (18.26mm vs 17.41mm vs 17.09mm vs 16.68mm; P=0.017). This was associated with improved survival in the overall population (2007–2011 vs 2012–2016: HR=1.65, 95% CI [1.33–2.06]; P<0.001 and 2012–2016 vs 2017–2021: HR =1.83, 95% CI [1.45–2.31]; P<0.001) and in each genotype (wtATTR, T60A and V122I). Despite a significant increase in the proportion of patients enrolled into clinical trials (0.0% vs 0.0% vs 2.6% vs 23.9%; P<0.001) and prescribed disease modifying therapy (5.7% vs 0.4% vs 4.8% vs 13.5%; P<0.001); the improved survival remained significant even after adjusting for clinical trials and disease modifying therapy (2012–2016 vs. 2017–2021: HR=1.65 95% CI [1.29–2.11], P<0.001). Conclusion Increased awareness and advances in cardiac imaging have been associated with a substantial increase in the diagnosis of ATTR-CA and at a progressively earlier stage of the disease, which has contributed to improved survival in recent years. These changes may have important implications for initiation and outcome of therapy. Given that ATTR-CA is now being diagnosed earlier, more data are needed to guide decisions on in whom and when to initiate treatment, and which treatments should be used at each disease stage. Furthermore, the changes in ATTR-CA phenotype at diagnosis urgently need to be factored into clinical trial design, given that pre-determined end-points based on trials performed in the past may no longer be appropriate, or at least sufficiently powered, or of adequate duration to evaluate efficacy of novel agents. Funding Acknowledgement Type of funding sources: None.

Leveraging extrachromosomal DNA to fine-tune trials of targeted therapy for glioblastoma: opportunities and challenges.

Glioblastoma evolution is facilitated by intratumour heterogeneity, which poses a major hurdle to effective treatment. Evidence indicates a key role for oncogene amplification on extrachromosomal DNA (ecDNA) in accelerating tumour evolution and thus resistance to treatment, particularly in glioblastomas. Oncogenes contained within ecDNA can reach high copy numbers and expression levels, and their unequal segregation can result in more rapid copy number changes in response to therapy than is possible through natural selection of intrachromosomal genomic loci. Notably, targeted therapies inhibiting oncogenic pathways have failed to improve glioblastoma outcomes. In this Perspective, we outline reasons for this disappointing lack of clinical translation and present the emerging evidence implicating ecDNA as an important driver of tumour evolution. Furthermore, we suggest that through detection of ecDNA, patient selection for clinical trials of novel agents can be optimized to include those most likely to benefit based on current understanding of resistance mechanisms. We discuss the challenges to successful translation of this approach, including accurate detection of ecDNA in tumour tissue with novel technologies, development of faithful preclinical models for predicting the efficacy of novel agents in the presence of ecDNA oncogenes, and understanding the mechanisms of ecDNA formation during cancer evolution and how they could be attenuated therapeutically. Finally, we evaluate the feasibility of routine ecDNA characterization in the clinic and how this process could be integrated with other methods of molecular stratification to maximize the potential for clinical translation of precision medicines.

A roadmap for clinical trial design in marginal zone lymphoma.

Marginal zone lymphoma (MZL) is commonly underrepresented in clinical trials collectively studying mostly nodal indolent lymphomas.In this manuscript we propose new inclusion and response criteria defined by MZL subtype and disease location for those with extranodal MZL. Progression of disease within 24 months is associated with poor outcomes in MZL and future studies should assess the efficacy of novel agents in this population.

Relative efficacy of lasmiditan versus rimegepant and ubrogepant as acute treatments for migraine: network meta-analysis findings

BackgroundIn the absence of head-to-head trials, comprehensive evidence comparing onset of efficacy of novel agents for acute treatment of migraine is lacking. This study aimed to explore the relative efficacy of lasmiditan (serotonin [5-hydroxytryptamine] 1F receptor agonist) versus rimegepant and ubrogepant (calcitonin gene-related peptide antagonists) for the acute oral treatment of migraine through network meta-analysis (NMA).MethodsData included in the NMA were identified through a systematic literature search (conducted April 2018, updated May/December 2020) of phase II–IV, randomised controlled trials (RCTs) in adults with chronic/episodic migraine with/without aura. Treatments included: lasmiditan 50, 100, 200 mg; rimegepant 75 mg; ubrogepant 25, 50, 100 mg. Pairwise treatment comparisons from Bayesian fixed-effect/random-effects NMA, adjusted by baseline risk where appropriate, were conducted. Comparisons were reported as odds ratios with 95% credible intervals. Early-onset efficacy endpoints included: pain freedom at 2 hours and pain relief at 1 and 2 hours. Adverse drug reaction (ADR) profiles were summarised. Heterogeneity and inconsistency in the network were explored; sensitivity analyses investigated robustness of findings.ResultsAcross 12 RCTs included in the base case, females represented >80% of included patients (mean age 37.9–45.7 years). Odds of achieving both pain freedom and pain relief at 2 hours were higher with lasmiditan 100 and 200 mg versus rimegepant 75 mg and ubrogepant 25 and 50 mg. Results for pain relief at 1 hour were consistent with those at 2 hours, but fewer comparisons were available. There were no statistically significant differences between lasmiditan 50 mg and ubrogepant or rimegepant for any outcome. Sensitivity analyses were in the same direction as base case analyses. Most commonly reported ADRs (incidence ≥2%) were: dizziness, fatigue, paraesthesia, sedation, nausea/vomiting and muscle weakness with lasmiditan; nausea with rimegepant; and nausea, somnolence and dry mouth with ubrogepant.ConclusionsThe efficacy findings of this indirect comparison indicate that lasmiditan 100 mg or 200 mg might be an appropriate acute treatment option for patients with migraine seeking a fast onset of action. Differently from rimegepant and ubrogepant, lasmiditan use is associated with mainly neurological events, which are mostly mild or moderate in severity and self-limiting.350/350 words

Epitheliod hemagioendothelioma (EHE) patient-derived model (PDX): Drug activity assessment and validation of novel biomarkers.

11566 Background: EHE is an ultra-rare sarcoma marked by two specific fusions, WWTR1-CAMTA1 (̃90%) and YAP1-TFE3 (̃10%). The clinical course of EHE ranges from indolent to highly aggressive, often associated with systemic paraneoplastic symptoms. Molecular predictors of clinical outcome are unknown. While surgery is the mainstay of treatment in the localized setting, management of advanced disease is challenging due to the rarity and poor sensitivity to conventional chemotherapy. This hampers the conduct of large prospective clinical trials. We report herein the first available EHE PDX (developed at the Istituto Nazionale Tumori, Milan, Italy) (INT), to assess the activity of old and new anticancer agents in EHE and inform future clinical studies. We also report on the preliminary results of a prospective observational study, ongoing in collaboration with The EHE Rare Cancer Charity (UK) and The EHE Foundation (US) aimed at identifying prognostic factors. Methods: A PDX of EHE in SCID mice was generated at INT from a patient (pt) suffering with the aggressive clinical variant, presenting with systemic symptoms. The PDX fully reproduces the originating clinical tumor in terms of morphology, biology ( WWTR1- CAMTA1 positive), overall transcriptomic profile. 2D (monolayer) and 3D (sferoids) cell cultures were established following PDX disaggregation. We have started assessing the comparative activity of currently available drugs (doxorubicin, sirolimus), while the efficacy of novel agents is undergoing. In parallel, we analyzed the presence of a selection of inflammatory cytokines in prospectively collected blood samples from EHE pts who entered an international observational study and we looked at their presence and modulation in the PDX model. Results: PDX experiments showed almost negligible activity of doxorubicin while sirolimus induced an 80% tumor volume inhibition. Biochemical analysis in tumors explanted from sirolimus-treated mice confirmed the down-regulation of mTOR downstream signaling. Among all cytokines, Growth and Differentiation Factor-15 (GDF-15) was found significantly over-expressed in serum of EHE pts (n = 23), particularly those with the most aggressive clinical variant, compared to healthy subjects (n = 23; p< 0.01). Consistently, EHE PDX and cell culture were found to release in the blood/culture medium GDF-15. Sirolimus was found to down-regulate GDF-15 release in both in vivo and in vitro EHE models. Conclusions: Our preliminary results indicate that this EHE PDX model is suitable i) for comparatively assessing the activity of anticancer drugs, and ii) for identifying and pre-clinically validating novel biomarkers. The role of GDF-15 in EHE progression deserves further investigation.

Clinicobiological characteristics and treatment efficacy of novel agents in chronic lymphocytic leukemia with IGLV3-21R110

Clinicobiological characteristics and treatment efficacy of novel agents in chronic lymphocytic leukemia with IGLV3-21R110

Novel Therapies for the Treatment of HER2-Positive Advanced Breast Cancer: A Canadian Perspective.

The advent of anti-HER2 targeted therapies has dramatically improved the outcome of HER2-positive breast cancer; however, resistance to treatment in the metastatic setting remains a challenge, highlighting the need for novel therapies. The arrival of new treatment options and clinical trials examining the efficacy of novel agents may improve outcomes in the metastatic setting, including in patients with brain metastases. In the first-line setting, we can potentially cure a selected number of patients treated with pertuzumab + trastuzumab + taxane. In the second-line setting, clinical trials show that trastuzumab deruxtecan (T-DXd) is a highly effective option, resulting in a shift from trastuzumab emtansine (T-DM1) as the previous standard of care. Moreover, we now have data for patients with brain metastases to show that tucatinib + trastuzumab + capecitabine can improve survival in this higher-risk group and be an effective regimen for all patients in the third-line setting. Finally, we have a number of effective anti-HER2 therapies that can be used in subsequent lines of therapy to improve patient outcomes. This review paper discusses the current treatment options and presents a practical treatment sequencing algorithm in the context of the Canadian landscape.

Efficacy of novel agents in patients with nephropathy associated with POEMS syndrome

ObjectiveTo evaluate the clinical characteristics and outcomes of patients with nephropathy associated with POEMS syndrome who received novel agents in combination with dexamethasone therapy, and renal pathological changes based on repeat biopsy in some patients after these novel-agent-based therapies.MethodsThe records of patients with nephropathy associated with POEMS syndrome in a single hospital from May 2017 to February 2021 were retrieved and studied in detail. All the patients received four cycles of initial novel-agent-based regimens such as bortezomib and dexamethasone (BD) or thalidomide plus dexamethasone (TD) or lenalidomide plus dexamethasone (RD) treatment. We further evaluated the pathological efficacy of these novel agents by repeat renal biopsy.ResultsTwelve patients with an average age of 48.6 ± 8.3 years diagnosed with nephropathy associated with POEMS syndrome were enrolled in this study. The duration from disease onset to renal biopsy was 28(8.3 ~ 54.5) months. All patients achieved good clinical responses in different degree after four cycles of initial novel agents in combination with dexamethasone therapy. After the treatment with novel-agent-based regimens, the levels of proteinuria decreased in most patients and were negative in five patients. The levels of serum creatinine (SCr) decreased in ten patients. Serum M protein was negative in four patients and still positive in the other eight patients. The levels of serum vascular endothelial growth factor (VEGF) were detected in seven patients, which were all decreased. The levels of interleukin-6 (IL-6) were detected in eight patients, which were also decreased. Repeat biopsies were performed after four cycles of novel-agent-based therapies in four patients who were all treated with BD treatment. Mesangiolysis, mesangial cells proliferation, endothelial cells proliferation, subendothelial space widening and acute renal tubulointerstitial lesions improved, the chronic renal tubulointerstitial lesions were stable.ConclusionsNovel agents improved clinical manifestations in patients with nephropathy associated with POEMS syndrome. In addition, novel-agent-based regimens such as BD treatment improved renal pathological manifestations, which suggested that novel agents could improve renal prognosis of the patients from the perspective of renal pathology.

Advances in treatment of elderly primary central nervous system lymphoma.

The management of older individuals (≥60years) with primary central nervous system lymphoma remains a clinical challenge. Identification of optimal therapy and delivering adequate dose intensity are two of the major issues in treating elderly patients. Premorbid performance status and comorbidities influence individualised treatment approaches and geriatric assessment tools are increasingly utilised. Optimal induction treatment remains high-dose methotrexate-based immunochemotherapy, delivery is feasible in the majority of patients and the goal of treatment remains achieving complete remission. Consolidation strategies are also relevant in the elderly, aiming to maximise duration of response and quality of life (QoL). Potential options include high-dose therapy with haematopoietic stem cell consolidation, non-myeloablative chemotherapy and whole-brain radiotherapy. Efficacy of novel agents, such as Bruton tyrosine kinase inhibitors and lenalidomide, have been reported; these represent an alternative for elderly patients unfit for chemotherapy. Prognosis remains poor, improvement of outcomes in this age group is urgently needed.

Toxicity and antitumor activity of novel agents in elderly patients with cancer included in phase 1 studies.

IntroductionThe number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer.MethodsData from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008-2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity.ResultsThe mean age was 58.7 (range: 18-87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7).ConclusionsThis retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.

Splicing Modulation Perturbs Key Survival Pathways and Sensitizes Chronic Lymphocytic Leukemia to Venetoclax Treatment

Splicing Modulation Perturbs Key Survival Pathways and Sensitizes Chronic Lymphocytic Leukemia to Venetoclax Treatment

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

Limitations of animal epilepsy research models: Can epileptic human tissue provide translational benefit?

Advancement of understanding the etiology and treatment of epilepsy has largely depended on the use of acute and chronic animal models. An alternative approach, which is being increasingly used by a select number of laboratories worldwide, is to perform functional mechanistic studies in brain slices of living human tissue resected during surgery for drug resistant epilepsies. Pharmacoresistant epilepsy is a major clinical problem with a significant proportion of patients not receiving any symptomatic benefit from available anti-epileptic drugs. Animal models of epilepsy have dominated the landscape with regard to research and development, however they have failed to deliver new agents that would provide seizure control in patients with drug refractory epilepsy. Moreover, these models have considerable issues with respect to validity and animal welfare considerations. A compelling alternative is the use of live human epileptic tissue, which recapitulates a number of key features of refractory epilepsy. The use of live epileptic human tissue offers unprece­dented opportunities to understand the mechanisms associated with difficult to treat epilepsy whilst also permitting studies of efficacy of novel agents that are being developed to alleviate epilepsy in drug resistant patients.

Second Autologous Stem Cell Transplant As Salvage Therapy in Multiple Myeloma - the Oregon Health and Science University Experience

Background: Though the available number and efficacy of novel agents for multiple myeloma (MM) have improved in recent years, it remains an incurable disease with relapse inevitable in nearly all patients. Autologous stem cell transplantation (ASCT) as consolidation after induction remains the standard of care for transplant-eligible patients with randomized studies showing progression-free survival (PFS) greater than 4 years (Atttal et al., N Engl J Med 2017; 376:1311-1320). Relapse outcomes are also improving with PFS now greater than 3 years in some settings (Bahlis, et al., Leukemia 2020 Jul;34(7):1875-1884). For fit patients with good response to a first ASCT, a second autologous transplant (SAT) can be considered. The American Society for Blood and Marrow Transplantation (ASBMT) and the International Myeloma Working Group (IMWG) guidelines suggest SAT should be considered for those whose first ASCT resulted in remission duration >18 months (Giralt et al., Biol Blood Marrow Transplant 2015; 21:2039-2051). CIBMTR data note 600-700 SATs are performed annually. Most data on SAT come from single-center retrospective series, though pooled analyses note median PFS >1 year and median OS >30 months (Hagen and Stiff, Biol Blood Marrow Transplant 2019 Mar;25(3):e98-e107). Here we present our institution's experience with salvage SAT for MM analyzing treatment outcomes and toxicities. Methods: We performed a single-center retrospective review of all MM patients at Oregon Health and Science University who received SAT for myeloma as salvage therapy. Planned tandem transplants were excluded. Demographic and disease characteristic data at time of original diagnosis and at time of SAT were extracted and responses assessed by IMWG criteria. OS and PFS from SAT were calculated by Kaplan Meier method with progression or death from any cause counted as events for PFS and censoring at last known follow-up for live patients. Results: Baseline characteristics: Sixty-eight patients were identified who received SAT between 1999 and 2020. Durie-Salmon staging at diagnosis was available for 30 patients; 16 (24%) 3A, 7 (10%) 2A, 1 1B (1%), 6 (9%) 3b. The median age at time of SAT was 61 (range 45 -74). The median time between first and second ASCT was 5.5 years, (range 1.1 -15.2 years). Median PFS after first ASCT could be calculated for 53 patients and found to be 2.5 years (range 0.3 - 10). First ASCT conditioning regimen and dosing were available for 56 patients; 55 (81%) received melphalan with 53 (78%) receiving 200mg/m2, 2 (3%) receiving 140mg/m2, 1 (2%) received busulfan + TBI. The average number of lines of therapy prior to SAT was 2.8 (range 1-14). SAT preparative regimens were available for 67 patients: 59 (87%) received melphalan 200mg/m2, 6 (9%) received melphalan 140mg/m2, 1 (2%) received BEAM, 1 (2%) received melphalan 200mg/m2 and bortezomib. All SAT patients received peripheral blood stem cell mobilization. Outcomes: 37 (54%) patients have died at time of data collection. Median OS after SAT was 3.09 years while median PFS was 1.65 years. Treatment related mortality (TRM, defined as death not due to progression within 100 days of SAT) occurred in 1 patient (2%). Long term complications included 10 patients found with other malignancies after SAT (5 with basal or squamous cell skin carcinoma, 2 with MDS, 2 GI malignancies, 1 prostate). Conclusion: Our institution's experience with SAT for MM suggests it's an effective salvage treatment with low treatment-related mortality, though with a shorter PFS than after first transplant. Most patients were able to receive and tolerate full dose melphalan 200mg/m2 for SAT. Disclosures Silbermann: Sanofi-Aventis: Consultancy, Research Funding; Janssen: Consultancy; Karyopharm: Consultancy. Maziarz:Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding; Novartis and Athersys: Other: DSMB participant; Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Athersys: Patents & Royalties.

The clinical characteristics of patients with primary plasma cell leukemia and the efficacy of novel agents and hematopoietic stem cell transplantation

Objective: To analyze the immunophenotype and cytogenetic characteristics of primary plasma cell leukemia (pPCL), and to evaluate the efficacy of bortezomib and hematopoietic stem cell transplantation as main treatment. Methods: A retrospective cohort study was conducted including 42 pPCL patients admitted to Peking University People's Hospital from January 1998 to March 2019. All patients were followed up until December 31, 2019. The immunophenotype and cytogenetic characteristics were compared with historical data of multiple myeloma (MM). Thirty-nine patients were divided into bortezomib-based group (29 cases) and non-bortezomib group (10 cases). All patients were also divided into hematopoietic stem cell transplantation (HSCT) group (15 cases) and non-HSCT group (24 cases).Chi-square test was used for efficacy comparison, and Kaplan-Meier method was used for univariate prognostic analysis. Cox proportional hazards model was used for multi-variant analysis. Results: pPCL accounted for 2.6% of the total patients with plasma cell diseases during the same period. There were 22 males and 20 females, with a median age of 50 (30-77) years old at diagnosis. In immunophenotype analysis, tumor cells in pPCL patients also expressed CD38, CD138, CD45, which was similar as patients with MM. However the expression of CXCR4 were more frequently seen in pPCL(73.1% vs. 34.7%, P= 0.000), while intensity of CD9 and CD200 was lower (40.7% vs. 62.5%, P =0.028, 33.3% vs. 58.0%, P=0.021).Overall response rate of bortezomib-based therapy was superior to non-bortezomib therapy (69.0% vs.50.0%). The median survival was 18.2 (0.2-95.7)months, and the 1-and 2-year survival rates were 61.9% and 37.4%, respectively. Multivariate prognostic analysis suggested that age (P= 0.027) and efficacy(P= 0.035)were significantly correlated with survival.HSCT resulted in superior survival compared with chemotherapy alone(26.8 vs. 8.1 months, P=0.021). Conclusions: Immunophenotypes and cytogenetic abnormalities in patients with pPCL are different from those with multiple myeloma. Bortezomib based regimens improve response rate and survival of pPCL. Hematopoietic stem cell transplantation also predicts survival benefits.