Current Response Criteria Research Articles

Experimental study on non-load bearing multi-span sandwich wall panels for blast mitigation

Sandwich wall panels are known for their ability to provide resistance over a wide deformation range, rendering them suitable for blast resistance applications. These panels consist of layers of concrete with an insulating core, offering a structural solution with enhanced performance. Quasi-static testing was conducted on multi-span sandwich wall panels with intermediate connections to evaluate their behavior under controlled loading conditions. A total of twelve two-span details were examined and selected to match the standard designs employed in the Tilt-Up Construction (TCA) and Prestressed/Precast Concrete Industry (PCI). Among these details, three belonged to the TCA type with two duplicates, while the remaining two were representative of PCI designs with three duplicates. The results obtained from the quasi-static testing indicate that insulated sandwich wall panels possess sufficient deformation capability to meet the current blast response criteria. To assess the findings of the static experiments to the prevailing response limits, the outcomes were distilled into a multi-linear static resistance analysis. The findings support the use of insulated precast concrete (PC) sandwich wall panels, highlighting their suitability for blast-resistant designs within the constraints of current blast design limitations. Specimens with Halfen connectors showed 32 % higher energy absorption and a 58 % advantage over Stud connectors, making them superior for robust blast resistance applications.

Quantitative MYD88 L265P Analysis Represents a Powerful Tool for Assessing Disease Response and Evaluating Clinical Trial Performance in Waldenstrom's Macroglobulinemia

Serum IgM measurements represent the current standard for assessing changes in disease burden in Waldenström's Macroglobulinemia (WM). Many agents used to treat WM can significantly affect serum IgM levels without impacting the underlying burden of clonal lymphoplasmacytic cells thereby producing discordant findings. Such agents can raise (CD20-directed monoclonal antibodies, IMiDs), or lower (BTK-, proteasome-, MTOR- inhibitors) serum IgM levels, and impact categorical response assessment. Somatic mutations in MYD88 are found in 95-97% of WM patients, and support tumor growth through activation of multiple pro-survival pathways that include HCK/BTK, SYK and ERK. Nearly all MYD88 mutations in WM are of the L265P variant. Previous studies by us and others have shown that serial quantitative measurements of both bone marrow (BM) and peripheral blood (PB) MYD88 L265P (c.978 T>C) by allele-specific PCR can be used to assess changes in underlying BM disease burden (Blood 121:2051-2058; Leukemia 28:1698-1704). However, the utility of using quantitative allele-specific MYD88 L265P (qMYD88 L265P) analysis has not been studied in prospective clinical trials. As such, we performed a comprehensive study of qMYD88 L265P response assessment utilizing BM and PB CD19-selected tissue across 5 prospective clinical studies in WM: Ixazomib, Dexamethasone and Rituximab (IDR; NCT02400437) Ibrutinib monotherapy (IBR; NCT02604511); Venetoclax monotherapy (VEN; NCT02677324); Ibrutinib plus Ulocuplomab (IBR/ULO; NCT03225716); and Ibrutinib plus Venetoclax (IBR/VEN; NCT04273139). Changes in MYD88 L265P ΔCt were assessed as reported above with ΔCt = Mutant Ct - Wild-type Ct, and higher ΔCt values indicating a lower mutant allele burden, with each ΔCt unit reduction representing a 50% decrease in mutant MYD88 L265P burden. Changes in MYD88 L265P ΔCt were compared to changes in underlying BM disease burden and categorical response assessment using the current (IWWM-11) response criteria (Semin Hematol. 60:97-106). Across all five trials, BM (r=0.52; p<0.001) and PB (r=0.43; p<0.001) MYD88 L265P ΔCt changes from baseline were highly correlated at best response with corresponding changes in underlying BM disease burden determined by repeat BM biopsies. As shown in Fig. 1, comparing changes from baseline in BM MYD88 L265P ΔCt assessments across studies showed marked differences, with greatest reductions observed in patients treated with IBR/VEN, IDR, and VEN alone, than for those treated with IBR alone or IBR/ULO. Similar findings were also observed for corresponding PB MYD88 L265P ΔCt assessments from baseline, with changes in PB MYD88 L265P ΔCt strongly correlating with those of BM MYD88 L265P ΔCt findings across all 5 clinical trials (r=0.67; p<0.001), thereby signifying the ability to use PB MYD88 L265P ΔCt assessments to evaluate treatment responses. We next compared findings from BM and PB MYD88 L265P ΔCt to changes from baseline in serum IgM levels across all 5 trials. At best response, major categorical responses denoted by >50% reduction in serum IgM using IWWM-11 criteria showed commensurate decreases in BM and PB MYD88 L265P ΔCt from baseline in patients receiving IBR/VEN, IDR and VEN alone ( Fig. 2). In contrast, minimal changes in BM and PB MYD88 L265P ΔCt from baseline were observed at best response for most major responders on IBR or IBR/ULO, including individuals who achieved very good partial responses denoted by >90% decrease in IgM by IWWM-11 criteria. In this first prospective evaluation of BM and PB qMYD88 L265P response assessment, we show that both BM and PB L265P qMYD88 analysis can provide more accurate assessment of treatment related changes in disease burden over the current standard of IgM response assessment alone, and can be used to more robustly evaluate clinical trial performance byidentifying treatments or regimens that produce more meaningful tumor reductions in WM patients.

MRD‐NEGATIVITY AFTER FRONTLINE DLBCL THERAPY: POOLED ANALYSIS OF 6 CLINICAL TRIALS

MRD‐NEGATIVITY AFTER FRONTLINE DLBCL THERAPY: POOLED ANALYSIS OF 6 CLINICAL TRIALS

Roux-en-Y Gastric Bypass in Patients with Super Obesity: Primary Response Criteria and Their Relationship with Comorbidities Remission.

The prevalence of super obesity has increased considerably in recent years, representing up to the 0.5% of the population. Even though bariatric surgery induces significant weight loss in these patients, it has been reported that up to 50% of the patients with super obesity will fail according to the current primary response criteria. To evaluate and compare different primary response criteria and their impact regarding comorbidities remission. A total of 104 patients with super obesity who underwent Roux-en-Y gastric bypass (RYGB) were identified in our institution from March 2004 to February 2019. An evaluation of the primary response at a 2-year follow-up was made using different criteria. A multivariate analysis was made to evaluate related variables to comorbidities remission. Two years later, the rate of patients who achieved an EWL > 50%, %EWL > 70%, and BMI < 35kg/m2 were 84.5%, 52.1%, and 62%, respectively. Regarding the comorbidities, 85%, 84.8%, and 81.1% of the patients improved or remitted T2D, HBP, and hyperlipidemia, respectively. An EWL > 50% 2years later was related to complete remission of hyperlipidemia (p = 0.047), whereas weight regain above 10% is a risk factor for failure of complete remission of HBP in 3years. More than 75% of patients with super obesity yield an EWL > 50% 2years later. In terms of hyperlipidemia, it is desirable to achieve an EWL of at least 50%. Whereas for T2D and HBP, a minimum of 25% TWL yields 72% and 60.5% of complete remission.

Graded Renal Response Criteria for Light Chain (AL) Amyloidosis

Graded Renal Response Criteria for Light Chain (AL) Amyloidosis

Amyloidosis Composite Response Score Incorporating the Depth of Organ Response

Background:Systemic light chain (AL) amyloidosis is a plasma cell disorder characterized by multisystem deposition of misfolded immunoglobulin light chains produced by clonal plasma cells. Hematologic and organ responses with treatment have been shown to correlate with survival as early as 3 months from initiation of first-line treatment. Our group recently developed and validated a model integrating organ and hematologic responses for assessment of treatment outcomes at 6 months. Although current organ response criteria do not consider the depth of organ response, this has been shown to have prognostic utility in newly diagnosed patients. So, we designed this study to evaluate a composite hematologic and organ scoring system that also considers the depth of organ response at 1 to 6 months from initiation of first-line treatment.Methods:We included patients with AL amyloidosis who had at least one major organ involvement (cardiac, renal and/or liver involvement) and who had not started a second line treatment by 6 months from the time of initiating first-line treatment. For each patient, we calculated an organ response score and a hematologic response score at 1, 2, 3, 4, 5, and 6 months from initiation of first-line treatment. A score was assigned for each depth of hematologic response as follows: complete response=0, very good partial response=1, partial response=2, and no response/progressive disease=3). To calculate organ response, a score was assigned to each organ based on the depth of organ response (Muchtar et al. 2018): non-evaluable=0, complete response=1, very good partial response=2, partial response=3, and no response=4. The final organ response score was obtained by calculating the average of the individual involved organ scores. We then calculated the composite hematologic and organ response (HOR) score by adding the organ and hematologic responses at each interval and compared overall survival (OS) between patients with HOR score ≤ 5 (group 1) and those with score > 5 (group 2).Results:The cohort included 730 patients diagnosed with AL amyloidosis between February 10 th, 2006 and July 9 th, 2019. Median age was 63 (IQR: 56-69), and 65% were male. The involved light chain was Lambda in 75% of cases. Cardiac, renal, and liver involvement were found in 81%, 61%, and 17% of patients, respectively. Among all patients, 28% underwent autologous stem cell transplantation during their disease course. The median follow up in the entire cohort was 7.0 (95%CI: 6.4-8.0) years and OS was 3.6 (95%CI: 2.6-4.4) years. At 1 to 4 months, we observed a statistically significant difference in OS between patients with HOR score ≤5 vs. >5. However, there was no difference in OS between the 2 groups at 5 and 6 months. These results are presented in Table 1.Conclusion:A composite hematologic and organ response score that takes into consideration the depth of organ response can discriminate 2 groups of patients with distinct survival outcomes as early as 1 month from treatment initiation and maintains its predictive ability for up to 4 months. The lack of predictive ability beyond 4 months in this study may be due to limited sample size especially in group 2 as more patients achieve deeper responses with time. This approach can provide the basis for early changes in treatment but needs validation in future studies. [Display omitted] DisclosuresDispenzieri: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; Glaxo SmithKline: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; BeiGene: Consultancy; Regeneron Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dingli: GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Alexion: Consultancy. Kumar: Oncopeptides: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Peripheral Blood Complete Remission Provides Added Value to the Classical Definition of Morphologic Complete Remission - a Prospective Cohort Study of 1441 Patients with MDS, CMML and AML Treated within the Austrian Azacitidine Registry

Peripheral Blood Complete Remission Provides Added Value to the Classical Definition of Morphologic Complete Remission - a Prospective Cohort Study of 1441 Patients with MDS, CMML and AML Treated within the Austrian Azacitidine Registry

Meaningful response criteria for myelodysplastic syndromes

Standardizing response criteria for myelodysplastic syndromes (MDS), a clinically and biologically heterogeneous group of disorders, has been historically challenging. The International Working Group (IWG) response criteria, first proposed in 2000 and modified in 2006 and 2018, represent the best effort by a group of international experts to define a set of clinically meaningful end-points in MDS. These criteria have been adopted in many MDS clinical trials, allowing for comparisons of response across trials. However, clinical experience has also revealed some limitations of these criteria, and most of the end-points proposed by the IWG require further validation. In this review, we present a critical analysis of the current MDS response criteria from both a practical standpoint and based on currently available clinical trial data. Potential areas for improvement in the criteria are highlighted, which may be considered in future iterations of the response criteria.

OAB-036: Graded renal response criteria and revised renal progression criteria for light chain (AL) amyloidosis

<h3>Background</h3> Renal light chain (AL) amyloidosis manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as >30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. <h3>Methods</h3> AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response to therapy and with renal involvement were included. Four renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression: renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, >60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. <h3>Results</h3> Seven hundred and thirty-seven patients were included. The median age was 63. Renal stage I, II and III were assigned to 34%, 52% and 14% of patients, respectively. Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71%, at 6-month, 12-month and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27%, 34%, 15% and 24% of patients, respectively. A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P<0.001). Prediction of risk for RRT based on renal response depth improved at 12- and 24-months and at best renal response. Overall survival discrimination based on renal response depth was noted as early as 12 months from therapy initiation and improved with time. eGFR progression (≥25% decrease in eGFR) and proteinuria progression (at least 50% increase to ≥3g/day) were predictive for time to RRT. <h3>Conclusions</h3> We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decision on therapy changes or augmentation based on response depth as early as 6-month before irreversible renal failure has developed.

Minimal Residual Disease in Multiple Myeloma: Something Old, Something New.

Simple SummaryCurrently, response rates in multiple myeloma (MM) have increased dramatically, with more than 50% otablef those who respond satisfying complete response criteria. Achieving frequent deep responses has necessarily led to test conceptual advantages for assessing and treating MM patients with only minimal residual disease (MRD). In this review, we present and discuss the clinical relevance, methodology, and challenges for measuring MRD in MM.The game-changing outcome effect, due to the generalized use of novel agents in MM, has cre-ated a paradigm shift. Achieving frequent deep responses has placed MM among those neoplasms where the rationale for assessing MRD is fulfilled. However, its implementation in MM has raised specific questions: how might we weight standard measures against deep MRD in the emerging CAR-T setting? Which high sensitivity method to choose? Are current response criteria still useful? In this work, we address lessons learned from the use of MRD in other neoplasms, the steps followed for the harmonization of current methods for comprehensively measuring MRD, and the challenges that new therapies and concepts pose in the MM clinical field.

Direct Assessment of IgA and IgG Paraprotein By Hevylite Assay and Correlation to IMWG Response and Progression-Free Survival in Newly Diagnosed, Transplant-Eligible Multiple Myeloma Patients in the Prospective Phase III GMMG-MM5 Trial

Direct Assessment of IgA and IgG Paraprotein By Hevylite Assay and Correlation to IMWG Response and Progression-Free Survival in Newly Diagnosed, Transplant-Eligible Multiple Myeloma Patients in the Prospective Phase III GMMG-MM5 Trial

Posttreatment dFLC less than 10 mg/L predicts superior organ response and longer time to next treatment in newly diagnosed light-chain amyloidosis patients treated with bortezomib

Recently, a difference between involved and uninvolved free light chains (dFLC) less than 10 mg/L after treatment (stringent dFLC response) was reported to be associated with superior survival in light-chain (AL) amyloidosis. We conducted a retrospective study of AL amyloidosis patients treated with bortezomib to investigate the predictive value of a stringent dFLC response. Two hundred and thirty-five patients were included. The cardiac and renal responses were much higher in patients achieving a stringent dFLC response (86.5% versus 42.7% and 75.9% versus 38.2%, p < .001). Patients with a stringent dFLC response had significantly longer overall survival and time to next treatment (TNT). Among the very good partial response (VGPR) patients, the TNT of stringent dFLC responders was superior to those of the remaining VGPR patients (p = .045) and comparable to those of complete response patients. In conclusion, a stringent dFLC response might be added to current response criteria for AL amyloidosis.

Dissociated Response in Metastatic Cancer: An Atypical Pattern Brought Into the Spotlight With Immunotherapy.

When evaluating metastatic tumor response to systemic therapies, dissociated response is defined as the coexistence of responding and non-responding lesions within the same patient. Although commonly observed on interim whole-body imaging, the current response criteria in solid cancer do not consider this evolutive pattern, which is, by default, assimilated to progression. With targeted therapies and chemotherapies, dissociated response is observed with different frequencies, depending on the primary cancer type, treatment, and imaging modality. Because FDG PET/CT can easily assess response on a lesion-by-lesion basis, thus quickly revealing response heterogeneity, a PET/CT dissociated response has been described in up to 48% of women treated for a metastatic breast cancer. Although some studies have underlined a specific prognostic of dissociated response, it has always ended up being described as an unfavorable prognostic pattern and therefore assimilated to the “Progressive Disease” category of RECIST/PERCIST. This dichotomous imaging report (response vs. progression) provides a simple information for clinical decision-support, which probably explains the relatively low consideration for the dissociated response pattern to chemotherapies and targeted therapies until now. With immune checkpoint inhibitors, this paradigm is quickly changing. Dissociated response is observed in around 10% of advanced lung cancer patients and appears to be associated to treatment efficiency. Indeed, for this subset of patients, a clinical benefit of immunotherapy and favorable prognosis are usually observed. This specific pattern should therefore be considered in the future immunotherapy-adapted criteria for response evaluation using CT and PET/CT, and specific clinical managements should be evaluated for this response pattern.

Minimal Residual Disease in Multiple Myeloma: Current Landscape and Future Applications With Immunotherapeutic Approaches.

The basic principle that deeper therapeutic responses lead to better clinical outcomes in cancer has emerged technologies capable of detecting rare residual tumor cells. The need for ultra-sensitive approaches for minimal residual disease (MRD) detection is particularly evident in Multiple Myeloma (MM), where patients will ultimately relapse despite the achievement of complete remission, which is commonplace due to remarkable therapeutic advances. Consequently, current response criteria on MM have been amended based on MRD status and MRD negativity is now considered the most dominant prognostic factor and the most valuable indicator for a subsequent relapse. However, there are particular limitations and several aspects for MRD assessment that remain open. This review summarizes current data on MRD in the clinical management of MM, highlights open issues and discusses the challenges and the endless opportunities arising for both patients and clinicians. Furthermore, it focuses on the current status of MRD in clinical trials, its dynamics in addressing debatable aspects in the clinical handling and its potential role as the prevailing factor for future MRD-driven tailored therapies.

Randomized phase II trial of MIBG versus MIBG/vincristine/irinotecan versus MIBG/vorinostat for relapsed/refractory neuroblastoma: A report from the New Approaches to Neuroblastoma Therapy Consortium.

10500 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. It is not clear if putative radiation sensitizers improve upon this activity. The primary aim of this trial was to identify the MIBG treatment regimen with highest response rate among: MIBG monotherapy (Arm A); MIBG/Vincristine/Irinotecan (Arm B); MIBG/Vorinostat (Arm C). The secondary aim was to compare toxicity across arms. Methods: We conducted a multicenter, randomized phase II trial. Patients 1-30 years with relapsed/refractory high-risk neuroblastoma were eligible with at least one MIBG-avid site and adequate autologous stem cells (ASCs). All patients received MIBG 18 mCi/kg on Day 1 and ASC on day 15. Patients on Arm A received only MIBG; patients on Arm B also received vincristine (2 mg/m2) IV on Day 0 and irinotecan (50 mg/m2) IV daily on Days 0-4; patients on Arm C also received vorinostat (180 mg/m2) orally once daily on days -1 to 12. The primary endpoint was response after one course according to NANT response criteria. The trial was designed as a pick-the-winner study with a maximum of 105 eligible and evaluable patients to ensure an 80% chance that the arm with highest response rate is selected, if that response rate is at least 15% higher than the other arms. Results: 114 patients enrolled. Three patients were ineligible and 6 eligible patients never received MIBG, leaving 105 eligible and evaluable patients (36 Arm A; 35 Arm B; and 34 Arm C; 55 boys; median age 6.5 years). 9 patients had received prior MIBG monotherapy, 65 prior irinotecan, and 7 prior vorinostat. After one course, the response rates (Partial Response or better) on Arms A, B, and C were 17% (95% CI 7-33%), 14% (5-31%), and 32% (18-51%). An additional 4, 4, and 7 patients met NANT Minor Response criteria [partial response in one disease category (e.g., bone marrow) and stable disease in other categories] on Arms A, B, and C, respectively. On Arms A, B, and C, rates of any grade 3+ non-hematologic toxicity were 19%, 49% and 32%; rates of grade 3+ diarrhea were 0%, 11%, 0%; and rates of grade 3+ febrile neutropenia were 6%, 11%, and 0%. Conclusions: The combination of vorinostat/MIBG had the highest response rate, with manageable toxicity. Vincristine and irinotecan do not improve the response rate to MIBG and are associated with increased toxicity. These data provide response rates for MIBG monotherapy in a contemporary patient population assessed with current response criteria. Clinical trial information: NCT02035137.

Expanding on Current Definitions of Hematologic Improvement in MDS, CMML and AML: Landmark Analyses of 1301 Patients Treated with Azacitidine in the Austrian Registry of Hypomethylating Agents By the AGMT-Study Group

Expanding on Current Definitions of Hematologic Improvement in MDS, CMML and AML: Landmark Analyses of 1301 Patients Treated with Azacitidine in the Austrian Registry of Hypomethylating Agents By the AGMT-Study Group

Abstract 3247: Dynamic clonality of T cell receptor differentiate atypical progression in NSCLC patients treated with PD-1/PD-L1inhibitors

Abstract Background:The advent of immune checkpoint inhibitors (ICI) has radically changed the paradigm of care for patients with non-small cell lung cancer (NSCLC). However, response patterns of tumors treated with immunotherapies may differ compared with conventional chemotherapeutic agents or targeted therapies, and accurate assessment of the response can be radiologically challenging. Most of the current immune-related response criteria are designed to identify pseudoprogression but not hyperprogressive disease (HPD). The objective of the current analysis was to explore the biomarkers which can distinguish different patterns of responses of in ICI-treated NSCLC patients.Methods:Among patients with NSCLC treated with ICI at our Institute, at least 2 CT scans before ICI therapy (baseline and the most recent scan before baseline) and 1 CT scan during treatment were mandatory for radiological evaluation. The tumor growth rate (TGR) was calculated from the sum of the largest diameters of the target lesions as per RECIST version 1.1 to evaluate the percentage increase in tumor volume per month. HPD was defined as delta TGR exceeding 50%. Pseudoprogression was defined as initial progression, followed by complete response or partial response or stable disease. Flow cytometry was used to obtain CD3+CD8+ T cells from peripheral blood mononuclearcells. Immunosequencing of the CDR3 regions of TCRb chains was performed. TCR clonality is compared pre-therapy to initial evaluation. Results:A total of 51 patients were included in our study. By the time of first radiological assessment,11 cases were defined as Responders (21.6%), 16 patients with Stable Disease (31.4%), 24 cases defined as Progressors (47.1%).Six patients meet the criteria for HPD. During the following treatment, 3 of 24 progressors were confirmed to have pseudoprogression. The degree of TCR clonality change ranged from 2.17 to 0.64 times in all patients. Clinical response is significantly correlated with increased repertoire clonality of CD3+CD8+ T cells (P = 0.01). Among three kinds of disease progression, pseudoprogression showed an increase in TCR clonality than true progression patients (1.47 vs. 0.79, P=0.01). Interestingly, the decrease of TCR clonality is greater in patients developed typical PD than in HPD (-0.19 vs. -0.05, P=0.03). Our further analysis showed that Patients who demonstrated RECIST-PD with an increased clonality had a longer median PFS compared to patients with a declined clonality (8.9 versus 2.4 months, p = 0.01).Conclusion: The results demonstrate that the change in clonality of CD3+CD8+ T cell receptor can differentiate atypical patterns of progression in patients with NSCLC treated with ICI. Results of this TCR test performed at regular intervals during ICI treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response. Citation Format: Jiefei Han, Zhijie Wang, Yuqi Wang, Si Chen, Hua Bai, Jianchun Duan, Jie Wang. Dynamic clonality of T cell receptor differentiate atypical progression in NSCLC patients treated with PD-1/PD-L1inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3247.

Report from the SWOG Radiation Oncology Committee: Research Objectives Workshop 2017.

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR.

Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria.

Organ recovery following anti-plasma cell therapy is associated with improved outcome in patients with AL amyloidosis. Current organ response criteria do not consider the depth of response. Newly diagnosed AL amyloidosis patients who had involvement of at least one evaluable organ and documentation of organ response were included. Cardiac response was seen in 182 patients. Time to cardiac response was 9.4 months. Renal response was seen in 278 patients, at a median time to response of 6 months. Hepatic response was seen in 70 patients, with a median time to response of 6.1 months. In all organs, the deeper the organ response achieved, the longer the survival. This led to four organ response criteria: complete organ response (nadir NT-proBNP ≤400 pg/mL; nadir proteinuria ≤200 mg per 24 h; nadir alkaline phosphatase ≤×2 lower limit of normal); very good partial organ response (>60% reduction in parameter not meeting complete organ response definition); partial organ response (31-60% reduction in parameter); and non-responder (≤30% reduction in organ response parameter). Cardiac and renal progression were associated with baseline organ impairment and inversely associated with the depth of organ response. Grading the depth of organ response provides additional valuable prognostic information for newly diagnosed AL amyloidosis patients.

Immunophenotypic Evidence for Reactive Polyclonal Marrow Plasmacytosis in Multiple Myeloma Patients Receiving Long-Term Lenalidomide Therapy

Introduction: Maintenance therapy with lenalidomide (LEN) is considered standard of care in the US, supported by meta analysis showing that LEN maintenance is associated with significantly longer progression free survival (PFS) and overall survival (OS). In a previously reported study of MM patients (pts) treated with extended courses of LEN, we have described a polyclonal Ig and FLC elevation exceeding the upper limit of normal (up to 3-4 X the ULN) and associated with striking polyclonal bone marrow (BM) plasmacytosis (up to 20% of plasma cells (PCs)), occurring with a relatively high frequency (20% of pts) and associated with better outcome (Zamarin, Leukemia, 2013). Importantly, we cautioned about the risk of misinterpretation of this polyclonal Ig response and plasmacytosis. Since Immuno-histochemical staining (IHS) may often be an unreliable tool to distinguish between a reactive polyclonal plasmacytosis from monoclonal disease, especially when the percentage of PCs in the BM is relatively low (5 -15%), we aimed at confirming the polyclonal nature of this often unrecognized and paradoxical response to prolonged LEN exposure, and at validating the important role of BM assessment by flow cytometry (FACS) in this setting. Methods: Pts analyzed in this study were enrolled at MSKCC on three randomized, first line therapy, clinical trials (NCT01109004, NCT01208662, and NCT00807599). All pts were kept on LEN maintenance until POD, toxicity, or major event. BM aspirate and biopsy with IHS were performed as per standard of care. Eight-fluorochrome FACS method (minimum of 1 x 106 cells) was used for 2014 samples employing a surface marker cocktail (CD117 PC5.5, CD19 BV421, CD138 APC, CD56 PC7, CD45 APC-H7, CD38 BV510) and cytoplasmic Kappa FITC/Lambda PE staining. Ten-fluorochrome (minimum of 5 x 106 WBCs) method was used in 2015 and performed employing a surface marker cocktail (CD117 PC5.5, CD19 PC7, CD138 APC, CD56 APC-R700, CD45 APC-H7, CD81 Pacific Blue, CD38 BV510, CD27 BV605) and cytoplasmic Kappa FITC/Lambda PE staining. Results: Among 147 pts enrolled in the three trials, 55 achieved serologic CR after first line therapy. Of those, 46 had a BM biopsy with FACS analysis available. Among these 46 patients, bone marrow plasmacytosis as assessed by light microscopy of BM aspirate and biopsy ranged from 2% to 15% (32 pts had PCs ≤ 5%, 14 PCs > 5%). Among the 14 pts with > 5% PCs, 2 had PCs = 15%, 9 had PCs = 10%, and 3 between 6% and 9%. By FACS, 9 of 14 pts showed no clonal or phenotypically aberrant PCs. The percentage of aberrant PCs among all PCs in the other 5 pts remained low (≤7.3%). Among the 2 pts with PC = 15%, the percentage of aberrant PCs among all PCs was 0% and 7.3%. In pts with PC = 10%, the percentage of aberrant PCs among all PCs was 0% (6 pts), or ranged from 0.17% to 5.1% (3 pts). Figure 1 depicts representative pt cases with BM plasmacytosis estimated at 15% by light microscopy. PCs were gated based on CD38 and CD138 expression as well as forward and side scatter (not shown). Blue dots represent kappa LC expression; Red lambda LC. Proportion of aberrant PCs among total PCs in the sample is quantitated and shown using high sensitivity MRD detection with 10-color panel with 6-million event acquisitions. Panel A shows a pt with 15% PC in the BM with no residual disease confirming the polyclonal nature of the plasmacytosis. Panel B shows a pt with 15% PC exhibiting a low proportion of aberrant PCs (green) among a predominant background of normal polytypic PCs. In contrast, Panel C shows a pt with early relapsed disease with 15% PCs exhibiting a high proportion of aberrant PCs (99% of all PCs). Conclusions: These results confirm the common and striking polyclonal plasmacytosis (up to 15% PCs in this cohort) associated with prolonged LEN exposure, and the importance of FACS in the assessment of BM plasmacytosis in these MM pts. In the setting of current MM response criteria established by the IMWG and NCCN guidelines, mandating a BM plasmacytosis Disclosures Hassoun:Novartis: Consultancy; Binding Site: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Research Funding. Roshal:BD Biosciences: Consultancy. Landau:Prothena: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Spectrum Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Korde:Medscape: Honoraria. Landgren:Merck: Honoraria; BMS: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria.