Minor Response Research Articles

DNA methylation inhibition in myeloma: Experience from a phase 1b study of low-dose continuous azacitidine in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma

The DNA methyltransferase inhibitor azacytidine (aza) may reactivate pathways associated with plasma cell differentiation, cell cycle control, apoptosis, and immune recognition and thereby restore sensitivity to lenalidomide (len) and dexamethasone (dex) in relapsed and/or refractory multiple myeloma (RRMM). We aimed to develop an aza regimen that reaches epigenetically active levels 8 times in 28 days with less bone marrow toxicity than the myeloid malignancy standard of 7 consecutive doses to enable safe combination with len. Aza was escalated from 30 mg/m2 once a week up to a predefined maximum of 50 mg/m2 twice a week in combination with GFR-adjusted len (≥ 60 mL/min: 25 mg, 3059 mL/min: 10 mg) day 1 to 21 every 28 days and dex 40 mg once a week followed by a limited expansion study to a total N of 23 at the highest tolerated dose. Fifty-one patients (pts) with RRMM were screened, 42 were treated and 41 were evaluable for response based on at least 1 response assessment or progression after treatment start. The median number of prior lines of therapy was 5 (1-11) and 81% (34) were refractory to len and/or pomalidomide (pom). Two DLTs occurred in different cohorts, 1 neutropenic fever in 1/6 pts on the aza 40 mg/m2 twice a week GFR ≥ 60 mL/min cohort and 1 GGT elevation in 1/6 pts on the aza 50 mg/m2 GFR 30-59 mL/min cohort. An MTD was not reached and aza 50 mg/m2 SC twice a week was chosen for the expansion study. At least possibly related Grade 3/4 AEs occurred in 28 pts (67%) with the following in > 1 pt: neutropenia (N = 16, 38%), anemia (N = 6, 14%), lymphopenia (N = 5, 12%), thrombocytopenia (N = 4, 10%), leukopenia (N = 4, 10%), febrile neutropenia (N = 4, 10%), fatigue (N = 3, 7%), fever (N = 2, 5%), and infection (N = 2, 5%). At a median follow up time for alive pts of 60.2 months (range: 36.1-82.5 months), the overall response rate (≥ partial response) and clinical benefit response rate (≥ minor response) was 22 and 32%, respectively, with 4 very good partial responses (10%), 5 partial responses (12%), and 4 minor responses (10%). The median PFS was 3.1 months (95% confidence interval [CI]: 2.1-5.1 months), median TTP 2.7 months (95% CI: 2.1-7.5 months), and median OS 18.6 months (95% CI: 12.9-33.0 months). Achieving at least minor response and reaching TTP > 6 months was associated with approximately 35% lower median plasma levels of the enzyme that inactivates aza, plasma cytidine deaminase (CDA, P< .0001). Two of the len refractory pts achieved longer disease control than with any prior regimen and 1 responded immediately after progression on len, bortezomib, and prednisone. Analyses of the methylation state of over 480,000 CpG sites in purified myeloma cells at screening were possible in 11 pts and on day 28 in 8 of them. As in other studies, the majority of differentially methylated CpGs compared to normal plasma cells were hypomethylated in myeloma. Treatment decreased the number of CpGs that were differentially methylated in normal plasma cells by > 0.5% in 6 and by > 5% in 3 of the 8 pts, most pronounced in 2 pts with clinically convincing aza contribution who achieved a reduction in overall differentially methylated CpGs by 23 and 68%, respectively, associated with increased expression of immunoglobulin genes. The study demonstrated tolerability of twice a week SC aza at 50 mg/m2 with len and dex in RRMM and suggested aza may help overcome the len/pom refractory state, possibly by activating differentiation pathways. Relatively low response rates and association of clinical benefit with low plasma levels of the aza inactivating enzyme CDA suggest the aza regimen will need to be optimized further and pt selection may be required to maximize benefit.

Anterior mediastinal large cell neuroendocrine carcinoma with elevated AFP: A case report and review.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive cancer that typically presents in the lung. The current case report describes a 56 year old male who presented to Strong Memorial Hospital with progressive dyspnea and was revealed to have a large anterior mediastinal tumor with metastases to axillary, hilar and mediastinal lymph nodes. Tumor marker results revealed an elevated plasma level of α-fetoprotein (AFP), which initially pointed towards a diagnosis of teratoma, but the tumor stained positive for neuroendocrine markers CD56, chromogranin, and synaptophysin on biopsy, consistent with LCNEC. AFP-positive tumor cells were identified, and no alternate cause for the elevated AFP was identified. The patient underwent genetic testing revealing the tumor to be ALK, ROS1, KRAS, BRAF and EGFR wild type. The patient received 6 cycles of chemotherapy with cisplatin (80 mg/m2) and etoposide (100 mg/m2) and then radiation with an initial minor response. The patients course was complicated by the development of superior vena cava syndrome requiring emergency stenting. The results of the current case suggest that AFP may be worthy of further exploration as a potential tumor marker in LCNEC.

Prolonged, Continuous Treatment of Hairy Cell Leukemia Patients With Recombinant Interferon-α2a

AbstractInterferons are not curative in hairy cell leukemia (HCL), and retreatment is necessary in most patients whose therapy is stopped. In an attempt to maintain or improve responses, we administered recombinant interferon-α2a (rlFN-α2a) continuously to patients with HCL who initially responded to this therapy. Of 53 evaluable patients enrolled in this study, 32 have received rlFN-α2a continuously for a median of 5 years. Patients received 3 million units of rlFN-α2a subcutaneously (SC) daily for 6 months, followed, in responding patients, by the same dose three times weekly. Twenty-one patients (40%) discontinued IFN after a median of 29 months, seven of whom developed resistant disease in association with anti-IFN antibodies. Treatment produced high response rates: complete response plus partial response (CR + PR) = 40 of 53 (76%), CR + PR + minor response (MR) = 43 of 53 (82%), with no differences in response rates between patients with and without splenectomy. Sixteen patients who had MR at 18 months had PR with prolonged treatment, nine of whom had a significant further reduction in the hairy cell infiltrate in the bone marrow (BM). The median granulocyte and platelet counts have continued to increase and the median serum soluble interleukin-2 receptor (slL-2R) level has continued to decrease with prolonged treatment. Two patients developed erythrocytosis that may be treatment related, but no other new toxicities were noted with prolonged treatment. We conclude that prolonged, continuous rlFN-α2a treatment has acceptable toxicity, is not associated with late development of IFN resistance, and results in continued hematologic improvement with time on treatment. This is a US government work. There are no restrictions on its use.

LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTI-INSTITUTIONAL PHASE II STUDY

BACKGROUNDRAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib is an orally bioavailable MEK1/2 inhibitor found to have significant central nervous system penetration in a preclinical model.OBJECTIVEThe primary objective of this multi-institutional open-label phase II study was to assess preliminary efficacy of binimetinib in progressive pediatric LGG. The study included strata for both neurofibromatosis type I (NF1) and non-NF1 associated tumors, as well as a target validation (surgical) stratum. NF1 and surgical strata remain open to enrollment and will be reported separately.METHODSChildren aged 1–18 years with previously treated recurrent or progressive LGG were eligible. The dose of binimetinib was 32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements.RESULTSFifty-seven eligible patients without NF1, median age 8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in the first year due to toxicity, and an additional 27 required dose reduction. The most common drug-attributable grade 3 toxicities included creatine kinase elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal weakness improved or resolved with dose reduction or cessation. Grade 4 toxicities included creatine kinase elevation (n=2) and transient colitis (n=1). Of 44 patients with preliminary response data available, 22 (50%) showed a minor (n=7) or partial (n=15) response.CONCLUSIONBinimetinib is active, with manageable toxicities, in children without NF1 with progressive LGG.

LGG-25. A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY. TRAM-01

BACKGROUNDPediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. We hypothesize that we will observe responses in recurrent/refractory PLGG treated with trametinib.METHODSThis is a multicenter phase II including three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Patients will receive daily oral trametinib for a total of 18 cycles of 28 days. A total of 104 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.RESULTSAs of January 7 2020, 28 patients have been enrolled (NF1: 6 patients, KIAA1549-BRAF fusion: 17, other: 5 including 3 patients FGFR1 alteration). Median age is 8.5 years (range 2.5–25.4 years). Median follow-up is currently 4.6 months (range 0.16–14.7 months). Twenty patients are currently evaluable. Best response includes: 1 complete response (5%), 3 partial response (15%), 4 minor response (20%), 8 stable disease (40%), 4 progressive disease (20%). 8 patients (28,5%) discontinued treatment: 4 for progressive disease, 3 adverse event (alanine aminotransferase increase), 1 withdrew.CONCLUSIONTrametinib is potential effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

IMG-04. RESPONSE ASSESSMENT IN PEDIATRIC HIGH-GRADE GLIOMA: RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY WORKING GROUP

INTRODUCTIONResponse criteria for pediatric high-grade gliomas (pHGG) have varied historically and across clinical trials. Compared to adult HGG, pHGG response assessment has unique challenges. An international Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was established to develop pHGG response assessment criteria.METHODSPediatric and adult neuro-oncologists, neuro-radiologists and experts in imaging informatics developed a consensus statement and established a unified response assessment for biopsy-proven pHGG, excluding DIPG. This was achieved by identifying major challenges, reviewing existing literature and current practices, and finally developing recommendations through an iterative process.RESULTSCategories for response assessment include complete response, partial response, minor response, stable disease and progressive disease. Refractory disease is excluded. Criteria used to determine response assessment include quantitative evaluation of measurable disease, qualitative assessment of diffusion imaging, presence or absence of new lesions, clinical status using performance score, and vascular endothelial growth factor inhibitor and/or corticosteroid use. Response is determined over 2-time points ≥ 8 weeks apart, and when progressive disease is unclear, guidance for repeat MRI imaging and/or utility of repeat biopsy is described. A number of recommendations are also given to standardize response assessment across clinical trials including MRI protocol sequence recommendations for brain and spine, definitions for measurable and non-measurable disease, and imaging time points with post-operative considerations. In addition, guidance is given for differentiating vasogenic edema versus tumor invasion in non-enhancing disease.CONCLUSIONConsensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.

Identification and characterization of antigen-specific CD4+ T cells targeting renally expressed antigens in human lupus nephritis with two independent methods

In the search for anti-renal autoreactivity in human lupus nephritis, we stimulated blood-derived CD4+ T cells from patients with systemic lupus erythematosus with various kidney lysates. Although only minor responses were detectable, these experiments led to the development of a search algorithm that combined autoantibody association with human lupus nephritis and target gene expression in inflamed kidneys. Applying this algorithm, five potential T cell antigens were identified. Blood-derived CD4+ T cells were then stimulated with these antigens. The cells were magnetically enriched prior to measurement with flow cytometry to facilitate the detection of very rare autoantigen-specific cells. The detected responses were dominated by IFN-γ-producing CD4+ T cells. Additionally, IL-10-producing CD4+ T cells were found. In a next step, T cell reactivity to each single antigen was independently evaluated with T cell libraries and [3H]-thymidine incorporation assays. Here, Vimentin and Annexin A2 were identified as the main T cell targets. Finally, Vimentin reactive T cells were also found in the urine of three patients with active disease. Overall, our experiments show that antigen-specific CD4+ T cells targeting renally expressed antigens arise in human lupus nephritis and correlate with disease activity and are mainly of the Th1 subset.

NCOG-18. IS THE RANO CRITERIA FOR LOW-GRADE GLIOMA RELIABLE IN THE CLINICAL SETTING? – A RELIABILITY STUDY

Abstract INTRODUCTION Magnetic resonance imaging (MRI) is a fundamental component of longitudinal neuro-oncology evaluation and decision-making. The Response Assessment in Neuro-Oncology criteria for low-grade gliomas (RANOLGG) was designed as an outcome measure for clinical trials. Thus, this project intends to study the reliability of RANOLGG in the clinic setting. METHODS 21 pairs of brain MRIs, that averaged three years apart, were selected from 21 patients with tissue diagnosis of WHO grade 2 gliomas. Two neuro-oncologists and two neuro-radiologists reviewed and independently scored the MRI pairs according to RANOLGG categories of progressive disease, stable disease, minor response, partial response, and complete response. Kappa-Fleiss (KF) was used to evaluate agreement among reviewers. RESULTS Reviewers awarded identical scores in only 33% of MRI pairs and there was a complete disagreement in one MRI pair. Overall reliability of the criteria in the clinical setting is moderate (KF = 0.44). Agreement between neuroradiologists (KF = 0.51) and between neuro-oncologists (KF = 0.48) were similar. Interpretation of post-contrast T1-weighted images had a better agreement (KF = 0.31) than T2/FLAIR-weighted images which had a poor agreement (KF = -0.02). Classification of progression versus non-progression had only a moderate agreement (KF= 0.49). History of radiation therapy or chemotherapy did not influence the criteria reliability (fisher exact text, p = 0.58, p =0.27, respectively). CONCLUSION RANOLGG reliability in the clinical setting is moderate, therefore it should be used cautiously for clinical decision-making. Other tools that can support the neuro-oncologist in the follow-up of patients with low-grade glioma are additional MRI sequences other than T2/FLAIR and contrast – weighted images, computer-aided diagnosis such as volumetrics, spectroscopy, positron emission tomography, and multidisciplinary tumor boards. Likewise, when image criteria for low-grade gliomas are designed, T2/FLAIR should be used guardedly, due to low interpretation agreement.

CTNI-24. A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY. TRAM-01

Abstract BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This multicenter phase II included three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Primary objective is to evaluate overall response rate after daily oral trametinib administration for 18 cycles each 28 days duration. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. RESULTS As of June 1 2020, 37 patients have been enrolled (NF1: 7 patients, KIAA1549-BRAF fusion: 22, other: 8 (including 5 patients with FGFR1 alterations). Median age is 9.3 years (range 2.3–25.4). Median follow-up is 8.8 months (range 0–19.3). Twenty-eight patients are evaluable. Best response includes: 4 partial response (PR) (14%), 5 minor response (MR) (18%), 18 stable disease (64%), 1 progressive disease (3.5%). Median time to response is 2.8 months (range 2.4–11.3). Median duration of response is 8.0 months (range 0.6–16.8. Progression free survival at 12 months is 83.1% (95% CI 70.5–98.0%) and median progression free survival has not reached. Nine patients (24%) discontinued treatment: 3 for progressive disease, 4 adverse events (3 alanine aminotransferase increase, 1 paronychia), 2 for other reasons. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Quality of Life (QoL) and Clinical Outcomes in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Receiving Ixazomib-Lenalidomide-Dexamethasone (IRd) in a Real-World Setting

The goal of treatment of relapsed/refractory multiple myeloma (RRMM) is to control the disease, prolong survival, reduce disease-related symptoms, and improve quality of life (QoL). Comprehensive evaluation of new treatment regimens in RRMM pts is worthwhile. We aimed to evaluate QoL, treatment satisfaction, response to treatment and safety during Ixazomib-Lenalidomide-Dexamethasone (IRd) treatment as ≥ 2nd line in RRMM pts in a real world setting. Adult pts with RRMM who have been assigned IRd as ≥2nd line treatment were enrolled in multicenter observational prospective study. Treatment response was evaluated by IMWG 2011, adverse events (AEs) - by CTCAE v.4.0. Pts filled out RAND SF-36 and ESAS-R at baseline and at 1 and 3 mos, and thereafter every 3 mos till 18 mos after IRd treatment start; Patient Treatment Satisfaction Cheklist (PTSC) - at each time-point after IRd treatment start. For analysis of meaningful QoL changes during IRd treatment the proportion of pts with baseline significant QoL impairment who experienced meaningful QoL improvement during IRd treatment was evaluated as well as the number of pts without baseline QoL impairment who maintained it during IRd treatment. For statistical analysis GLM paired test and GEE were employed with adjustment to age, gender and baseline QoL. In total, 40 pts with RRMM were enrolled into the pilot study: median age - 64 years (range, 33-80), 29% males, Durie-Salmon stage at study entry: I/II/III - 3/41/56%, ECOG status 0/1 - 68.7%, 2/3 - 31.6%. Median time since initial MM diagnosis - 51.4 mos (range, 2.9-100.7), disease status at study entry: relapsed - 26%, refractory - 21%, relapsed and refractory - 53%. Median number of lines of prior therapy is 3 (range, 1-3). At the time of analysis the median number of IRd cycles administered is 5, median follow-up - 4.6 (0.4-13.7) mos. Treatment response was not evaluated in 11 pts: 1 - death (at 3 months), 1- refusal, 9 - too early for evaluation. Out from 29 pts one patient achieved complete response (CR), seven pts achieved partial response (PR) and one patient - very good partial response (VGPR), 12 - minor response (MR). Thus, a clinical benefit rate was 70%. Also, seven pts achieved stable disease (23%), one patient was primary refractory to IRd (3.5%), one patient died (3.5%). At the time of analysis all the pts with CR/PR/VGPR (30%) maintained their response to treatment, 4 pts (13%) maintained stable disease and 9 pts (30%) maintained minor response; 7 pts (23%) experienced disease progression. AEs were revealed in 47% pts: grades 1-2 AEs - 12 pts; grades 3-4 AEs - 4 pts; SAEs - 3 pts (neurological toxicity, gastric bleeding, hypotension), all pts with SAEs discontinued IRd treatment. Baseline QoL was dramatically impaired by the majority of SF-36 scales with significant QoL impairment in 42% pts. The most worsening was revealed for physical functioning, role functioning, general health and vitality (Mean scores varied from 24.6 to 47.0 out from 100 scores). At baseline 88% pts had moderate-to severe symptoms (≥4 scores on the scale from 0 to 10); moderate-to severe worse wellbeing, tiredness, pain and shortness of breath had 72,5%, 67,5%, 61,5% and 45% pts, respectively. At 1 month of IRd treatment QoL meaningfully improved or was stable without significant impairment in 61% pts, at 3 months - in 50% pts. In 1 mos of IRd treatment significant improvement was revealed for physical functioning (GLM, 44.9 vs 54.7, p=.01) and general health (GLM, 47.8 vs 56.3, p&amp;lt;.001). Further during IRd treatment no significant QoL worsening was identified (GEE, p&amp;gt;.05). At 1 month of treatment, meaningful decrease of shortness of breath (in 42% pts), tiredness (36%), and pain (28%) was revealed; at 3 months of IRd treatment this proportion was 33%, 27%, and 13%, accordingly. Regarding treatment satisfaction pts reported the following: at 1 month after treatment start 94% of pts were satisfied with symptoms decrease due to IRd, 89% pts confirmed that IRd was convenient and 97% pts reported global satisfaction with IRd; at 3 months of treatment all the pts confirmed the convenience of IRd regimen, 84% pts were satisfied with IRd treatment. The results obtained in a real-world setting demonstrate clinical benefits of IRd regimen in RRMM pts, which were achieved without negatively affecting QoL and with satisfactory symptom control in these heavily pretreated patients. IISR funded by Takeda Disclosures Ionova: BMS: Research Funding; Takeda: Research Funding. Vinogradova:Novartis: Honoraria, Research Funding.

Five-Year Follow-Up of Ibrutinib Plus Rituximab Vs Placebo Plus Rituximab for Waldenstrom's Macroglobulinemia: Final Analysis From the Randomized Phase 3 iNNOVATETM Study

Five-Year Follow-Up of Ibrutinib Plus Rituximab Vs Placebo Plus Rituximab for Waldenstrom's Macroglobulinemia: Final Analysis From the Randomized Phase 3 iNNOVATETM Study

Long-Term Follow-up of Ibrutinib Treatment for Rituximab-Refractory Waldenström’s Macroglobulinemia: Final Analysis of the Open-Label Substudy of the Phase 3 iNNOVATETM Trial

Long-Term Follow-up of Ibrutinib Treatment for Rituximab-Refractory Waldenström’s Macroglobulinemia: Final Analysis of the Open-Label Substudy of the Phase 3 iNNOVATETM Trial

Extensive Variability in Platelet Count, Bleeding, and Quality of Life Outcome Measures in Adult and Pediatric Immune Thrombocytopenia: An Appraisal from a Critical Review of the Literature

Introduction: Despite publication of standardized platelet count response definitions by the immune thrombocytopenia (ITP) International Working Group (IWG) in 2009, there remains considerable variability in the definition of platelet count outcomes across ITP studies. Moreover, there is no widely-accepted bleeding scale, health-related quality of life (HRQoL) inventories, or definition of remission for use in ITP patients, all critical outcome measures not addressed in the IWG Report. This heterogeneity makes comparison of response rates and outcomes between studies challenging. Therefore, to better understand current practices and inform future standardization efforts, we performed a systematic review of ITP studies to characterize how these outcomes have been measured in the decade following publication of the IWG Report. Methods: We performed a systematic review of PubMed/MEDLINE-indexed manuscripts published from January 1, 2010 through December 31, 2019 that described a platelet count, bleeding, and/or HRQoL measure in reflection of treatment response in adult and pediatric ITP. Following initial search, two authors (H.A. and R.G.) screened each abstract for inclusion, then read each included full text manuscript to collect outcome measures. Interventional studies with ≥10 patients and observational studies with ≥50 patients were included; manuscripts without abstracts and non-English language manuscripts were excluded. Results: Studies. The PubMed/MEDLINE search revealed 1562 manuscripts; following abstract screening and manuscript review, 168 manuscripts met inclusion criteria for the study. Of the 168 studies, 110 studies evaluated adults, 41 evaluated children, and 17 evaluated both adults and children; 99 were prospective (including 32 randomized trials) and 69 were retrospective observational studies. Platelet Outcomes. 141 studies (including 28 randomized trials, 53 non-randomized prospective studies and 60 retrospective observational studies) reported platelet response outcomes and 11 reported platelet count remission definitions. Of the 141 reporting response outcomes, 61 (43%) used IWG definitions and 80 (57%) did not. Of these 80 studies, there were a total of 21 distinct platelet count outcome definition schemes (Figure 1). The majority of randomized trials (22/28, 79%) and other prospective studies (37/53, 70%) did not use IWG definitions; instead, a plurality of these studies used a Plt ≥50 × 109/L to define a treatment response, without definitions for complete, partial, or minor response. Most retrospective observational studies (39/60, 65%), however, used IWG definitions. Of the 11 studies reporting remission definitions, a platelet count of ≥100 × 109/L with or without treatment over a time period of ≥6 months was the most commonly used definition of remission, although a minority of studies used thresholds of ≥50 × 109/L or ≥150 × 109/L. Bleeding Outcomes. Bleeding outcomes were reported in a systematic fashion in only a minority of studies (67/168, 36%), which used a total of 21 distinct bleeding outcome reporting schemes. A plurality of adult studies used the WHO Bleeding Scale and a plurality of pediatric studies used the Buchanan and Adix Score, Figure 2. HRQoL Outcomes. HRQoL outcomes were reported in a small minority of studies (15/168, 9%), which used a total of 8 different HRQoL instruments (6 adult instruments and 2 pediatric instruments), Table. Conclusions: Despite prior attempts to standardize evaluation of platelet response to treatment in ITP, there remains wide variability in the definition of both treatment response and remission. In particular, most prospective and randomized studies published following release of the 2009 IWG report have used study-specific platelet count response thresholds, whereas retrospective observational studies were much more likely to adopt the IWG-recommended platelet response definitions. Despite the fact that ITP is a bleeding disorder and its impact on HRQoL has been well-documented, most ITP studies published in the past decade did not evaluate bleeding in any systematic way and fewer still evaluated the impact of treatment on HRQoL. Further standardization of platelet count, bleeding, and HRQoL outcomes in both pediatric and adult ITP is greatly needed, especially for future randomized trials, to allow for more meaningful comparison of response rates and efficacy between studies. Disclosures Al-Samkari: Agios: Consultancy, Research Funding; Argenx: Consultancy; Amgen: Research Funding; Dova: Consultancy, Research Funding; Rigel: Consultancy. Arnold:Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Principia: Consultancy. Grace:Novartis: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Agios: Research Funding.

Emerging Role of Adoptive T Cell Therapy for EBV Induced Nasopharyngeal Carcinoma (NPC) - a Systematic Review

Introduction: Nasopharyngeal carcinoma (NPC) is defined as the cancer of squamous epithelium lining nasopharynx. The single most common culprit of undifferentiated NPC is the Epstein-Barr virus (EBV). Recurrent local-regional or metastatic NPC cannot be treated with repeated chemo-radiotherapy because of poor overall survival and profound effect of these therapies on quality of life. One safer approach is immunotherapy with autologous EBV specific cytotoxic T lymphocytes (EBV-CTLS) targeted to the EBV antigens EBNA1, latent membrane protein LMP1, and LMP2 expressed by most NPC tumors. This study aims to review the efficacy and toxicity of adoptive immunotherapy with EBV-CTLS in patients with EBV induced NPC. Methods: A systematic search of PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in EBV induced NPC patients from inception to May 28, 2020. Out of 604 studies, 07 phase I and II clinical trials were selected for the systematic review. Results: A total of 134 patients (pts) were evaluated out of 157 pts. 56 had a locoregional disease, 63 had distant metastasis, 15 had both locoregional disease as well as distant metastasis, 8 were in remission and disease status was unknown in 5 pts. Li et al. (2015) in their phase I clinical trial on 20 NPC pts with ECOG performance status of &amp;lt;3 after chemoradiotherapy (CCRT) showed overall response rate (ORR) of 95% with complete response (CR) in 19 patients. One patient showed progressive disease (PD). Median progression-free survival (PFS) was observed to be 16 months. Eighteen (90%) pts showed disease-free survival of greater than 12 months after adoptive cell therapy (ACT). Grade (G) ≥3 adverse events (AEs) included leukopenia (5%) and neutropenia (5%). Phase I/II dose-escalation trial by Louis et al. (2010) on 23 pts showed ORR of 48.7% (20% CR, 13.3% undetermined complete response [Cru], 15.4% PR) among pts with active disease. Eight pts remained in remission while 10 had metastatic disease at the time of infusion. PD was 21.7%, Stable Disease (SD) 13%, and 3 pts (13%) had recurrent disease. The median time to progression was 1059 days with PFS of 65% and 52% at 1 and 2 years respectively while the (Overall Survival) OS was 87% and 70% at 1 year and 2 years respectively. There was a higher risk of disease progression (HR: 3.91, P= 0.015) and decreased overall survival (HR: 5.55, P=0.022) in metastatic disease as compared to locoregional disease. Huang J. et al (2017) conducted a phase I/ II trial in 21 pts with a mean waiting period of 71 days after chemotherapy. Two CTL infusions were given 2 weeks apart. Two pts (9.5%) maintained SD but all other pts (85%) showed PD after 8 weeks follow- up. One patient achieved CR (4.8%). Hence, ORR was 4.8% while median PFS and OS were of 2.2 months and 16.7 months respectively. In a phase II trial, 24 patients completed 6 EBV- CTL therapy cycles after receiving chemotherapy cycles of Gemcitabine and Carboplatin. ORR was observed to be 42.9% (CR 5.7%, PR 31.7%). SD was 20% while PD was 31.4%. Median OS was 29.9 months (95% CI 20.8-39.3) with 1, 2, and 3-year rates being 77.1%, 62.9%, and 37.1 % respectively. Median PFS was 7.6 months (95% CI 7.4-8.4). All G≥3 AE occurred during chemotherapy. (Chia et al, 2014) Secondino et al. (2011) conducted a phase I/II study in 11 NPC patients who also received chemotherapy consisting of cyclophosphamide and fludarabine. After a mean follow-up of 4 weeks, ORR was 27% (PR 18%, Minor Response [MR] 9%). PD was reported to be 45% and SD 27%. Median PFS at 6 months was 54% (6/11 pts). Only G≥3 AE reported was neutropenia (36%). Phase I/II trial by Comoli et al. (2005) evaluated 10 EBV-related stage IV NPC in progression after CCRT. After receiving two to twenty-three EBV-specific CTLs infusions, 2 patients showed PR (20%), 40% of pts maintained SD and all others showed evidence of PD (40%) at 1-2 months follow up. Median PFS was 6.5 months. Smith et al (2012) in their phase I trial on 14 patients with locoregional and metastatic NPC reported SD 71.4% and PD 28.6% of patients at a median follow up of 1 month. Median OS and PFS were 17.4 months and 4.5 months respectively. No G≥3 AEs were reported. Conclusion : Adoptive Immunotherapy with EBV-CTLS has shown impressive efficacy with improvement in median PFS and OS and a favorable safety profile. Key Words: Adoptive cell therapy, Cytotoxic T lymphocytes, nasopharyngeal carcinoma, Phase I/II clinical trials, Epstein-Barr virus. Disclosures Anwer: Celgene: Research Funding; AbbVie Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Millennium Pharmaceuticals: Research Funding.

Update of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

Update of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma

Background: PT-112 is a novel pyrophosphate-platinum conjugate with a multi-modal mechanism of action that induces immunogenic cell death and is not susceptible to DNA-repair drug resistance pathways. In phase I studies in solid tumors, PT-112 demonstrated safety and efficacy as single agent and in combination with PD-L1 checkpoint inhibitor avelumab, crossing a range of dose levels (DL) and tumor types, including in heavily pre-treated patients (pts) non-responsive to immunotherapy and refractory to other modalities. Non-clinical, in vivo research using advanced imaging technology demonstrated that PT-112 reached the highest concentrations in bone tissue (osteotropism). Moreover, PT-112 was highly active in the orthotopic, immune-competent Vk*MYC mouse model of multiple myeloma, including drug-resistant transplant variants. Thus, a rationale for PT-112 as an investigational candidate in multiple myeloma was established. Here, we present results of a phase I dose escalation study of PT-112 in pts with relapsed or refractory multiple myeloma (RRMM). Methods: A 3+3 design was used to determine the recommended phase 2 dose (RP2D) for PT-112 (28-day cycle IV days 1, 8, 15) in pts with evaluable RRMM who had exhausted available therapies (Tx), with adequate bone marrow (abs neutrophil count ≥ 1.0 x 109/L; platelet count ≥ 50 x 109/L; and hemoglobin ≥ 8.0 g/dL) and renal function (calculated creatinine clearance ≥ 30 mL/min), and ECOG PS 0-2. Results: A total of 24 pts were treated with PT-112 monotherapy across 6 DLs: 125 mg/m2, 3 pts; 180 mg/m2, 4 pts; 250 mg/m2, 5 pts; 300 mg/m2, 4 pts; 360 mg/m2, 4 pts; 420 mg/m2, 4 pts. Patients had a median age of 72 years and were heavily pre-treated, with a median of 8 prior lines of systemic Tx: 22 (92%) pts were triple-class refractory with 19 (79%) pts penta-refractory, and 3 (13%) pts refractory to BCMA-based therapies. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (58%), neutropenia (42%), diarrhea (38%), and nausea (38%). 38% of pts had ≥1 grade 3 non-hematologic TRAE, with no grade 4 non-hematologic TRAEs reported. One dose-limiting toxicity (DLT) of grade 4 neutropenia occurred at the 420 mg/m2 DL. In addition, due to frequent dose reductions and modifications at this DL, the safety committee declared 360 mg/m2 as the RP2D. Among 8 patients who received a starting dose at / above the RP2D, 2 had stable disease and 4 experienced responses to PT-112 Tx. These included a confirmed partial response (PR) achieved in a 79-year-old pt with kappa free light chain (FLC) disease treated at 360 mg/m2, whose previous Tx included combination regimens with most approved therapies (penta-refractory) and stem cell transplantation. FLC levels declined by 65% from baseline on PT-112 therapy and the pt remained progression free for 4.5 months. A 72-year-old pt treated at the 420 mg/m2 DL, reduced to 250mg/m2 every other week over the course of Tx due to grade 3-4 cytopenias, had a confirmed minor response. Prior Tx with multiple lines given over 9 years included stem cell transplantation, most approved therapies (penta-refractory), prior investigational antibody and CAR-T cell Tx (primary refractory to CAR-T). The patient was M-protein negative, kappa FLC levels declined by 32% following the first dose reduction, and the pt remained progression free and clinically stable without complaints for 4.5 months. Additionally, two transient, unconfirmed PRs occurred in patients at the 420mg/m2 DL: in a triple-class-refractory 82-year-old previously treated with 5 lines of Tx, with 70% reduction in kappa FLC during cycle 1; and in a penta-refractory 85-year-old, who experienced disappearance of M-protein during cycle 1 and Gr 4 neutropenia (DLT). Conclusions: PT-112 monotherapy was feasible and well tolerated in this heavily pre-treated, multi-refractory multiple myeloma population, and the Phase I clinical data appear to validate the developmental hypothesis, built upon activity in the Vk*MYC mouse model of multiple myeloma. Responses were confirmed in 25% of patients treated at / above the RP2D using single-agent PT-112, an encouraging result in a dose escalation trial conducted in heavily refractory patients. Activity of PT-112 in RRMM patients may be explained by its osteotropism and its unique mechanism of action compared to other drug classes used to treat this disease. Further clinical study of PT-112 in RRMM is warranted in a phase 2 clinical trial. Disclosures Ailawadhi: Celgene: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Phosplatin: Research Funding; Takeda: Honoraria. Vogl:Janssen: Consultancy; Celgene: Consultancy; MorphoSys: Consultancy; Takeda: Consultancy; Active Biotech: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm: Consultancy. Ames:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Yim:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Price:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Jimeno:Phosplatin Therapeutics: Current Employment, Current equity holder in private company.

Behavioral and corticosterone responses to carbon dioxide exposure in reptiles

The use of carbon dioxide (CO2) exposure as a means of animal euthanasia has received considerable attention in mammals and birds but remains virtually untested in reptiles. We measured the behavioral responses of four squamate reptile species (Homalopsis buccata, Malayopython reticulatus, Python bivitattus, and Varanus salvator) to exposure to 99.5% CO2 for durations of 15, 30, or 90 minutes. We also examined alterations in plasma corticosterone levels of M. reticulatus and V. salvator before and after 15 minutes of CO2 exposure relative to control individuals. The four reptile taxa showed consistent behavioral responses to CO2 exposure characterized by gaping and minor movements. The time taken to lose responsiveness to stimuli and cessation of movements varied between 240–4260 seconds (4–71 minutes), with considerable intra- and inter-specific variation. Duration of CO2 exposure influenced the likelihood of recovery, which also varied among species (e.g., from 0–100% recovery after 30-min exposure). Plasma corticosterone concentrations increased after CO2 exposure in both V. salvator (18%) and M. reticulatus (14%), but only significantly in the former species. Based on our results, CO2 appears to be a mild stressor for reptiles, but the relatively minor responses to CO2 suggest it may not cause considerable distress or pain. However, our results are preliminary, and further testing is required to understand optimal CO2 delivery mechanisms and interspecific responses to CO2 exposure before endorsing this method for reptile euthanasia.

Złożona translokacja wariantowa t(9;22;6;17;1) w przebiegu leczenia przypadku przewlekłej białaczki szpikowej.

The presence of the Philadelphia chromosome (Ph) in chronic myelogenous leukaemia (CML) is a specific cytogenetic change resulting from a reciprocal translocation between chromosomes 9 and 22. In 5–10% of newly diagnosed cases there are variant translocations (vPh) involving more chromosomes. This paper presents the case of a CML patient with a complex variant translocation involving chromosomes 1, 6, 9, 17 and 22. A molecular analysis did not reveal any muta­tion in the kinase domain of BCR-ABL1 gene or the mutation of TP53 gene. After the first-line treatment with imatinib no cytogenetic or molecular response was obtained. The change of treatment to dasatinib resulted in a minimal cytogenetic response (minCyR) followed by a minor cytogenetic response (mCyR). The application of nilotinib in the third-line treatment resulted in a complete molecular response (CMolR) and therapy success. The likely reason for the failure of the first- and second-line treatment was the loss of a fragment of the 17p13 region as a result of a variant translocation. The change can be a functional equivalent of the loss of one copy of TP53 . The analysis of presented case confirms the significance of the detailed evaluation of the composition of vPh complex variant translocations as well as importance of combination cytogenetic and molecular diagnostics in CML treatment monitoring. It makes possible to adequate diagnose higher-risk patients and apply effective treatment strategies if an aberration is identified.

Quantitative Detection of Minor Defects in Metal Materials Based on Variation Coefficient of CT Image

In order to perform precise quantitative detection of internal minor defects in additive manufacturing of metal materials based on industrial CT, a quantitative detection method for minor defects in metal materials based on gray-scale variation coefficient of minor defects in CT image is presented. Firstly, based on the analysis of gray-scale features of minor defect regions in CT image, a minor defect image response model is constructed by combining the point spread function (PSF) and noise approximate Gaussian distribution, and the correspondence between the minor defects of different sizes and the local variation coefficient of CT image is derived, and a quantitative detection method based on the coefficient of variation of minor defect region in CT image is established for minor defects of AM metal materials. Industrial CT experiments were then conducted by processing a series of minor defect reference test blocks of different sizes with TC4 titanium. Experiment results show that the defect size and the coefficient of variation reflect a good linear relationship of monotonous increase, with correlation more than 0.996, and the quantitative results of minor defects based on the coefficient of variation method accord well with the measurement results of the microscope, with relative error controlled within 4%. Obviously, this method characterized by simple measurement process and high practical value has improved the quantitative precision of minor defects in industrial CT.