Citations

Abstract Background Light chain (AL) amyloidosis is a plasma cell neoplasm associated with high early mortality and severe morbidity that can cause severe disability. We explored the impact of AL amyloidosis on symptoms and well-being from the perspectives of patients and health care providers who regularly care for AL patients. We intended to develop a conceptual understanding of patient-reported outcomes in AL amyloidosis to identify the context of use and concept of interest for a clinical outcome assessments tool in this disease.Method Twenty patients and 10 professionals were interviewed. Patient interviews captured the spectrum of amyloidosis experience including time from diagnosis, type of organ involvement, and presence and type of treatment received. Interviews with professionals included physicians, advanced practice providers, registered nurse, and a patient advocate; these interviews covered similar topics. Results The impact of AL amyloidosis on patients’ life was multidimensional, with highly subjective perceptions of normality and meaning. Four major themes from patients and experts included diagnosis of AL amyloidosis, living with AL amyloidosis, symptom burden, and social roles. Barriers to patient-reported outcomes data collection in patients were additionally explored from experts. The themes provide a comprehensive understanding of the important experiences of symptom burden and its impact on daily life from AL amyloidosis patients’ and from the perspectives of professionals who care for patients with AL amyloidosis. Conclusion These findings further the conceptual understanding and identification of a preliminary model of concept of interest for development of a clinical outcome assessments tool for AL amyloidosis.

Because up to 12% of obstetric patients meet criteria for the diagnosis of thrombocytopenia in pregnancy, it is not infrequent that the anesthesiologist must decide whether to proceed with a neuraxial procedure in an affected patient. Given the potential morbidity associated with general anesthesia for cesarean delivery, thoughtful consideration of which patients with thrombocytopenia are likely to have an increased risk of spinal epidural hematoma with neuraxial procedures, and when these risks outweigh the relative benefits is important to consider and to inform shared decision making with patients. Because there are substantial risks associated with withholding a neuraxial analgesic/anesthetic procedure in obstetric patients, every effort should be made to perform a bleeding history assessment and determine the thrombocytopenia etiology before admission for delivery. Whereas multiple other professional societies (obstetric, interventional pain, and hematologic) have published guidelines addressing platelet thresholds for safe neuraxial procedures, the US anesthesia professional societies have been silent on this topic. Despite a paucity of high-quality data, there are now meta-analyses that provide better estimations of risks. An interdisciplinary taskforce was convened to unite the relevant professional societies, synthesize the data, and provide a practical decision algorithm to help inform risk-benefit discussions and shared decision making with patients. Through a systematic review and modified Delphi process, the taskforce concluded that the best available evidence indicates the risk of spinal epidural hematoma associated with a platelet count ≥70,000 × 10 6 /L is likely to be very low in obstetric patients with thrombocytopenia secondary to gestational thrombocytopenia, immune thrombocytopenia (ITP), and hypertensive disorders of pregnancy in the absence of other risk factors. Ultimately, the decision of whether to proceed with a neuraxial procedure in an obstetric patient with thrombocytopenia occurs within a clinical context. Potentially relevant factors include, but are not limited to, patient comorbidities, obstetric risk factors, airway examination, available airway equipment, risk of general anesthesia, and patient preference.

Abstract Background To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). Methods Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). Results A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). Conclusions In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Abstract Background: Endocrine deficiencies are common following craniospinal irradiation (CSI) in children with brain tumors, but empirical data comparing outcomes following proton (PRT) and photon radiation therapy (XRT) are limited. Methods: This retrospective chart review compared the incidence of hypothyroidism, growth hormone deficiency (GHD), and adrenal insufficiency (AI) in patients with medulloblastoma treated with XRT and PRT between 1997 and 2016. All patients received CSI and had routine endocrine screening labs to evaluate for thyroid dysfunction, GHD, and AI. We used proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) comparing the development of hypothyroidism, AI, and GHD between radiation modalities, adjusting for age at diagnosis, sex, race/ethnicity, and CSI dose.Results: We identified 118 patients with medulloblastoma who were followed for a median of 5.6 years from the end of radiotherapy. Thirty-five (31%) patients developed hypothyroidism, 71 (66%) GHD, and 20 (18%) AI. Compared to PRT, XRT was associated with a higher incidence of primary (28% vs. 6%; HR=4.61, 95% CI 1.2-17.7, p=0.03) and central hypothyroidism (33% vs. 9%; HR 2.35 (0.8-6.8, p=0.12). GHD and AI incidence rates were similar between the groups. Conclusions: Primary and central hypothyroidism occur less often after PRT CSI, compared to XRT CSI. This suggests that the thyroid and pituitary glands receive less radiation after spine and posterior fossa boost RT, respectively, using PRT.

Background: Light chain (AL) amyloidosis is a rare disease in which deposits of insoluble amyloid derived from immunoglobulin light chains accumulate and cause dysfunction of organs including the heart and kidneys. In order to reverse organ damage and improve overall survival, treatment must provide rapid, deep, and sustained hematologic responses. Although therapies approved for the treatment of multiple myeloma have demonstrated some efficacy, there are currently no health authority-approved treatments for AL amyloidosis. A retrospective observational study was undertaken to characterize patients and describe treatment patterns in patients with AL amyloidosis from real-world data in the US. Methods: Data were extracted from Optum Electronic Health Records (EHR) and Optum Clinformatics Data Mart (claims) databases. Eligible patients had (1) a diagnosis of AL amyloidosis (ICD-10 code E85.81) on or after January 1, 2008 or (2) a diagnosis of amyloidosis (ICD-9 codes 277.30, 277.39; ICD-10 codes E85.89, E85.9) on or after January 1, 2008 and at least one line of therapy (LOT) comprising one or more of the following treatments: bendamustine bortezomib, carfilzomib, cyclophosphamide, daratumumab, dexamethasone, doxorubicin, elotuzumab, etoposide, interferon alfa-2a, interferon alfa-2b, ixazomib, lenalidomide, melphalan, panobinostat, pomalidomide, prednisone/prednisolone, thalidomide, vincristine, or autologous stem cell transplant. Patients were required to have continuous medical enrollment during the 365 days prior to the index amyloidosis diagnosis date (claims data) or have first active date at least 365 days prior to index amyloidosis date (EHR data), must not have had prior cancer in the 365-day period prior to the index amyloidosis diagnosis date, and must have been age ≥18 years at time of amyloidosis diagnosis. Patients treated with dexamethasone only or dexamethasone and prednisolone only for ≤90 days and those treated with prednisone/prednisolone only irrespective of duration were excluded. LOTs were defined by a start date, an end date, and a distinct regimen made up of ≥1 drugs. Patients may have multiple sequential LOTs during the available follow-up period. Comorbidities were scored according to the Charlson Comorbidity Index (CCI). A score of 0 reflects no comorbidities; higher scores reflect increased mortality risk and the maximum score is 24. Descriptive statistics are provided for patient characteristics at index diagnosis date for patients who had ≥1 LOT, distribution of regimens in each LOT, treatment attrition, and duration of treatment in each line of therapy and by regimen. Results: Data from 1688 patients (Optum claims, n=624; Optum EHR, n=1064) were included in the analysis (Figure). Median age at diagnosis was 67 years and 55.7% of patients were male. Almost 70% of patients had an index diagnosis date between 2013 and 2019. The median CCI score at index diagnosis date (based on comorbidities in the 365-day pre-index diagnosis period) was 1 and 10.9% of patients had a stem cell transplant on or after the index diagnosis date. The three most common comorbidities were hypertension (50.8%), renal failure (26.2%), and congestive heart failure (24.6%). Median follow-up period was 28 months. Treatment information for regimens used by ≥5% of patients for LOT1 is summarized in the Table. The most common treatment regimen for LOT1 was a proteasome inhibitor (PI), an alkylating agent, and a steroid (n=392, 23.2%); this combination was used for an average of 111 days. Of patients treated with this combination, the most common regimen was bortezomib, cyclophosphamide, and dexamethasone (VCd), used by 358 patients. Steroid only (dexamethasone for ≥90 days) regimens accounted for 16.4% and a PI ± steroid for 13.2% of LOT1. A limitation of the study is that assumptions were used to classify AL amyloidosis vs other types of amyloidosis. Conclusions: VCd is the most commonly used regimen in patients with newly-diagnosed AL amyloidosis. This is consistent with clinical guidelines and real world data from Europe (Palladini et al, EHA 2020), supporting this regimen as the current standard of care for treatment of patients with newly-diagnosed AL amyloidosis. Disclosures Dispenzieri: Celgene: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding. Hoffman:Loxo: Current equity holder in publicly-traded company; Celgene: Honoraria, Speakers Bureau. Wong:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Fortis: Research Funding; Roche: Research Funding; GSK: Research Funding; Amgen: Consultancy; Bristol Myers Squibb: Research Funding. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Abonour:BMS: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Honoraria, Research Funding; Celgene: Consultancy. D'Souza:Amgen, Merck, TenoBio: Research Funding; Akcea, Imbrium, Janssen, Pfizer: Consultancy. Lee:Janssen: Current Employment. Nair:Janssen: Current Employment. Potluri:SmartAnalyst Inc.: Current Employment. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Lam:Janssen: Current Employment. Mehra:Janssen: Current Employment.

Introduction: VRD (bortezomib, lenalidomide, dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone) are the two most commonly used triplet induction regimens in transplant eligible patients with multiple myeloma (MM). VCD is commonly used in patients with renal dysfunction at diagnosis. Given the variable results seen in head to head comparison of these (or similar) regimens to date, no definitive conclusion can be made on whether they are equivalent. This large CIBMTR registry study compares the outcomes with VRD vs. VCD induction therapy in patients undergoing upfront autologous stem cell transplant (ASCT). Methods: Patients were included if they underwent upfront ASCT for MM from January 2013 to December 2018 within 6 months of diagnosis, received VRD or VCD induction therapy and achieved at least a partial response pre-transplant. Of 1,135 patients, 914 patients received VRD and 221 received VCD therapy. Cox proportional hazards models were created for progression-free survival (PFS) and overall survival (OS). The following covariates were adjusted in the models: induction regimen (main effect), age, sex, race, performance score, hematopoietic cell transplant-comorbidity index (HCT-CI), estimated glomerular filtration rate (eGFR) at diagnosis, immunoglobulin subtype, cytogenetics, ISS stage, response status at transplant, melphalan dose, and maintenance therapy. Results: As shown in Table 1, patients in the VRD and VCD cohorts had similar age at transplant, adjusted HCT-CI scores, and distribution of high-risk cytogenetics. Patients in the VCD group were more likely to have renal impairment and ISS stage III disease. An eGFR (mL/min/1.73m2) at diagnosis < 60 was seen in 26% of VRD patients vs. 48% of VCD patients. ISS stage III was seen in 17% vs. 34% of patients, respectively. Treatment and Response: Pre-transplant response in the VRD cohort was: complete response (CR)- 17%, very good partial response (VGPR)- 48% and partial response (PR)- 35%. Response in the VCD cohort was: CR- 17%, VGPR- 42% and PR- 41%. Conditioning dose was melphalan 200 mg/m2 in 80% of patients receiving VRD vs. 69% in the VCD group. Post-transplant response was at least VGPR in 74% vs. 75% of patients, respectively. Maintenance in the VRD group was: lenalidomide based (+/- bortezomib)- 80%, bortezomib based- 5%, other-3% and none- 12% of patients. In the VCD group, maintenance was: lenalidomide based- 63%, bortezomib based- 11%, other- 1% and none- 24%. Survival: Patients receiving VRD induction had superior outcomes compared to VCD induction with median PFS from transplant of 44.6 (38.0-55.8) months vs 34.1 (25.8-44.7) months, p 0.004 respectively. Median OS was not reached for either group, with 5-year OS 79 (74-83)% for VRD and 60 (50-69)% for VCD, p <0.001. Univariate PFS and OS outcomes by induction regimen and eGFR at diagnosis are shown in Table 2 and Figure 1. Multivariate analysis is shown in Table 3. After adjusting for prognostic factors, there was no statistically significant difference between the two induction regimens, with hazard ratio (HR) for PFS in the VCD vs VRD group being 1.22 (95% CI: 0.96-1.55, p=0.10). ISS stage, cytogenetics, disease status prior to transplant, and maintenance were independent prognostic factors for PFS. Similarly, on multivariate analysis for OS, there was no statistically significant difference in the two groups, with HR for OS in VCD vs VRD group being 1.33 (95% CI: 0.93-1.92, p=0.12). ISS stage, cytogenetics, disease status prior to transplant, and maintenance were independent prognostic factors for OS. Conclusions: In patients with MM undergoing upfront transplant after VRD or VCD induction, no difference in outcomes was seen based on the induction therapy received after adjusting for other prognostic factors. As several MM patients with renal dysfunction are started on VCD, it is reassuring to see that VCD was not associated with inferior PFS, likely due to the eventual transition to maintenance therapy in the majority due to subsequent improvement of renal function. The use of maintenance treatment was uniformly associated with superior outcomes. Disclosures Sidana: Janssen: Consultancy. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Giralt:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinuum: Other: Advisory board, Research Funding; Amgen: Other: Advisory Board, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; OMEROS: Research Funding; SPECTRUM Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding; PFIZER: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensenn: Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Research Funding; MILTENYI: Research Funding; JAZZ Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Qazilbash:Janssen: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. D'Souza:Janssen: Consultancy; Akcea: Consultancy; Imbrium: Consultancy; Merck: Research Funding; Pfizer: Consultancy; Teneobio: Research Funding; Amgen: Research Funding.

Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma subtype with a 5-year survival of ~64%. While DLBCL is treated using immunochemotherapy (IC) with curative intent, 20%-40% of patients do not reach remission or relapse post IC. Clonal somatic mutations have been associated with aging, hematologic malignancies (predominately myeloid), and reduced OS in the general population. The objective of this study was to evaluate the association of clonal somatic mutations with event-free survival (EFS) and overall survival (OS). Methods We studied newly diagnosed DLBCL cases treated with IC who were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). Clinical and treatment data were abstracted from medical records and all patients were systematically followed for disease outcomes. Pre-treatment DNA was extracted from matched peripheral blood and paraffin-embedded tumor tissue, and whole exome sequencing was conducted at 100x coverage. From the peripheral blood, allele counts from GVCF files produced by HaplotypeCaller in GATK were extracted for 42 genes commonly associated with clonal hematopoiesis (e.g. DNMT3A, TET2, and ASXL1). Mutations were deemed clonal somatic if the population minor allele frequency was <0.5% in ExAC and had a variant allele fraction (VAF) that deviated from 0.5 using a binomial distribution test at p<0.001. Furthermore, mutations had to have a minimum alternate read count of at least 5 reads, a VAF greater than or equal to 10%, and met at least one of the following criteria: CAVA impact of "HIGH"; pathogenic/likely pathogenic per ClinVar; or reported in COSMIC at least 10 times. EFS was defined as time from diagnosis to disease progression, relapse, retreatment, or death due to any cause. The association of clonal somatic mutations with prognosis was estimated using Kaplan-Meier curves, and hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression. Associations were adjusted for age at diagnosis, sex, and the International Prognostic Index (IPI). Results The study consisted of 261 DLBCL patients treated with IC. The median age at diagnosis was 65 years (range 20-90) and 56% were male. With a median follow-up time of 5.1 years (range 0.1-15.0), there were 100 events and 80 deaths. A total of 17 (6.5%) patients had clonal somatic mutations, and16 patients were over the age of 60. A total of 8 (of 42) genes had clonal somatic mutations, with SF3B1, ASXL1, and TET2, being the most frequent (4 individuals per gene). VAFs ranged from 0.10 to 0.28 and none of the patients had multiple mutations. Additionally, the clonal somatic variants found in the peripheral blood were abscent in the tumor sample. Of the 17 patients with clonal somatic mutations, 12 had an event while 88 patients without a mutation had an event. In a univariate analysis, clonal somatic mutations were associated with inferior EFS (HR=2.55, 95% CI 1.39-4.68, p=0.002; Figure 1A). After adjusting for age, sex, and IPI, clonal somatic mutations remained associated with inferior EFS (HR=2.02, 95% CI 1.09-3.74, p=0.026). Clonal somatic mutations were also associated with inferior OS in the univariate analysis (HR=2.06, 95% CI 0.99-4.29, p=0.053), which attenuated after multivariate adjustment (HR=1.59, 95% CI: 0.76-3.34, p=0.22, Figure 1B). Although based on small numbers, mutations in SF3B1 were associated with inferior EFS (HR=3.25, 95% CI 1.16-9.12, p=0.025), but did not reach significance for OS (HR=2.56, 95% CI 0.78-8.38, p=0.120). Conclusions In this novel study of newly diagnosed DLBCL patients, clonal somatic mutations were identified in 6.5% of patients and were associated with inferior outcomes. Additional research is required at deeper sequencing to validate these findings and integration with tumor genomics is required to understand the prognosis of DLBCL patients with smaller clonal populations. Disclosures Shah: Dren Bio: Consultancy. Maurer:Celgene / BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Martin:Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Kite: Consultancy; Cellectar: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Teneobio: Consultancy. Witzig:AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding; MorphSys: Consultancy. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding. Novak:Celgene/BMS: Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding.