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Risk Factors for Early Sudden Cardiac Death in Patients with Systemic Light-Chain Amyloidosis on Treatment
Abstract Introduction: Despite advances in therapy for patients with light-chain (AL) amyloidosis, mortality remains high in the first 6 months after diagnosis in those on treatment (Blood 2017;129:2111). The early deaths are usually sudden cardiac deaths (SCD); a prior study showed that troponin I level and lack of response to therapy influenced survival (Br J Haematol 2008;143:369). In January 2021 at the approval of daratumumab with cyclophosphamide, bortezomib and dexamethasone for AL (Dara/CyBorD), the FDA label warned that patients with higher cardiac staging may be at risk for fatal cardiac events. We sought to analyze risk factors for SCD in patients on treatment, defining SCD as a sudden unexpected death caused by loss of cardiovascular function (Arrhythm Electrophysiol Rev 2016;5:177). Methods: From a database of 398 patients with AL amyloidosis collected from 2005-2019, we identified patients who suffered out-patient SCD on treatment within 180 days of diagnosis. We recorded baseline age, gender, systolic BP, presence of syncope, LVEF, FLC, cardiac biomarkers, NYHA class, cycles of treatment with bortezomib, and data on SCD. For comparison we identified an age and gender matched group who achieved complete or very good partial responses (CR or VGPR) based on standard criteria and recorded that group's data (J Clin Oncol 2012;30:4541). We compared these datasets by two-tailed Mann-Whitney and where appropriate by contingency table analysis. We computed the medians of the involved FLC, BNP and troponin for all the cases to determine the frequency with which patients in either group had baseline values above or below those medians. Results: Comparative results are shown in Table 1. We identified 13 SCD and 74 age and gender matched CR/VGPR patients. Compared with the CR/VGPR group, both hypotension and exertional syncope were significantly more common in the SCD group, indicating the presence of autonomic dysfunction. NYHA class 3 or 4 status was also more common in the SCD group (40% and 13% vs 26% and 13% in the CR/VGPR group). In addition, more SCD patients were Mayo cardiac stage III (80% vs 46% in the CR/VGPR group) (Blood 2004;104:1881; J Clin Oncol 2004;22:3751). The SCD patients had significantly lower LVEF and higher iFLC and were significantly more likely to have iFLC values above the median. Similarly they had significantly higher BNP and troponin-I levels and were more likely to have values above the medians. The causes of death were unclear in 9 cases but were described by witnesses as due to syncopal events associated with micturition, climbing stairs, or light exertion. In 4 cases seen in emergency rooms, PEA was documented in 3 and septic shock in 1. The SCD patients had a median of 1 cycle of subcutaneous bortezomib-based therapy (CyBorD) (range, 1-5). Three patients received daratumumab subcutaneously with CyBorD. The median starting dose of bortezomib was 1.3mg/m2 (0.7-1.5) usually on a weekly schedule; 2 patients initiated therapy at 1.5mg/m2 weekly, one of whom had had progression of disease (POD) after 2 cycles of oral melphalan and dexamethasone and then had further progression despite completing 3 cycles of CyBorD (POD=1). Eight patients were inevaluable for hematologic response (NR=8), 2 achieved PR after 2 and 4 cycles of CyBorD (PR=2), and of the 3 who got Dara/CyBorD, 1 was inevaluable, 1 achieved VGPR after C1 and 1 CR in C2 (CR/VGPR=2), before having SCD. Conclusion: These findings indicate the contribution that the presence of autonomic dysfunction makes in this population of AL patients with advanced cardiac disease and high levels of iFLC, key variables in the revised Mayo staging system (J Clin Oncol 2012;30:989). The potential pre-morbid significance of exertional syncope has been identified previously (Am J Cardiol 1997;80:1242). In conclusion, this case series suggests that compared with AL amyloid patients who achieve CR or VGPR with treatment, patients who suffer early SCD on treatment have symptoms indicative of autonomic dysfunction and may benefit from in-patient initiation of treatment and from obtaining insurance approval for Dara/CyBorD but starting therapy with weekly subcutaneous daratumumab and dexamethasone, adding cyclophosphamide and bortezomib at a later timepoint based on hematologic response. Moreover, weekly assessment of FLC response is reasonable in these patients in order to guide therapy and adjust supportive care. Figure 1 Figure 1. Disclosures Comenzo: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding.
BackgroundThere is a medical need in platinum resistant ovarian cancer patients. Median progression-free survival (PFS) is 3.4 months with chemotherapy and 6.7 months with chemotherapy-bevacizumab combination regimens.1 RECIST overall response rate (ORR) is 11.8% and 27.3%, respectively. The ORR is 15.9% for bevacizumab as a monotherapy with a median PFS of 4.4 months.2MethodsNCT03596281 An open-label phase 1b trial with a modified toxicity probability interval design to evaluate the combination of a flat dose of 400mg bevacizumab for 6 cycles and 200mg pembrolizumab until disease progression, unacceptable toxicity or completed 24 months of treatment in patients with platinum resistant ovarian cancer. The primary evaluation criteria is safety, the secondary endpoint is the efficacy.Results19 patients have been enrolled between January 2019 and February 2021 in 6 French centers. Patients‘ characteristics are reported (table 1). No dose limiting toxicities were observed. Grade 3 treatment related adverse events occurred in 3 patients (i.e. arterial thromboembolism, bowel perforation, proteinuria and sepsis). No grade 4/5 toxicities were induced. A median of 7 cycles (range 3–14) were administered. Median follow-up of patients was 4.1 months (1.8–23). The RECIST ORR was 26.3% (1 complete response and 4 partial responses) (table 2). The disease control rate was 78.9%. The time to progression was not yet reached in 6 patients. The ORR was equivalent whether patients have been pretreated or not with bevacizumab (27.3 and 25% respectively) (table 3). The ORR according to the combined positive score (CPS) for the evaluation of PD-L1 was 50.0% for CPS≥10% (n=4), 30.0% for a CPS≥1% (n=10) and 25.0% for CPS<1 (n=8) (table 4).ConclusionsA chemotherapy-free regimen combining pembrolizumab and bevacizumab was well tolerated and showed encouraging results in heavily pretreated platinum resistant ovarian cancer patients independent of their previous challenge with antiangiogenic agents.AcknowledgementsFunding for this research was provided by Fondation Cancer du Luxembourg and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT03596281ReferencesPujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Onco Off J Am Soc Clin Oncol 32,1302–1308 (2014).Cannistra SA, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol Off J Am Soc Clin Oncol 33,5180–5186 (2007).Ethics ApprovalThis study was approved by CPP Sud Méditerranée V institution’s Ethics Board; approval number 18.020 (EudraCT number 2017-004197-34).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
BackgroundA majority of patients with advanced NSCLC develop disease progression with first-line immune-checkpoint inhibitors (ICI) ± chemotherapy. In the setting of ICI resistance, effective strategies to provide deep and durable responses are urgently needed. Lifileucel (LN-144) and LN-145 are centrally manufactured (cryopreserved drug-product, 22-day manufacturing process) autologous TIL products that have demonstrated activity in advanced melanoma, cervical cancer, and head and neck carcinoma.1–4 Here, we report the first safety and efficacy data for LN-145 as monotherapy in patients with advanced NSCLC.MethodsIOV-COM-202 (NCT03645928) is a phase 2 multicenter, multicohort, open-label study evaluating autologous TIL cell therapy in patients with solid tumors. We report data from Cohort 3B, investigating LN-145 monotherapy in patients with advanced or metastatic NSCLC. Eligibility required 1–3 prior lines of systemic therapy, including either ICI or oncogene-directed therapy. Treatment included nonmyeloablative lymphodepletion, TIL infusion, and ≤6 interleukin-2 doses. Primary endpoints were safety (incidence of Grade ≥3 treatment-emergent adverse events [TEAEs]) and objective response rate (ORR, investigator-assessed using RECIST v1.1). Exploratory biomarker analyses, including T-cell receptor (TCR) repertoire, were performed.ResultsAs of 24June2021, 28 patients received LN-145 (full-analysis set [FAS]; table 1) and 24 were efficacy-evaluable; all had received prior ICI. TIL were most commonly harvested from lung metastases (57.1%). Safety was consistent with the underlying disease and known TEAE profiles of nonmyeloablative lymphodepletion and interleukin-2. Grade ≥3 TEAEs in ≥30% of patients were thrombocytopenia and anemia. The ORR in the FAS and efficacy-evaluable set was 21.4% (6/28) and 25.0% (6/24; figure 1), respectively. Median duration of response was not reached and 83% (5/6) of responses were ongoing at last follow-up (median study follow-up, 8.2 months). One patient had a complete metabolic response, ongoing at 20.7 months; 2 responses occurred in patients who were PD-L1–negative. All responders received ≥2 prior lines of systemic therapy. Twenty-six patients had TIL available from the final drug-product for TCR repertoire analysis; mean (min-max) number of unique TCR clones was 13,142 (3093–35,734) and Shannon Entropy index was 7.34 (3.7–12). Updated data will be presented.Abstract 458 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable setAbstract 458 Table 1Baseline patient demographic and clinical characteristics; efficacy parametersConclusionsLN-145 was successfully manufactured and one-time treatment produced an expected safety profile and durable responses in heavily pretreated patients with NSCLC, regardless of PD-L1 expression. The activity of LN-145 monotherapy is encouraging and warrants further investigation of LN-145 as a single-agent and in combination in patients with NSCLC in ongoing studies IOV-LUN-202 (NCT04614103) and IOV-COM-202 Cohorts 3A and 3C (3B closed to enrollment).AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Writing support was provided by Amanda Kelly (Iovance); graphics support was provided by Cognition Studio (Seattle, WA, USA).Trial RegistrationNCT03645928ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.. Thomas SS, et al. J Clin Oncol 2021;39: (suppl; abstract 9537).Jazaeri A, et al. J Clin Oncol 2019;37: (suppl; abstract 2538).Jimeno A, et al. J Immunother Cancer 2020;8: (suppl; abstract A378).Ethics ApprovalThe study was approved by Advarra Institutional Review Board, approval number Pro00035064 and all study participants provided written consent via signature of the IRB-approved Informed Consent form.
BackgroundImmune checkpoint inhibitors (ICI) are standard-of-care in the treatment of several types of cancer; however, an unmet medical need exists for early-line combination therapies that are able to provide higher response rates, more durable responses, and manageable long-term safety. Lifileucel (LN-144) and LN-145, adoptive cell therapies using tumor-infiltrating lymphocytes (TIL), have demonstrated encouraging efficacy with acceptable safety in patients with advanced cancer that has failed ICI.1–2 To improve efficacy and safety of early-line treatment options, we explored a combination of TIL and pembrolizumab in patients with ICI-naïve melanoma, head and neck squamous cell carcinoma (HNSCC), and cervical cancer.MethodsIOV-COM-202 (NCT03645928) and C-145-04 (NCT03108495) are ongoing Phase 2 multicenter, multicohort, prospective, open-label studies evaluating TIL cell therapy in ICI-naïve patients with solid tumors. We report efficacy and safety from IOV-COM-202 (Cohort 1A: lifileucel and pembrolizumab in patients with unresectable or metastatic melanoma; Cohort 2A: LN-145 and pembrolizumab in patients with advanced, recurrent, or metastatic HNSCC) and C-145-04 (Cohort 3: LN-145 and pembrolizumab in patients with stage 4b, persistent or recurrent cervical cancer who have not received prior systemic therapy). Eligibility across cohorts included ECOG PS ≤1, ≥1 resectable lesion (diameter ≥1.5 cm post-resection) for TIL manufacturing, and ≥1 measurable lesion for response assessment (by investigator per RECIST v1.1). Lifileucel and LN-145 are cryopreserved TIL infusion products generated at central GMP facilities in a 22-day process. Treatment included tumor resection for TIL manufacturing, followed by 1 dose of pembrolizumab, nonmyeloablative lymphodepletion (cyclophosphamide and fludarabine), TIL infusion, ≤6 interleukin-2 doses (600,000 IU/kg IV), and continued pembrolizumab for ≤24 months.ResultsAs of 09July2021, 32 patients received TIL and pembrolizumab (full-analysis set [FAS]; table 1). Across all cohorts, the objective response rate (ORR) in the FAS was 56.3% (Cohort 1A [melanoma], 87.5%; Cohort 2A [HNSCC], 42.9%; Cohort 3 [cervical], 50.0%; figure 1). Among confirmed responders (n=17), 10 responses (58.8%) were ongoing at data cutoff, with a median study follow-up of 9.7 months. The treatment-emergent adverse-event (TEAE) profile was consistent with the underlying diseases and known profiles of pembrolizumab, nonmyeloablative lymphodepletion, and interleukin-2. The most common (≥30%) Grade ≥3 TEAEs were thrombocytopenia (53.1%), anemia (50.0%), neutropenia (46.9%), and febrile neutropenia (43.8%).ConclusionsThe observed efficacy, including ORR and CR rate, and acceptable safety profile are encouraging and warrant continued investigation of the combination of TIL and pembrolizumab in early-line treatment of patients with advanced cancer. Enrollment is ongoing; updated data will be presented.AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Writing support was provided by Amanda Kelly (Iovance); graphics support was provided by Cognition Studio (Seattle, WA, USA).Trial RegistrationNCT03645928 and NCT03108495ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.Jazaeri AA, et al. J Clin Oncol 2019;37 (suppl; abstract 182).Jimeno A, et al. J Immunother Cancer 2020;8 (suppl; abstract 353).Ethics ApprovalThe IOV-COM-202 study was approved by Advarra Institutional Review Board, approval number Pro00035064; the C-145-04 was approved by WIRB Copernicus Group, approval number 7-1425772-1. All study participants provided written consent via signature of the IRB-approved informed consent form.Abstract 492 Table 1Baseline demographic and clinical characteristics and efficacyAbstract 492 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable set*
BackgroundLifileucel (LN-144) and LN-145, adoptive cell therapies using autologous tumor-infiltrating lymphocytes (TIL), have demonstrated encouraging efficacy with acceptable safety in a variety of tumor types.1–4 The lifileucel Gen 2 clinical manufacturing process uses gas-permeable rapid expansion (G-Rex®, Wilson Wolf, Saint Paul, MN) bioreactors for TIL expansion.5 Static gas-permeable cell culture bags (EXP-Pak™, Charter Medical, Winston-Salem, NC) are alternate bioreactors that have been used for clinical manufacturing of T cells.6 In this study, TIL product characteristics were compared after expansion at small- and full-scale using EXP-Pak bags and G-Rex bioreactors.MethodsCryopreserved pre-REP TIL were cultured with OKT-3 and irradiated peripheral blood mononuclear cells in either small-scale (G-Rex 5M flasks or EXP-50 bags) or full-scale (G-Rex 500MCS or EXP-5L bags) conditions. The same culture media formulation was used throughout the process. Final harvested TIL products were characterized for the following quality attributes: total viable cells (TVC), purity (% viability), identity (% CD45+CD3+), and activity (IFN-gamma release). Additional characterization was performed to determine the TIL differentiation, central and effector memory subsets, activation, exhaustion status, and impurities using multi-color flow cytometry. The T-cell receptor (TCR) repertoires of the final products were assessed for unique CDR3 (uCDR3) counts and shared clones using RNA-seq.ResultsThe median (range) TVC from 6 small-scale runs of G-Rex condition was 90.8×109 (26.9×109–98.6×109) cells, and the corresponding TVC of EXP-Pak bag condition was 119×109 (63.2×109–141×109) cells. Full-scale runs (n=3) yielded similar TVC for G-Rex and EXP-Pak bag conditions. Both conditions had comparable purity, identity, and activity (table 1). 91–99% of TCR Vbeta clones of EXP-Pak bag TIL were present in G-Rex (table 2). Cell proliferation, cell cycle, and mitochondrial function of TIL generated from EXP-Pak bags and G-Rex flask methodologies will be presented.ConclusionsThe final TIL product generated in the EXP-Pak bag condition did not differ from cells produced in the G-Rex flask functionally or phenotypically and demonstrated similar growth profiles. These data support further evaluation of EXP-Pak bags for potential use in clinical and potential commercial TIL cell therapy manufacturing applications.AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Editorial support was provided by Amanda Kelly (Iovance).ReferencesSarnaik AA, et al. J Clin Oncol. 2021; doi: 10.1200/JCO.21.00612.Thomas SS, et al. J Clin Oncol. 2021;39 (suppl; abstract 9537).Jazaeri A, et al. J Clin Oncol. 2019;37 (suppl; abstract 2538).Jimeno A, et al. J Immunother Cancer. 2020;8 (suppl; abstract A378).Wardell S, et al. J Immunother Cancer. 2019;7 (suppl 1; abstract P226).BioProcess International. 2014 [white paper]. https://bioprocessintl.com/sponsored-content/efficacy-utility-new-exp-pak-closed-system-disposable-cell-expansion-bags-designed-cell-therapy-applications/Accessed July 23, 2021.Abstract 101 Table 1Summary of final TIL product attributesAbstract 101 Table 2Common uCDR3 clones and% overlap of TCR clones
TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.
Introduction While the approved dose of brentuximab in T cell lymphomas has been every 3 weeks on a 1.8 mg/kg schedule, earlier studies exploring weekly dosing showed that a dose of 1.2 mg/kg on a weekly dosing (every 3 out of 4 weeks) in pts with Hodgkin's lymphoma and hematologic malignancies may improve cancer response rates while still having manageable side effects3. We explored the weekly dosing schedule in 37 pts (pts) with mycosis fungoides/Sezary syndrome (MF/SS) and aggressive T cell lymphomas and compared to our experience with every 3 week dosing in 36 pts to evaluate tolerability and efficacy of the weekly schedule.. Methods We reviewed charts of 67 pts, 36 received dosing q 3 weeks and 37 received a dose weekly for 3 consecutive weeks on a 4-week schedule. Pts included MF/SS (n=35), gamma delta T cell lymphoma (n=2), anaplastic large cell lymphoma (n=12), Peripheral T cell Lymphoma (n=10), angioimmunoblastic T cell lymphoma (n=4), adult T cell leukemia (n=2), and NK-T cell lymphoma. Pts were treated with brentuximab vedotin at a dose of either 1.8 mg/kg every 3 weeks or 1.2 mg/kg weekly x 3 every 4 weeks. CD30 expression was scored by the pathologist in tumor biopsies as high (<50%), low (5-10%), or intermediate (>10%-49%). Toxicity data was recorded from the medical records and data analyzed descriptively. Results Of 67 pts in this study, the average age was 61. Doses were 1.8 mg/kg for the q 3 week schedule and 0.75 to 1.2 mg/kg for the weekly x 3 schedule. Cycles were 3-47 for q 3 weeks and 1-9.7 for weekly dosing. CD30 expression was high in 13% of pts, low in 43%, and absent in 6% with equal distribution between the weekly and q 3 week cohorts, as shown in Table 1. Dose adjustments were made in 67% of q 3 week and 61% of weekly pts for neurotoxicity (n=28), with a higher incidence in the q 3 week pts compared to those with weekly dosing (75% vs 53%, p=0.01) . Discontinuation for progression (25% vs 30%) was similar for both groups. In the weekly group, 8 pts had a stem cell transplant, including allogeneic transplantation in 3. Conclusion In the Phase II registration trial of brentuximab vedotin 1.8 mg/kg q3 weeks, 41% of pts had neuropathy (severe in 12%). 1 Forty two percent of discontinuations were for neuropathy. In our weekly schedule, incidence of neuropathy was lower and led to fewer treatment discontinuations. Our retrospective data shows that Brentuximab vedotin is well tolerated on a weekly dosing schedule and has activity in pts with MF/SS and aggressive T cell lymphomas. As in prior studies, responses were seen with low CD30 expression4, 5. Prospective clinical trials with a self-reported neurotoxicity scale and quality of life instruments should be performed address the impact of more frequent, lower doses of brentuximab vedotin on patient outcomes. 1 Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T et al.J Clin Oncol 2012; 30(18): 2190-2196. doi: 10.1200/JCO.2011.38.0402 2 Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P et al.Lancet 2017; 390(10094): 555-566. doi: 10.1016/S0140-6736(17)31266-7 3 Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA et al.Clin Cancer Res 2012; 18(1): 248-255. doi: 10.1158/1078-0432.CCR-11-1425 4 Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. J Clin Oncol 2015; 33(32): 3759-3765. doi: 10.1200/JCO.2014.60.3787 5 Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S et al.J Clin Oncol 2015; 33(32): 3750-3758. doi: 10.1200/JCO.2014.60.3969 Figure Disclosures Huntington: Pharmacyclics: Honoraria; DTRM: Research Funding; Genentech: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Astrazeneca: Honoraria. Xu:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
Background Patients with myeloproliferative neoplasms (MPNs) are faced with severe disease-related fatigue among a range of other constitutional and spleen-related symptoms. The MPN-Symptom Assessment Form (SAF) is recommended for use to characterize symptom burden (Scherber R, et al. Blood 2011). Within the SAF, a profile of 18 symptom items are evaluated ranging in severity from 0 (absent) to 10 (worst imaginable). The SAF is often summarized to the MPN-SAF Total Symptom Score (TSS) for analysis purposes - a single computed sum of the 10 most clinically meaningful symptom scores, including fatigue (Emanuel R, et al. J Clin Oncol 2012). Though the SAF includes a fatigue item, initial deployments of the MPN-SAF TSS incorporated a 0-10 scaled fatigue item taken from the Brief Fatigue Inventory (BFI; Mendoza T, et al. Cancer 1999). A subsequent version of the MPN-SAF TSS for use within myelofibrosis clinical trials (called the MFSAF v4; Gwaltney C, et al. Leuk Res 2017) employed a harmonized fatigue item. This analysis employing data from two studies was carried out to assess the use of the SAF fatigue item within the MPN-SAF TSS for consistency with the MFSAF v4. Methods Both BFI and SAF fatigue items were included in an initial online survey evaluating disease burden among patients with MPNs. Participants were assigned to survey variants as a function of their age. Survey variants included those to receive 1 instance of either the BFI or SAF fatigue item, instances of both BFI and SAF, or 2 instances of the same fatigue item. Surveying was aimed to assess the worst symptom experience in the patient's last 24 hours. Additionally, an independent survey assessing the impact of COVID-19 among MPN patients was deployed using the SAF fatigue item for the MPN-SAF TSS. This modified version was then used to test internal validity. Pearson correlation (r) and t-tests were used to assess association, Bland-Altman methods were used to evaluate systematic agreement between BFI and SAF fatigue scores, and Cronbach's alpha was used to measure internal consistency. Results There were 229 participants assigned both BFI and SAF fatigue items within the same survey. Among them, 51% (n=117) received the BFI item first and 49% (n=112) the SAF item first. No difference was seen between first and second fatigue scores (mean difference [first-second] = 0.00; 95%CI -0.18, 0.17). BFI and SAF fatigue scores were highly correlated (r=0.88, p<0.001) and showed 88.7% agreement in categorizing severe versus non-severe fatigue (score ≥ 7 versus < 7). Overall concordance in severity category was 73.4% (category [score range]: absent [0]; mild [1-3]; moderate [4-6]; severe [7-10]). Constructing the MPN-SAF TSS using the BFI and SAF fatigue components separately, the original and modified MPN-SAF TSS were nearly identical (r=0.997, p<0.001), and had equivalent internal consistency (both Cronbach's alpha=0.88). The Bland-Altman plot further indicates the 2 fatigue measures have high agreement with no evidence of directional bias and negligible overall bias (Figure 1: regression slope = -0.04, p=0.25; mean difference=0.22; 95%CI 0.05, 0.39). Within the COVID-19 survey (n=1217), the modified version of the MPN-SAF TSS was consistent with known correlates among disease characteristics (Emanuel R, et al. J Clin Oncol 2012). For example, more severe MPN-SAF TSS scores were highly correlated with low quality-of-life (n=1156, r = -0.50, p<0.001), and associated with those reporting spleen enlargement (n=301) versus not (n=617) (p<0.001; mean difference=7.7; 95%CI 5.4, 10.1). Conclusion The BFI and SAF fatigue items are highly consistent in raw score, severity category, and in contribution to the MPN-SAF TSS. There was no order effect seen in which fatigue item was asked first. The independent COVID-19 survey using the modified MPN-SAF TSS was validated and shows high internal consistent. In the ongoing development to capture the symptom experience, this analysis shows disease-related fatigue is equivalently measured using the SAF fatigue survey item in harmonization with the MFSAF v4. Disclosures Mesa: Bristol Myers Squibb: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; Incyte: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy.
BackgroundImmune checkpoint inhibitors (ICIs) are limited by the high incidence of immune-related adverse events (irAEs) occurring in up to 40% of solid tumor patients on anti-PD-1 monotherapy 1 2 and 72% in anti-CTLA-4/anti-PD-1 combination.3 4 These toxicities can cause treatment cessation, hospitalization and even death.5–7 IrAEs are variable in severity, timing, onset, and remain poorly understood. Amongst the different toxicities, skin irAEs are most frequent, occur the earliest, and are correlated with a positive prognosis.4 8 However, there is a lack of preclinical models to study checkpoint toxicity. We evaluated a murine model of allergic contact dermatitis (contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8+ T cells to gain a mechanistic understanding of skin checkpoint toxicity.MethodsC57BL/6 mice (n = 5 per group) were sensitized epicutaneously on shaved flank with hapten 0.5% DNFB on day -5 and elicited on their ears with DNFB on day 0. Starting four weeks later, mice were treated with either anti-programmed cell death protein (PD-1) or isotype. At the time of the first recall challenge only, mice were given either anti-PD-1 or isotype. Mice received subsequent rechallenges with DNFB to the ears and ear swelling was measured at various time points. Mice were depleted of circulating or skin CD8+ T cells by anti-CD8 mAbs from day 29 onwards, and maintained weekly, as in this model CD8+ T cells are the main hapten responder population. Samples were collected for histochemistry and analyzed by flow cytometry.ResultsOur data indicate that despite the depletion of circulating T cells, anti-PD-1 recipients mount a higher initial recall response to contact agents. Higher ear swelling was observed with increased inflammation in these mice. Our data suggest anti-PD-1 can liberate local T cell responses in the absence of a contribution from blood, and may offer a model to test therapeutic interventions to alleviate peripheral immune toxicities.ConclusionsOur results suggest that this murine model of contact hypersensitivity represents a potential model for skin immune checkpoint toxicities. This model of locally-mediated inflammatory recall may advance the goal of uncoupling toxicity from efficacy in patients with immune-related adverse events.Ethics ApprovalThe animal study was approved by Weill Cornell Medicine’s IACUC; approval number D16-00186.ReferencesNaidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015;26(12):2375–91. doi: 10.1093/annonc/mdv383.Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016;60:12–25. doi: 10.1016/j.ejca.2016.02.010.Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018;378(2):158–168. doi: 10.1056/NEJMra1703481.Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16(9):563–580. doi: 10.1038/s41571-019-0218-0.Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5(1):95. doi: 10.1186/s40425-017-0300-z.Wills B, Brahmer JR, Naidoo J. Treatment of complications from immune checkpoint inhibition in patients with lung cancer. Curr Treat Options Oncol 2018;19(9):46. doi: 10.1007/s11864-018-0562-9.Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139–148. doi: 10.1016/j.ejca.2015.11.016.Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol 2019:JCO1802141. doi: 10.1200/JCO.18.02141.
