Citations

Patients who develop therapy-related myelodysplastic syndromes (t-MDSs) or acute myeloid leukemia (t-AML) following prior chemotherapy or an autologous hematopoietic cell transplant (HCT), have a poor prognosis. An earlier analysis of allogeneic HCT (n=868, 1990-2004) showed 5-year overall survival (OS) and disease free survival (DFS) were 22% and 21% (reference). Furthermore, older age, graft source other than a HLA-matched sibling or HLA well matched unrelated donor (URD), t-AML not in remission or advanced t-MDS, and poor risk cytogenetics were associated with worse outcomes. Modern supportive care and conditioning regimens including reduced intensity (RIC) regimens may have improved outcomes. Therefore we analyzed 1531 HCT for t-AML (n = 772) or t-MDS (n = 759) performed from 2000 to 2014. The median age at transplant was 52 (18-77) for t-AML and 59 (18-74) for t-MDS. Eleven percent of patient with t-AML and 24% of patient with t-MDS had a prior autologous transplant. A myeloablative regimen was used for conditioning in 61% of patients with t-AML and 49% of patients with t-MDS (Table 1). For t-AML, the 5-year non-relapse mortality (NRM) and relapse rates (RR) were 33% (95% confidence interval [CI], 30-36) and 43% (40-47), respectively. For t-MDS, the 5 year TRM and RR were 32% (29-36) and 46% (43-50), respectively. Five year DFS and OS were 24% (21-27) and 25% (22-28), respectively, for patients with t-AML. Five year DFS and OS were 21% (18-24) and 27% (23-31), respectively, for patients with t-MDS. In multivariate analysis, t-AML OS and DFS was worse for: previous autologous transplant, relapsed disease at HCT, intermediate or adverse cytogenetics, partially matched and cord blood grafts, and RIC. For t-MDS: age greater than 60, previous autologous transplant, very high IPSS score, and use of HLA-partially matched unrelated grafts. A significant minority of patients with t-AML and t-MDS can achieve long-term remission with allogeneic HCT, yet risks of both NRM and relapse are still excessive. Relapse is the major cause of treatment failure. Disclosures Metheny: Takeda: Speakers Bureau; Incyte: Speakers Bureau. Weisdorf:Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy. Kebriaei:Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria; Kite: Honoraria.

BACKGROUND: Historically, one in five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT), a life-threatening interstitial pneumonitis. The current treatment paradigm consists of prompt discontinuation of bleomycin, administration of corticosteroids, antibiotics, hospital admission, respiratory therapy, or intensive care. BPT represents a challenge for patients with HL as it not only impairs respiratory function, but also has negative impacts on clinical outcomes. A collection of a dozen studies suggest BPT has a mortality rate just short of 10% of patients who develop BPT. Given recent data on bleomycin omission with negative interim PET scan, we assessed changes in BPT rates and severity over the past 15 years. Overall, treatment protocol characterization and patient characteristics most responsive to BPT treatment are poorly understood. OBJECTIVES: In this study, we investigated the clinical impact and treatment strategies in patients with BPT. Our goals were to: 1) Identify HL patients in the last decades who developed BPT and identify risk factors for BPT, 2) evaluate the impact of BPT on long-term clinical outcomes, and 3) characterize patterns of treatment strategies among patients with HL who develop BPT. METHODS: A single-center, retrospective analysis was preformed using patient data from the Mayo Clinic Lymphoma Database (Rochester, MN) consisting of 1,299 patients diagnosed with HL. All patients were diagnosed between 2003-2018. Inclusion criteria included 1) newly diagnosed, biopsy proven HL, 2) upfront treatment with ABVD, 3) treatment was received at our institution. All patients were assessed for clinically relevant HL characteristics including stage of disease, presence of bulky disease, presence of B symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, BPT risk factors, and bleomycin treatment regimen. BPT was clinically defined as 1) Presence of pulmonary symptoms, 2) bilateral interstitial infiltrates on imaging, and 3) no evidence of infectious etiology. Patients treated in the "Early Era" (2000s) were compared to patients in the "Recent Era" (2010s). Comparison of continuous variables between BPT groups was assessed with Wilcox rank-sum test. OS and PFS were estimated via the Kaplan-Meier method. Approval of the protocol by the Mayo Clinic Institutional Review Board (IRB) was obtained and all patients were consented accordingly. RESULTS: One-hundred twenty six patients met the inclusion criteria for this study. Median follow-up for PFS and OS was 5.5 years (95%CI = 4.8-6.4) and 5.8 years (95%CI = 5.0-7.0), respectively. The 10-year OS and PFS among all patients were 85.1% (95%CI = 77.8-93.1) and 86.3% (95%CI = 80.1-93.0), respectively. Forty-seven patients (37% of all patients) met criteria for BPT. The estimated 10-year OS for BPT and non-BPT patients were 74.7% (95%CI = 61.8-90.5) and 91.7% (95%CI = 83.9-100.0), respectively. The estimated 10-year PFS for BPT and non-BPT patients were 84.7% (95%CI = 74.8-95.8) and 87.0% (95%CI = 79.1-95.8), respectively. In univariable analysis, BPT negatively impacted OS (HR=3.6, 95%CI: 1.2-10.6). However, bleomycin omission did not impact OS (HR=1.3, 95%CI=0.5-3.7). BPT-mortality was 17%. In multivariable analysis, BPT was not significantly associated with OS after adjusting for baseline characteristics (HR=3.0, 95%CI=0.9-9.9). Patients were older (median: 46 vs 33 years) and received less bleomycin (median: 107 vs 215 units) compared to non-BPT patients. BPT was most often managed with bleomycin omission with 59% of patients (74 of 126 patients) having omitted bleomycin at some point during treatment. Patients treated in the "Recent Era" (2010s) had lower BPT rates (28% vs 48%), mortality (10% vs 21%), bleomycin dose (143 vs 204 units), and bleomycin cycles (7 vs 12 cycles), yet higher prophylactic bleomycin omission (59% vs 8%) compared to "Early Era" (2000s). Patients treated in the Recent Era compared to Early Era had a reduction of BPT treatment with steroids, hospital admission, respiratory therapy, and ICU admission by 12%, 22%, 14%, 13%, respectively. CONCLUSION: Overall, our data suggests BPT continues to impact OS in HL patients treated with ABVD, however BPT treatment is decreasing as management changed in recent years. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding.

Purpose: Multiple myeloma (MM) is a plasma cell (PC) malignancy with an increasing incidence in the US. Epidemiological studies demonstrate a 2-3 fold higher incidence of the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and MM with a ~4-year younger age of onset among African Americans (AA) compared to European Americans (EAs) (Fonseca, Leukemia, 2017). With equal access to care, AAs have better overall survival compared to EAs (Waxman, Blood, 2010). This disparity may be explained by ancestral-associated genetic predisposition of AAs to development of monoclonal gammopathies and to specific acquired, cytogenetically-defined subtypes. Using calculated genetic ancestry data, we have previously identified a higher prevalence of IgH translocations t(11;14), t(14;16) and t(14;20) in individuals with >80% African ancestry (Baughn, BCJ, 2018). Since SNP rs9344 encoding the CCND1 870G>A polymorphism has been reported in association with increased risk of t(11;14) (Weinhold, Nature Genetics, 2013), we investigated whether rs9344 correlates with African ancestry and with t(11;14) in our cohort of patients with plasma cell dyscrasias. Methods: We studied 898 patients with monoclonal gammopathies who had undergone uniform testing to identify MM-specific cytogenetic abnormalities. DNA from bone marrow samples was genotyped on the Precision Medicine Research Array and biogeographical ancestry was assessed using the Geographic Population Structure Origins tool (Elhaik, Nat Commun, 2014). Plasma cell proliferative disorder FISH of immunoglobulin (cIg)-stained positive plasma cells was performed as described (Baughn, BCJ, 2018). Individuals were divided into three ancestral groups: 1. EAs (<0.1% African ancestry and <30% Asian ancestry); 2. AAs (> 80% African ancestry); and 3. Other. Chi-squared test was used to determine the overall comparison between the 3 ancestral groups and also between ancestral groups 1 vs 2, and 2 vs 3 using pairwise comparison. All tests were two-sided with alpha level set at 0.05 for overall statistical significance. Pairwise comparison was considered statistically significant when p<0.025 based on Bonferroni method for multiple comparisons. Results: We identify increased risk of development of either a t(11;14), t(14;16) or t(14;20) in AAs (48.8%) compared to EAs (33.6%) (p-value=0.0051). To explore the genetic basis of increased t(11;14) specifically (37.4% AAs vs. 27.3% p-value=0.049), we evaluated the frequency of the G risk allele of rs9344 in relation to African ancestry. The frequency of the G risk allele was higher in AAs (0.81) compared to EAs (0.59) (p-value <0.0001) and also higher in t(11;14) cases (0.73) compared to non-t(11;14) controls (0.58) (p-value <0.0001). A multivariate model identified only rs9344 as significantly associated with t(11;14) after adjusting for age, gender and race group suggesting that it plays a role in the development of t(11;14) (p-value <0.001 for GG, p-value=0.005 for AG). To test if these results are replicable, we studied the MMRF CoMMpass cohort. This cohort includes individuals with newly diagnosed MM along with self-report race information and translocation data from long insert whole genome sequencing. Although t(11;14) was not enriched in self-reported Black individuals from this cohort (17.5% Black vs. 20.4% White, p-value=0.47), there was association between the rs9344 and self-reported Black race (p-value <0.0001) and with the presence of t(11;14) when the t(11;14) was analyzed by long insert whole genome sequencing (p-value=0.0001). Conclusions: To our knowledge, this study includes the largest group of African individuals with an abnormal plasma cell clone along with uniformly collected FISH, genotyping and ancestry data. We have identified in this diverse population the association of the CCND1 870G>A polymorphism (rs9344) with African ancestry and with t(11;14) suggesting that it plays a role in the development of t(11;14) plasma cell dyscrasias. Disclosures Elhaik: DNA Diagnostics Center: Consultancy. Baird:DNA Diagnostics Center: Employment. Cerhan:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; NanoString: Research Funding. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy. Dispenzieri:Alnylam: Research Funding; Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding.

Although some data (Scott, JCO 2017) suggest that myeloablative conditioning (MAC) is preferred for allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), these data were not informed by analysis of disease specific risk factors. We analyzed AML and MDS HCT outcomes stratified by the disease risk index (DRI) in order to identify the preferred transplant conditioning intensity (reduced-intensity conditioning [RIC] vs. MAC). In this large CIBMTR registry study we identified 4387 adult patients (age 40-65 years) who received HCT for AML (68%) or MDS (32%) between 2009 and 2015. DRI was stratified as low/ intermediate risk (1539 MAC and 999 RIC) and high/ very high risk (1121 MAC and 728 RIC). Examining the low/ intermediate risk DRI cohort (Table), RIC was associated with lower risk of TRM (HR=0.74, 95% CI 0.62-0.88; p<0.001) but significantly higher risk of relapse (HR=1.54, 95% CI 1.35-1.76; p<0.001). As a result, RFS in this cohort was significantly worse with RIC (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/ very high risk DRI cohort, RIC resulted in similar TRM (HR=0.83, 95% CI 0.68-1.00; p=0.051) but again significantly higher risk of relapse (HR=1.23, 95% CI 1.08-1.41; p=0.002). RFS in high/ very high risk DRI cohort was similar between RIC and MAC. Adjusted outcome curves for the 3 endpoints are shown in the Figure. In this large study of HCT for AML or MDS stratified by DRI, RIC was independent predictor of lower TRM, but significantly higher risk of relapse. The MAC was an independent predictor of lower relapse in both low/ intermediate and high/very high DRI groups. However, MAC only resulted in RFS benefit in the low/ intermediate group where the magnitude of impact on relapse was not offset by the higher TRM. In adults with AML or MDS aged 40-65 years, these data support MAC as the preferred conditioning intensity for low/ intermediate risk DRI, whereas MAC does not provide significant benefit in those with high/ very high risk DRI. Safer, yet still potent MAC regimens could benefit this higher risk group. Disclosures Bejanyan: Kiadis Pharma: Other: advisory board. Brunstein:Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria; Pfizer: Honoraria; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

Introduction: AML patients with intermediate or high-risk features often undergo allogeneic hematopoietic cell transplantation (alloHCT) during first complete remission (CR). The 2017 European LeukemiaNet guidelines for AML specify categories of CR: both with and without count recovery (CR vs. CRi) and with and without measurable residual disease (MRD). Previous smaller retrospective studies have suggested poorer survival outcomes after alloHCT for patients with responses less than CR. Methods: Eligible cases were determined using the CIBMTR registry. Each had AML in CR1, was ≥ 18 years, and underwent alloHCT between January 1, 2007 and December 31, 2015. MRD was defined based on the answers to qualitative questions on standard clinical reporting forms that ask if the patient is in either molecular or cytogenetic remission and if disease is detected in marrow by flow cytometry at time of HCT. The primary outcome was overall survival (OS), and secondary outcomes were non-relapse mortality (NRM), relapse and disease-free survival (DFS). The Kaplan-Meier method was used to estimate survival and cumulative incidence function was used to estimate relapse and NRM. Multivariable analysis (MVA) was performed using the Cox proportional hazards model to adjust for patient-, disease-, and transplant-related factors. Adjusted probabilities of DFS and OS, adjusted cumulative incidence curves of NRM and relapse were generated from final Cox regression models stratified on CR vs. CRi and weighted averages of covariate values using pooled sample proportion as weight function. Results: We identified 2492 cases (CR, n=1799; CRi, n=693). The main effect variable (CR vs. CRi) was missing in 262 additional patients; these patients were excluded when univariate analysis confirmed no significant associations, suggesting a random distribution of missing data. Patient characteristics are summarized in Table 1. Compared with patients with CR, patients with CRi were more likely to have a Karnofsky score <90 (38% vs. 31%) and an HCT-CI score 3+ (47% vs. 40%). Other variables were well matched between the groups. MVA demonstrated significantly increased likelihood of mortality in patients with CRi compared to those with CR with hazard ratio (HR) 1.27; 95% confidence interval (CI) (1.13-1.43) (Figure 1A). Other covariates significantly associated with shorter OS included older age, poor-risk cytogenetics, lower Karnofsky score, higher HCT-CI score, and higher white blood cell count at diagnosis. The adjusted OS probabilities at 5 year post-HCT accounted for factors from MVA model are 50% (95%CI 47-52) for patients with CR and 43% (95%CI 39-47) for patients with CRi. CRi was also associated with significantly increased NRM [HR 1.33, 95%CI(1.11-1.59)] with only a trend in increased relapse [HR 1.15, 95% CI(0.99-1.34), p=0.07] resulting in inferior DFS [HR 1.20, 95%CI(1.07-1.35)]. MRD status was available in a subset of 2297 patients, and pairwise comparison demonstrated that presence of MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD (Figure 1B). Pairwise interaction between the main effects (CR vs. CRi) and MRD status were tested with no significant findings at a level of 0.01, demonstrating that the effects of incomplete count recovery and MRD are independent of each other. Conclusions: Analysis of this large CIBMTR cohort demonstrates that survival outcomes differ among AML patients nominally in CR at the time of alloHCT. Patients with CRi and/or MRD have significantly shorter OS after alloHCT compared to those in CR, as well as shorter DFS and higher NRM. Further studies should focus on limiting NRM and reducing relapse to optimize post-alloHCT outcomes for patients with responses less than CR. Disclosures Percival: Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Jazz: Consultancy; Pfizer: Honoraria; Amgen: Research Funding; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Incyte: Research Funding; Pharmacyclics: Consultancy.

Applications in early-phase cancer trials have motivated the development of many statistical designs since the late 1980s, including dose-finding methods, futility screening, treatment selection, and early stopping rules. These methods are often proposed to address the conventional cytotoxic therapeutics for neoplastic diseases and cancer. Recent advances in precision medicine have motivated novel trial designs, most notably the idea of master protocol (eg, platform trial, basket trial, umbrella trial, N-of-1 trial), for the evaluation of molecularly targeted cancer therapies. In this article, we review the concepts and methodology of early-phase cancer trial designs with a focus on dose finding and treatment screening and put these methods in the context of platform trials of molecularly targeted cancer therapies. Because most cancer trial designs have been developed for cytotoxic agents, we will discuss how these time-tested design principles hold relevance for targeted cancer therapies, and we will delineate how a master protocol may serve as an efficient platform for safety and efficacy evaluations of novel targeted therapies.

Recent advances in biotechnology and cancer genomics have afforded enormous opportunities for development of more effective anticancer therapies. A key thrust of this modern drug development paradigm is successful identification of predictive biomarkers that can distinguish patients who might be sensitive to new targeted therapies. To respond to this challenge, a number of phase III cancer trial designs integrating biomarker-based objectives have been proposed and implemented in oncology drug development. In this article, we provide an updated review of commonly used biomarker-based randomized clinical trial designs, with a particular focus on design efficiency. When the efficacy of a new therapy may be limited to a biomarker-defined subgroup, the choice of an appropriate randomized clinical trial design should be guided by the strength of the biomarker’s credentials. If compelling evidence indicates that a targeted therapy is beneficial only in a particular biomarker-defined subgroup, an enrichment design should be used. If there is strong evidence that the treatment is likely to be more beneficial in the biomarker-positive patients but a meaningful benefit is also possible in the biomarker-negative patients, then a properly powered biomarker-stratified design (eg, a subgroup-specific or Marker Sequential Test strategy) would provide the most rigorous determination of the sensitive populations. If the evidence supporting the predictive value of the biomarker is weak and the treatment is expected to work in the overall population, then a fallback design could be used. Careful selection of an appropriate phase III design strategy that integrates evaluation of a new anticancer therapy and its companion diagnostic is critical to the success of precision medicine in oncology.

AbstractBackgroundInappropriate sinus tachycardia (IST) remains a clinical challenge because patients often are highly symptomatic and not responsive to medical therapy.ObjectiveTo study the safety and efficacy of stellate ganglion (SG) block and cardiac sympathetic denervation (CSD) in patients with IST.MethodsTwelve consecutive patients who had drug‐refractory IST (10 women) were studied. According to a prospectively initiated protocol, five patients underwent an electrophysiologic study before and after SG block (electrophysiology study group). The subsequent seven patients had ambulatory Holter monitoring before and after SG block (ambulatory group). All patients underwent SG block on the right side first, and then on the left side. Selected patients who had heart rate reduction ≥15 beats per minute (bpm) were recommended to consider CSD.ResultsThe mean (SD) baseline heart rate (HR) was 106 (21) bpm. The HR significantly decreased to 93 (20) bpm (P = .02) at 10 minutes after right SG block and remained significantly slower at 97(19) bpm at 60 minutes. Left SG block reduced HR from 99 (21) to 87(16) bpm (P = .02) at 60 minutes. SG block had no significant effect on blood pressure or HR response to isoproterenol or exercise (all P > .05). Five patients underwent right (n = 4) or bilateral (n = 1) CSD. The clinical outcomes were heterogeneous: one patient had complete and two had partial symptomatic relief, and two did not have improvement.ConclusionSG blockade modestly reduces resting HR but has no significant effect on HR during exercise. Permanent CSD may have a modest role in alleviating symptoms in selected patients with IST.