Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

Assessing the accuracy of multiparametric MRI to predict clinically significant prostate cancer in biopsy naïve men across racial/ethnic groups.

INTRODUCTION: The Prostate Imaging Reporting and Data System (PIRADS) has shown promise in improving the detection of Gleason grade group (GG) 2-5 prostate cancer (PCa) and reducing the detection of indolent GG1 PCa. However, data on the performance of PIRADS in Black and Hispanic men is sparse. We evaluated the accuracy of PIRADS scores in detecting GG2-5 PCa in White, Black, and Hispanic men. METHODS: We performed a multicenter retrospective review of biopsy-naïve Black (n = 108), White (n = 108), and Hispanic (n = 64) men who underwent prostate biopsy (PB) following multiparametric MRI. Sensitivity and specificity of PIRADS for GG2-5 PCa were calculated. Race-stratified binary logistic regression models for GG2-5 PCa using standard clinical variables and PIRADS were used to calculate area under the receiver operating characteristics curves (AUC). RESULTS: Rates of GG2-5 PCa were statistically similar between Blacks, Whites, and Hispanics (52.8% vs 42.6% vs 37.5% respectively, p = 0.12). Sensitivity was lower in Hispanic men compared to White men (87.5% vs 97.8% respectively, p = 0.01). Specificity was similar in Black versus White men (21.6% vs 27.4%, p = 0.32) and White versus Hispanic men (27.4% vs 17.5%, p = 0.14). The AUCs of the PIRADS added to standard clinical data (age, PSA and suspicious prostate exam) were similar when comparing Black versus White men (0.75 vs 0.73, p = 0.79) and White versus Hispanic men (0.73 vs 0.59, p = 0.11). The AUCs for the Base model and PIRADS model alone were statistically similar when comparing Black versus White men and White versus Hispanic men. CONCLUSIONS: The accuracy of the PIRADS and clinical data for detecting GG2-5 PCa seems statistically similar across race. However, there is concern that PIRADS 2.0 has lower sensitivity in Hispanic men compared to White men. Prospective validation studies are needed.

The Effect of Obesity on Operating Room Utilization in Breast Surgery.

BACKGROUND: The current obesity epidemic is associated with increased health care costs associated with comorbidities such as diabetes and heart disease as well as postoperative complications. However, the effect of obesity on operating room (OR) utilization, especially in common breast procedures, has not been completely evaluated. Our study is the first to examine the effect of patient obesity on operative time (OPT) for common breast procedures. METHODS: The American College of Surgeons National Surgical Quality Improvement Project databases for 2010-2018 were searched for this retrospective review. Patients undergoing common breast operations (lumpectomy, lumpectomy with sentinel lymph node biopsy (SLNB) (+/- injection), lumpectomy and axillary lymph node dissection (ALND), simple mastectomy, mastectomy with SLNB (+/- injection), and mastectomy with ALND) were filtered out by Current Procedural Terminology code and divided into three groups based on their body mass index (BMI) and weight. Using the two-sample t-test, OPT for the procedures was compared among the lowest and highest BMI and weight categories. We also used a linear regression t-test to demonstrate that for every unit increase in BMI, there was a corresponding increase in OPT for each procedure. RESULTS: When the lowest and highest BMI and weight groups were compared, significant differences in OPT (P < 0.0001) were seen for each of the procedures. Numerous factors that could affect the complexity of surgery and thus OR time were identified. The correlation between BMI and weight and OPT remained significant after controlling for these variables. The differences between the highest and lowest BMI groups were most pronounced for higher complexity procedures, such as lumpectomy with ALND and mastectomy with ALND, with average operating times increasing by 18.2 min and 18.6 min, respectively, for patients with a higher BMI. CONCLUSIONS: Patient BMI and weight significantly affect OPT for common breast procedures. Therefore, patient BMI should be taken into account to improve OR scheduling.

A comparative effectiveness analysis of the PBCG vs. PCPT risks calculators in a multi-ethnic cohort.

BACKGROUND: Predictive models that take race into account like the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPT RC) and the new Prostate Biopsy Collaborative Group (PBCG) RC have been developed to equitably mitigate the overdiagnosis of prostate specific antigen (PSA) screening. Few studies have compared the performance of both calculators across racial groups. METHODS: From 1485 prospectively recruited participants, 954 men were identified undergoing initial prostate biopsy for abnormal PSA or digital rectal examination in five Chicago hospitals between 2009 and 2014. Discrimination, calibration, and frequency of avoided biopsies were calculated to assess the performance of both risk calculators. RESULTS: Of 954 participants, 463 (48.5%) were Black, 355 (37.2%) were White, and 136 (14.2%) identified as Other. Biopsy results were as follows: 310 (32.5%) exhibited no cancer, 323 (33.9%) indolent prostate cancer, and 321 (33.6%) clinically significant prostate cancer (csPCa). Differences in area under the curve (AUC)s for the detection of csPCa between PCPT and PBCG were not statistically different across all racial groups. PBCG did not improve calibration plots in Blacks and Others, as it showed higher levels of overprediction at most risk thresholds. PCPT led to an increased number of avoidable biopsies in minorities compared to PBCG at the 30% threshold (68% vs. 28% of all patients) with roughly similar rates of missed csPCa (23% vs. 20%). CONCLUSION: Significant improvements were noticed in PBCG's calibrations and net benefits in Whites compared to PCPT. Since PBCG's improvements in Blacks are disputable and potentially biases a greater number of low risk Black and Other men towards unnecessary biopsies, PCPT may lead to better biopsy decisions in racial minority groups. Further comparisons of commonly used risk calculators across racial groups is warranted to minimize excessive biopsies and overdiagnosis in ethnic minorities.

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. Design, Setting, and Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). Main Outcomes and Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). Conclusions and Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.

Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin.

OBJECTIVE: A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. DESIGN: We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. RESULTS: At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. CONCLUSIONS: We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. TRIAL NUMBER: NCT00468910.

Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579).

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m(2) day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.

Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis.

IMPORTANCE: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. OBJECTIVE: To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. INTERVENTIONS: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. MAIN OUTCOMES AND MEASURES: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. RESULTS: Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis.

BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group. METHODS: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests. FINDINGS: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05). INTERPRETATION: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated. FUNDING: None.

A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era.

We investigated a recent (January 1999 to December 2009) cohort of 95 elderly Hodgkin lymphoma subjects. At diagnosis, median age was 67 years (range, 60-89 years), whereas 61% had significant comorbidity, 26% were unfit, 17% had a geriatric syndrome, and 13% had loss of activities of daily living. Overall response rate to therapy was 85%, whereas incidence of bleomycin lung toxicity was 32% (with associated mortality rate, 25%). With 66-month median follow-up, 2-year and 5-year overall survival were 73% and 58%, respectively (advanced-stage, 63% and 46%, respectively). Most International Prognostic Score factors were not prognostic on univariate analyses, whereas Cox multivariate regression identified 2 risk factors associated with inferior overall survival: (1) age more than 70 years (2.24; 95% CI, 1.16-4.33, P = .02) and (2) loss of activities of daily living (2.71; 95% CI, 1.07-6.84, P = .04). Furthermore, a novel survival model based on number of these risk factors (0, 1, or 2) showed differential 2-year OS of 83%, 70%, and 13%, respectively (P < .0001) and 5-year OS of 73%, 51%, and 0%, respectively (P < .0001).

Timing of initial antibiotic treatment for febrile neutropenia in the emergency department: the need for evidence-based guidelines.

Guidelines for the treatment of febrile neutropenia (FN) universally recommend the prompt initiation (<60 minutes) of antibiotic therapy for patients with this complication presenting to medical settings. Unfortunately, administration delays exist in emergency departments where patients with FN frequently seek care. Future guidelines should be based on investigations that clearly indicate the effectiveness of rapid antibiotic therapy. If definitive investigations identify an optimal time period for the initial administration of antibiotics for patients with FN, administrative efforts will be developed to improve the emergency department care of these critically ill patients with cancer.

Recruitment strategy cost and impact on minority accrual to a breast cancer prevention trial.

BACKGROUND: Recruitment of minorities to cancer prevention trials is difficult and costly. Early-phase cancer prevention trials have fewer resources to promote recruitment. Identifying cost-effective strategies that can replace or supplement traditional recruitment methods and improve minority accrual to small, early-phase cancer prevention trials are of critical importance. PURPOSE: To compare the costs of accrual strategies used in a small breast cancer prevention trial and assess their impact on recruitment and minority accrual. METHODS: A total of 1196 potential subjects with a known recruitment source contacted study coordinators about the SOY study, a breast cancer prevention trial. Recruitment strategies for this study included recruitment from within the Northwestern University network (internal strategy), advertisements placed on public transportation (Chicago Transit Authority (CTA)), health-related events, media (print/radio/television), and direct mail. Total recruitment strategy cost included the cost of study personnel and material costs calculated from itemized receipts. Incremental cost-effectiveness ratios (ICERs) were calculated to compare the relative cost-effectiveness of each recruitment strategy. If a strategy was more costly and less effective than its comparator, then that strategy was considered dominated. Scenarios that were not dominated were compared. The primary effectiveness measure was the number of consents. Separate ICERs were calculated using the number of minority consents as the effectiveness measure. RESULTS: The total cost of SOY study recruitment was US$164,585, which included the cost of materials (US$26,133) and personnel (US$138,452). The internal referral strategy was the largest source of trial contacts (748/1196; 63%), consents (107/150; 71%), and minority consents (17/34; 50%) and was the most expensive strategy (US$139,033). CTA ads generated the second largest number of trial contacts (326/1196; 27%), the most minority contacts (184/321; 57%), and 16 minority consents (16/34; 47%), at a total cost of US$15,562. The other three strategies yielded many fewer contacts and consents. The methods of health events, CTA ads, and the internal strategy showed some evidence of cost-effectiveness (ICER: US$581, US$717, and US$1524, respectively). The CTA strategy was the most cost-effective strategy for minority accrual (ICER: US$908). LIMITATIONS: Recall bias may have limited the accuracy of estimated time spent on recruitment by study personnel. Also, costs spent specifically on minority accrual were unobtainable; results may not be generalizable to other settings; and cost-effectiveness data for the methods of media, health events, and direct mail should be interpreted with caution since these methods generated few consents. CONCLUSIONS: Public transportation ads have the potential to generate numerous minority contacts and consents at a reasonable cost within an urban setting. Combined with traditional methods of recruitment, this method can lead to timelier study completion and increased minority accrual. Future research should prospectively track recruitment and costs in order to better assess the cost-effectiveness of recruitment methods used to target minority populations.

A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases.

INTRODUCTION: Palbociclib is highly efficacious and well tolerated in hormone-receptor positive (HR+) metastatic breast cancer (BC) but its activity for HER2+ BC with brain metastases (BM) is unknown. METHODS: In a single-arm phase II study we evaluated palbociclib with trastuzumab for patients with HER2+ MBC and BM. The primary endpoint was BM response rate. Circulating tumor DNA (ctDNA) was evaluated at baseline, and in a subset of patients at cycle 3 and progression. We also retrospectively identified additional patients with metastatic BC, active BM, and a ctDNA assessment prior to therapy for BM. RESULTS: Twelve patients with HER2+ MBC were enrolled, 4 with HR+ and 8 with HR- disease. No responses were seen. Best response was stable disease for 6 patients and progressive disease for 6 patients. The median PFS was 2.2 months, interquartile range (IQR) was 1.56 to 3.63 months. The median OS was 13.1 months and IQR was 9.4 to 23.8 months The CNS was the primary site of progression for all patients. The median variant allele fraction (VAF) of the dominant variant in each patient was 0.18% (interquartile range [IQR] 0.12%-0.47%) with a median number of somatic alterations of 1. We additionally evaluated ctDNA results from 26 patients with BC and active BM, among whom the median VAF was 11.8% (IQR 3.9%-27.3%) with a median number of alterations was 6 (IQR 4-9). Notably, progressive systemic disease was significantly less frequent in the trial cohort compared with additional retrospectively identified patients (8% vs. 81%). CONCLUSION: Palbociclib did not demonstrate activity in HER2+ MBC with BM. Patients with progressive BM but stable, responding, or absent systemic disease have low VAF and number of alterations detected by ctDNA analysis from blood.

Multicenter phase 2 study of romidepsin plus lenalidomide for previously untreated peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) are associated with poor prognosis when treated with cytotoxic chemotherapy. We report the findings of a phase 2 study evaluating a chemotherapy-free combination of romidepsin plus lenalidomide as initial treatment for patients with PTCL who were aged >60 years or noncandidates for chemotherapy. Treatment was initiated with romidepsin 10 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg taken orally from days 1 to 21 of 28-day cycle for up to 1 year. The primary objective was overall response rate (ORR). Secondary objectives included safety and survival. The study enrolled 29 patients with a median age of 75 years, including 16 (55%) angioimmunoblastic T-cell lymphoma (AITL), 10 (34%) PTCL- not otherwise specified, 2 ATLL, and 1 EATL. Grade 3 to 4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%), and anemia (28%). Grade 3 to 4 nonhematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), and infection (10%). At median follow-up of 15.7 months, 23 patients were evaluable and received a median treatment of 6 cycles. The ORR was 65.2% with complete response (CR) at 26.1%, including 78.6% ORR and 35.7% CR for AITL. Median duration of response was 10.7 months, with 27.1 months for patients achieving CR. The estimated 2-year progression-free survival was 31.5%, and 2-year overall survival was 49.5%. This study provides the first demonstration that the biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as #NCT02232516.

Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial.

BACKGROUND: Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide. METHODS: In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m(2) intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with ClinicalTrials.gov, number NCT00278525. FINDINGS: Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04-∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted. INTERPRETATION: Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed. FUNDING: None.

Prediction of menopausal status from estrogen-related gene expression in benign breast tissue.

The utility of archived paraffin-embedded breast tissue for risk-related research is often limited by missing menopausal status data. We tested the hypothesis that breast tissue gene expression patterns can improve menopausal stratification. Healthy high-risk participants in a clinical trial underwent breast random fine-needle aspiration (rFNA); 100 ng of RNA extracted from rFNA samples was reverse-transcribed; the expression of 28 estrogen-responsive genes was evaluated by real-time PCR. True menopausal status (TMS) was determined by measurement of plasma hormones and age. Differentially expressed genes and age were analyzed by logistic regression. The accuracy of the menopause prediction was assessed using receiver-operator characteristic (ROC) analysis, and validated in a second independent set of 44 women. In the test set, postmenopausal women demonstrated significantly lower expression of five estrogen-responsive genes: GREB1, PGR, TFF1, PRLR, and CCND1 (adjusted P < 0.03 for all). In the validation set, three of these genes were expressed at lower levels in postmenopausal women (GREB1, PGR, TFF1) (adjusted P < 0.06 for all). In the test set, the modeled area under the curve (AUC) for age and three genes was higher than for age >50 alone (AUC 96.1% vs. 87.2%, P = 0.002), and remained better than for age alone in the validation set (99.0% vs. 95.5%, P = 0.16). Estrogen-related gene expression in breast specimens can be used to improve menopausal classification, reducing the biological noise related to menopause in studies that seek to identify RNA or protein risk biomarkers in archived breast samples.

Pilot neoadjuvant trial in HER2 positive breast cancer with combination of nab-paclitaxel and lapatinib.

Lapatinib, a dual kinase inhibitor against epidermal growth factor receptor (EGFR) and human epidermal receptor two (HER2) has shown efficacy in treating HER2 positive breast cancer. Nanoparticle albumin bound (nab) paclitaxel was developed to reduce toxicities from paclitaxel and improve its efficacy. Thirty patients with stage I-III HER2 positive breast cancer were treated in the neoadjuvant setting with lapatinib 1,000 mg/day and nab-paclitaxel 260 mg/m(2) every 3 weeks for four cycles. The primary end point of the trial was clinical response rate (cRR) with secondary end points including pathologic complete response rate (pCR), tolerability of the combination, and marker response. The cRR was 82.8% (24 patients) with six (20.7%) patients having complete clinical response, 18 (62.1%) having partial clinical response, and five (17.2%) stable disease. A pCR was observed in five of the 28 patients (17.9%). The most frequent grade 2 toxicities were neuropathy in nine patients (30%), fatigue in seven patients (23.3%), rash in 11 patients (36.7%), and bone pain in 10 patients (33.3%). There was no significant drop in the left ventricular ejection fraction (LVEF). Of the tissue markers examined, we were not able to find a predictor of response. The combination of lapatinib and nab-paclitaxel was well tolerated and provided good efficacy in women with HER2 positive breast cancer. This combination offers an alternative non-anthracycline-containing regimen for women with HER2 positive breast cancer.

Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up.

We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 µg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853.