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AbstractActivation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.

Introduction: The delivery of online interventions in cancer patients/survivors has increased. The measurement of participation in online interventions is important to consider, namely, the challenges of the remote assessment of activity. The purpose of this study was to report the measures used to assess intervention compliance and other physical activity participation in two online yoga studies, the relationship between the multimethod measures used, and the ability of cancer patients to complete these measures. Methods: The methods described are of two online yoga studies (feasibility and pilot). Cancer patients were asked to participate in 60 min/week of online yoga for 12 weeks, complete a weekly yoga log, wear a Fitbit daily for 12 weeks, and complete a weekly physical activity log. Finally, Clicky®, a web analytics software, was used to track online yoga participation. Results: Eighty-four people participated across both studies, with 63/84 participating in online yoga, averaging 57.5 ± 33.2 min/week of self-reported yoga participation compared to 41.4 ± 26.1 min/week of Clicky® yoga participation (Lin concordance = 0.28). All 84 participants averaged 95.5 ± 111.8 min/week of self-reported moderate/vigorous physical activity compared with 98.1 ± 115.9 min/week of Fitbit-determined moderate/vigorous physical activity (Lin concordance = 0.33). Across both studies, 82.9% of the yoga logs were completed, the Fitbit was worn on 75.2% of the days, and 78.7% of the physical activity logs were completed. Conclusions: Weak relationships between self-report and objective measures were demonstrated, but the compliance rates were above 75% for the study measures. Future research is needed, investigating the intricacies of self-report physical activity participation in remote interventions and the validation of a gold standard measurement for online interventions.

Background The purpose of this study is to evaluate how prior breast augmentation impacts rates of complications and risk for reoperation after mastectomy with concurrent breast reconstruction. Methods Patients undergoing nipple-sparing, skin-sparing, or simple mastectomy with implant-based reconstruction from 2008 to 2018 were identified in a prospective database. Postoperative complications and reoperations were then analyzed comparing patients with prior augmentation to patients without history of previous breast surgery. Results A total of 468 patients were identified with a median follow-up of 4 years. Of these, 72 had prior augmentation mammoplasty. These patients underwent nipple-sparing (52, 72%), skin-sparing (15, 21%), or simple (5, 7%) mastectomy with immediate direct-to-implant (46, 61%) or tissue expander (26, 35%) reconstruction. On univariate analysis, this cohort had a lower body mass index (23.3 vs 25.3, P = 0.003), a higher rate of nipple-sparing mastectomy (72% vs 54%, P = 0.01), and a higher prevalence of stage I disease (44% vs 33%, P = 0.04). Differences in age, comorbidities, reconstructive techniques, tumor size, and neoadjuvant/adjuvant therapies were not significant. Overall complication rate between patients with or without prior augmentation did not significantly differ (51% vs 50%, P = 0.83); no significant differences in rates of surgical site infection, hematoma, mastectomy skin flap/wound necrosis, nipple complications, implant loss, or capsular contracture were found. Analysis of reoperations between patients with and without prior augmentation revealed no significant differences in average number of subsequent planned, unplanned, or total reoperations. On multivariate analysis, prior breast augmentation was found to be associated with significantly increased risk for undergoing ≥1 unplanned reoperation (odds ratio, 2.28; 95% confidence interval, 1.28–4.05, P = 0.005). Conclusions Prior augmentation mammoplasty does not significantly affect rates of postoperative complications after mastectomy with concurrent reconstruction. Although prior augmentation does not affect number of subsequent reoperations on average, it does increase the risk of experiencing 1 or more unplanned reoperation after mastectomy with reconstruction.

Introduction: FDA approval of JAK2-inhibitors for myelofibrosis (MF) has changed the landscape for treatment introducing possible increased complexity of clinical trial designs in MF. Many patients with MF will have insufficient response or intolerance to ruxolitinib, opening an opportunity for testing of novel agents alone or in combination. Novel trial designs exist for early stage (phase 1 and 2) studies. The Myeloproliferative Neoplasms Research Consortium (MPN-RC) is an NCI-funded academic group of laboratory and clinical scientists working to develop and evaluate treatments that will improve the survival of patients with MPNs focused on early stage trials in MF. This review was undertaken to understand the landscape of MF clinical trials and improve our approach to trial design. Methods: Studies with "myelofibrosis" as a condition were abstracted from clinicaltrials.gov using an application programming interface from 2010-2019 and reviewed for phase, trial design features, and endpoints. Trial design review captured such features as presence of dose escalation and approach (rule-based versus model-based/assisted) in the phase 1 setting. Observational and behavioral based studies were excluded. A total of 165 treatment interventional studies including MF patients (either MF as the primary cohort, or MF along with other MPN, myelodysplastic syndrome, or hematologic malignancies related cohorts) were reviewed. Primary and secondary endpoints were reviewed for quality of life, symptoms, or other patient-reported outcomes (PRO). Results: A median of 16.5 (range 13-20) trials were initiated per year; 92 (56%) phase 2, 54 (33%) phase 1; 17 (10%) phase 3 and 2 (1%) phase 4, with 77 (47%) industry sponsored (Figure 1). Among phase 1 trials, 41/54 (76%) included dose escalation, the majority employing a standard 3+3 design (or other rule-based design) or not specifically detailing the dose escalation schema. Less than 5 dose escalation trials were explicitly described as model-based or model-assisted. Almost half of the phase 1 trials (23/54; 43%) included combination treatment, with 17/23 (74%) using ruxolitinib or fedratinib. Among phase 2 trials, 82 (89%) were non-randomized and 10 (11%) randomized trials; 35/92 (38%) involved combination treatment and 57 (62%) single agent. Median actual/target enrollment for the phase 3 trials (n=16) was 192 patients (range 49-2233 patients); only 2 phase 3 trials were > 500 patients. Median number of total outcomes was 6.0 (range 1-28) across all studies with a median of 5.5 (range 1-28) for 2010-2014 versus 7.0 (range 1-22) for 2015-2019 (p=0.09). Overall 63/165 (38%) studies included at least one PRO endpoint; 15 (28%) phase 1, 33 (36%) phase 2 and 14 (82%) phase 3. Inclusion of PRO endpoints for years 2010-2014 was similar to studies started in years 2015-2019 [31/82 (38%) and 32/83 (39%)]. Industry sponsored studies included PRO endpoints more frequently [46/77 (60%) versus 17/88 (19%); p<0.001] than non-industry sponsored trials but this is primarily due to a higher proportion of phase 3/4 trials (n=17) being conducted by industry versus non-industry (n=2) (Figure 2). Conclusions: For phase 1 trials in MF, few dose-escalation trials included model-based or model-assisted methods. These designs are encouraged in order to maximize therapeutic benefits in MF, a rare cancer. Clinical trial designs in myelofibrosis have shifted in recent years as evidenced by an increase in number of endpoints, likely to accommodate new challenges in the post JAK2-inhibitors approval era. Use of patient-reported outcomes including quality of life and symptom assessment was high in the phase 3 setting, and continued use should be encouraged as endpoint assessments in MF clinical trial designs. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Mesa:LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Hoffman:Dompe: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy.

Background: Myelofibrosis (MF) is a clonal bone marrow disorder characterized by a constitutional symptoms, splenomegaly, anemia, elevated WBC and bone marrow fibrosis. Ruxolitinib is a JAK2 inhibitor approved for patients with Intermediate-2 (INT-2) or high risk disease based on dynamic international prognostic scoring system (DIPSS), however, there are limited options for patients with early disease. Interferon alpha (IFNa) is a cytokine therapy that has been used in treatment of chronic myelogenous leukemia and polycythemia vera (PV). In these diseases, there can be a reduction in the clonal burden in addition to a hematologic response. Therefore, we sought to use this therapy in patients with MF. Methods: Patients who had MF were enrolled on an IRB approved clinical protocol in a single arm, single institution study. Patients were stratified to either an early disease arm (characterized by intermediate 1 (INT-1) risk or advanced disease (Int-2 or high-risk disease based on DIPSS). Patients were started on ropeginterferon (interferon-alpha 2b) at 50 ug every two weeks, and the dose was titrated up to either 300 ug every other week, or until unacceptable toxicity. Patients were monitored for response based on IWG criteria. Results: Ten patients with MF have been enrolled on the study to date (Early: 3, Int/High: 7). Median age was 69.5 (39 - 88), four patients were female. Five patients had primary MF (PMF), 4 had post-essential thrombocythemia and 1 post PV MF. Five patients had previous treatment for their disease. Four patients continue to receive active treatment (2 early disease, and 2 advanced disease). Reasons for stopping include disease progression (3), toxicity (1), alternate treatment (1) and lack of benefit (1). The median number of cycles for those who ended treatment was 7.5 (4-47), and for those who remain on treatment, they range from 16 - 46 cycles. Five patients achieved a clinical improvement, 3 had a spleen response, and 2 had a symptom response. A grade 3 adverse event (AE) potentially attributable to the treatment occurred in 6 patients (60%), 4 (40.0%) patients had anemia, and 2 (20.0%) patients had lymphopenia. Only one patient discontinued therapy due to AEs (dizziness, atrial fibrillation). One death has occurred to date, due to an unrelated cause. Discussion: Ropeginterferon is a well-tolerated therapy that results in clinical improvement in half the patients, and appears to be well tolerated. These results, along with historic data suggesting possible reduction in clonal burden, suggest that ongoing studies are warranted to further understand the clinical benefit of ropeginterferon. Disclosures Zimmerman: Pharmaessentia: Current Employment. Mesa:Incyte: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Samus Therapeutics: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Bristol Myers Squibb: Research Funding. OffLabel Disclosure: Clinical trial

Introduction Essential thrombocythemia (ET) and polycythemia vera (PV) patients suffer from various symptoms that worsen quality of life (QOL), yet serial data on symptom changes resulting from therapy are sparse in the literature. Patient questionnaires from 2 large multicenter trials (MPN-RC 111, 112) were used to assess change in symptom burden and QOL over 12 months and impact of baseline symptom burden on subsequent change in ET / PV patients on hydroxyurea (HU) or pegylated interferon alfa-2a (PEG). Methods Trials MPN-RC 111 was a single-arm, open-label, phase II trial evaluating response to PEG in high-risk ET / PV patients with HU resistance/intolerance or splanchnic vein thrombosis (SVT; NCT01259817). MPN-RC 112 was a randomized, open-label, phase III trial comparing response to PEG versus HU in cytoreductive therapy naïve high-risk ET / PV patients diagnosed < 5 years ago (NCT01258856). Measures Patients reported disease-related symptoms via the validated Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF), QOL via the European Organisation for the Research and Treatment of Cancer Core QOL Questionnaire (EORTC QLQ-C30), and (if applicable) PEG-related symptoms (flu-like symptoms, injection site irritation, blurry vision, vision change, flushing) at baseline, 3, 6, 9, and 12 months. Analysis Mixed models assessed mean changes from baseline in the MPN-SAF Total Symptom Score (TSS), MPN-SAF items, QOL, and PEG-related symptoms in MPN-RC 111, 112 PEG, and 112 HU patients. Mixed models also assessed the impact of baseline symptom burden (high [TSS ≥ 20] versus low) on subsequent change in PEG (MPN-RC 111 and 112) and HU patients. Results Patients Of the 135 enrolled MPN-RC 111 patients, 20 with SVT and 1 with no questionnaires were excluded. Of the remaining 114, 64 (56%) / 50 (44%) had ET / PV. Patients were 51% / 48% female. Median age was 65 / 64 years, and median time since diagnosis was 38 / 55 months. 31% / 22% had prior thrombosis, and 19% / 56% had splenomegaly. Of the 168 enrolled MPN-RC 112 patients (82 PEG, 86 HU), 2 with no questionnaires were excluded. Of the remaining 166, 79 (48%) / 87 (52%) had ET / PV. Patients were 50% / 33% female. Median age was 60 / 62 years, and median time since diagnosis was 3 / 3 months. 25% / 29% had prior thrombosis, and 11% / 37% had splenomegaly. Symptoms Questionnaire completion rates ranged from 90 - 99%, 87 - 100%, and 75 - 96% for on-treatment MPN-RC 111, 112 PEG, and 112 HU patients. At baseline, TSS (0 [absent] - 100 [worst imaginable]) and QOL (0 [very poor] - 100 [excellent]) means (SDs) were 19.5 (18.4) and 71.6 (20.1) for MPN-RC 111, 17.0 (13.6) and 67.9 (24.3) for MPN-RC 112 PEG, and 14.6 (11.4) and 73.8 (18.8) for MPN-RC 112 HU patients. On average, MPN-RC 111 patients had significant improvement of TSS, fatigue, abdominal pain, abdominal discomfort, dizziness, numbness, night sweats, and fever; MPN-RC 112 PEG patients had significant worsening of fever; and MPN-RC 112 HU patients had significant worsening of inactivity (no mean changes indicating improvement were observed). PEG patients had significant worsening of PEG-related symptoms. The greatest improvements occurred in the 46 (40%), 27 (33%), and 23 (28%) MPN-RC 111, 112 PEG, and 112 HU patients with high baseline symptom burden. On average, PEG patients with high baseline symptom burden had significant improvement of TSS, fatigue, early satiety, abdominal pain, abdominal discomfort, inactivity, headache, concentration, dizziness, numbness, insomnia, cough, night sweats, itching, bone pain, fever, weight loss, and QOL, while those with low baseline symptom burden had significant worsening of TSS, early satiety, headache, itching, and bone pain. On average, HU patients with high baseline symptom burden had significant improvement of TSS, early satiety, abdominal discomfort, headache, dizziness, numbness, insomnia, itching, and weight loss, while those with low baseline symptom burden had significant worsening of TSS, early satiety, abdominal discomfort, inactivity, concentration, and sexual desire/function (Figures 1 and 2). Conclusions Although no statistical comparisons were made across trials, overall improvements were seen in MPN-RC 111 but not 112. Patients with high baseline symptom burden experienced the greatest improvements in symptom burden and QOL during treatment with PEG or HU, which may explain the improvements seen in the more advanced patients in MPN-RC 111 compared to 112. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Yacoub:Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Silver:PharmaEssentia: Speakers Bureau. Mesa:Bristol Myers Squibb: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy.

Background:Case reports suggest photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an effective treatment for refractory mycosis fungoides (MF). No prospective trials have examined the use of ALA-PDT in MF. Objective:We aimed to assess the efficacy of ALA-PDT in refractory MF. Methods:This was a prospective study at Mayo Clinic in Scottsdale, Arizona in patients ≥ 18 years with plaque-stage treatment-refractory MF. Monthly sessions of ALA with blue light PDT were administered for up to six months. Responses were measured by Composite Assessment of Index Lesion Severity (CAILS) and Physician Global Assessment (PGA). Ad hoc analysis with modified CAILS (mCAILS) was performed, eliminating hyperpigmentation from scoring. Results:Eleven patients (30 total lesions) were treated. Six patients completed the trial per protocol. Objective response rates were 36.4% by PGA (10.9-69.2%), 18.2% by CAILS (2.3-51.8%), and 36.4% by mCAILS (10.9-69.2%). Limitations:Five patients did not complete all six PDT cycles per protocol, possibly accounting for reduced efficacy. Conclusion:ALA-PDT with blue light irradiation was moderately effective and well tolerated in refractory plaque stage MF. Lower response rates compared to similar trials may be partially explained by utilization of strict lesional assessment criteria and other variations in methodology. Disclosures Mangold: MiRagen:Research Funding;Sun Pharma:Research Funding;Elorac:Research Funding;Kirin:Membership on an entity's Board of Directors or advisory committees;Solagenix:Research Funding. OffLabel Disclosure: Photodynamic therapy is a two-step therapy in which a drug that acts as a photosensitizer is administered to target a diseased tissue, followed by illumination with visible light to activate the drug and destroy the target tissue. PDT has been used to treat internal cancers as well as treatment of cancer and precancer of the skin.

Introduction: Response assessment at day 100 post Autologous Stem Cell Transplant (ASCT) is associated with long-term relapsed free survival (RFS) and overall survival (OS) in multiple myeloma (MM). The International Myeloma Working Group (IMWG) are the preferred criteria to define best response to treatment and define relapse. In the last years, response assessment has incorporated minimal residual disease (MRD) status -associated with improved RFS and OS (Munshi et al); and PET/CT combined with clinical characteristics -also associated with favorable outcomes (Zamagni et al. NCT01910987; MMY3033). The 2016 IMWG MRD criteria, combined imaging (PET/CT) plus next-generation sequencing (NGS) MRD-negative to define complete response (CR). To our knowledge, there is limited data examining the correlation and prognostic value of MRD and FDG-PET/CT at day 100 post ASCT in MM. IN this study, we aimed to determine the prognostic valued of MRD by NGS combined with PET/CT in RFS and OS status after high dose chemotherapy and ASCT in MM. Methods: Patients who underwent ASCT for MM at Mayo Clinic Arizona and had MRD and PET/CT data were included in the study. Clinical data was obtained via retrospective chart review. Cytogenetic risk (CyR) was classified using the mSMART criteria . Disease and ASCT related characteristics were compared by MRD status. MRD was measured by NGS on bone marrow aspirates using the previosly validated clonoSEQ ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) tracking the IgH, IgK and IgL rearrangements at a minimum sensitivity level of 10-5. MRD was defined by residual clonal cells per million nucleated cells as: negative= 0, borderline= 1-5, positive >5. PET/CT scans were performed locally at baseline and at day 100. Comparisons were performed using the chi-square test for categorical variables, Wilcoxon rank-sum test for continuos variables, McNemar's test and Cohens's Kappa for agreement measures. Results: A total of 103 patients had matched MRD and PET/CT assessment around day 100 (+/-9 days) and were included in the analysis. Median age at diagnosis was 62 years (range, 54-66 years), 71 patients (68.9%) were men. CyR was standard risk in 49 (47.6%), high-risk in 39 (37.9%) and unknown in 15 (14.6%) patients. Most 75 (72.8%) patients were MRD positive, 16 (15.5%) were MRD negative, and 12 (11.7%) borderline. The median main MRD clone detected was 64 (range 0-91,874). 70 patients (68%) and 33 (32%) had a negative and positive PET/CT respectively. The median follow-up time was 18 months (range, 13-31 months). At the time of data analysis, 10 patients (9.7%) had relapsed and only 4 (3.9%) had died. There was a high-correlation between MRD status and PET/CT, 31 patients (93.9%) with positive PET/CT were also MRD positive (p=0.0027). There were no statistical differences between PET/CT and CyR (p=0.95). We analyzed the correlation using the FREQ procedure (McNemars's test); there was a strong association between positive PET/CT and positive MRD in 31/33 patients (93.9%, high sensitivity), and low association for negative PET/CT the negative/borderline MRD in 26/70 (37.1%, low specificity; p<0.001). The agreement measure between the PET/CT and MRD using negative/borderline combined had a kappa of 0.23 (95% CI 0.11, 0.35) indicating a fair agreement beyond chance (Figure 1). PET/CT-CT was a statistically significant predictor of worse RFS (HR 3.53, 95%CI: 1.02-12.24, p<0.0337) and OS (HR 11.38, 95%CI: 1.18-109.56, p<0.0078) (Figure 2-3, respectively). MRD was not predictive of neither RFS (HR 1.72, 95%CI: 0.36-8.14, p<0.49) or OS (p<0.16). Conclusions: In conclusion, we demonstrate that the combination of MRD by NGS (clonoSEQ ®) and PET/CT at day 100 are complementary and have a high sensitivity (true positive rate) and fair correlation of agreement but low specificity (true negative rate). PET/CT was the best most sensitive technique to prognosticate RFS and OS. We did not find prognostic correlation of MRD with RFS and OS. However, our findings might be confounded by the low risk of relapse and death, a longer follow-up may demonstrate clinically important differences. Our results add evidence that MRD plus PET/CT improve the definition of CR in MM patients post ASCT. Prospective studies are needed to elucidate the optimal timing and role of combined MRD, PET/CT with other prognostic markers of clinical outcomes. Disclosures Larsen: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fonseca:Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy.