ALBERT

Description: Abstract 4519 Background: Despite advances in our understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) coupled with availability of more effective therapies, it remains an incurable disease. Combining cytoreduction from high-dose (chemo- or chemoradio-) therapy with adoptive immunotherapy forms the basis of an autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy. However, when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT, conflicting results have been reported. Accordingly, we performed a systematic review of published studies comparing auto-auto HCT with auto-allo HCT in patients with newly diagnosed MM. Methods: A systematic search of MEDLINE thru Nov 5, 2011, and pertinent conference proceedings, was conducted. Included studies allocated newly diagnosed MM patients to auto-allo HCT if an HLA-matched sibling donor was available versus auto-auto if sibling donor was not available (biologic randomization). Independent, dual data extraction was performed. Pooling of data from similar outcomes was done using the random-effects model. Results: Our search identified 152 publications, of which five (manuscript=four, abstract=one) met inclusion criteria. The five included trials enrolled 1538 patients (auto-allo=565, auto-auto=973). At least a very good partial response was assessed in one study (522 patients) and did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87–1.09), p=0.66]; but complete remission, assessed in five studies (1130 patients), was higher in the auto-allo HCT arm [RR(95% CI) =1.65 (1.25–2.19), p=0.0005]. Event-free survival did not differ among auto-allo HCT group versus auto-auto HCT group on per-protocol analysis [hazard ratio (HR) (95% CI) = 0.78 (0.58–1.05)), p=0.11] of three trials (409 patients), or ITT analysis [HR(95% CI) = 0.83 (0.60–1.15), p=0.26] in three trials (1229 patients). Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR(95% CI) = 0.88 (0.33–2.35), p=0.79] in two trials (214 patients), or by ITT [HR(95% CI) = 0.80 (0.48–1.32), p=0.39] analysis in three trials (1229 patients). Non-relapse mortality (NRM) was worse with auto-allo HCT [RR(95%CI) = 3.55 (2.17–5.80), p

Description: Introduction Patients older than 70 years with acute myeloid leukemia (AML) are generally considered to have poor prognosis. As a result, many patients are routinely not offered active treatment and/or are referred to palliative hospice care based on the assumption that their expected survival will be well below 6 months. However, a substantial number of patients live beyond 6 months indicating that management decisions ought to be individualized taking into considerations patients' preferences about benefits and harms of treatments and estimated survival prognostication. Methods Using large Moffitt AML database we identified all consecutive patients (n=305) with AML older than 70 who received high or low intensity chemotherapy to develop a multiple logistic regression model to assess the probability of survival at 12 month since diagnosis of AML. Patients who were censored prior to 12 months were considered not eligible (n=300). The final model was determined by the backward elimination method. We assessed discrimination of the model by performing ROC (receiver operating characteristic) analysis and calibration by using Hosmer-Lemeshow (H-L) goodness-of-fit test. We also performed regret-based decision curve analysis (DCA) to compare three decision strategies over all possible patient's preferences: "Do Not Treat/Refer to Hospice" vs. "Treat All" with chemotherapy vs. "Use Model" to guide decision about treatment (to treat or not to treat depending on the survival estimates in a relationship to the patient's preferences). In DCA, the preferences are captured by determining the threshold probability (T) of disease (AML) outcome at which a patient is indifferent between benefits (B) and harms (H) of treatment according to: T=1/[1+B/H]. The T can be elicited by asking a simple question concerning regret of omission (failure to benefit) vs. regret of commission (causing unnecessary harm): "how many more times would you regret not receiving a health intervention that could improve disease outcome (survival) compared with unnecessary and potentially harmful administration of treatments?" (http://bmcmedinformdecismak.biomedcentral.com/articles/10.1186/1472-6947-10-51) Based on our previous study, we assumed that if treatment is administered, it is associated with hazard ratio (HR) of death reduction by 0.35 in the baseline analysis. The best strategy is the one associated with the least amount of regret. Results The prognostic model consisted of the following variables; cytogenetic status, ECOG PS, type of AML (De Novo vs. Secondary), and WBC level. A total of 112 patients (37%) survived at least 12 months. The model has good discrimination (area under curve=0.80) and excellent calibration [HL (chi2)=4.3; p=0.83] (Fig 1). DCA analysis showed that strategy "Do Not Treat/Refer to Hospice" was always inferior to the strategies "Treat" vs. "Use Model" (Fig 2). The decision strategy "Treat All" patients with AML older than 70 was best strategy for the threshold probability ranging from 1 to 46%. That is, as long as the patient would regret of not receiving benefit of treatment between 99 to 1.17 more than unnecessary receiving potentially harmful chemotherapy treatment, "Treat All" represents the best decision strategy for the management of elderly patients with AML. If the harms of treatments are more important to the patient (B/H

Description: Background: Despite availability of novel agents to treat mantle cell lymphoma (MCL), the disease remains incurable with standard therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) is generally offered in the setting of relapsed or refractory disease. Reduced intensity conditioning (RIC) allo-HCT has expanded availability of the procedure for patients deemed ineligible to receive a myeloablative (MAC) regimen in the past due to advanced age or associated comorbidities. We performed a systematic review and meta-analysis to assess the totality of evidence pertaining to efficacy of allo-HCT (RIC or MAC) in MCL. Materials and methods: A comprehensive search of MEDLINE/PUBMED from inception until July 04, 2015 was undertaken. Data were collected on treatment benefits (event-free (EFS), progression-free (PFS) and overall survival (OS) and harms (non-relapse mortality (NRM) and graft-versus host disease (GVHD)). Results: Fifty-nine manuscripts were identified of which 16 met inclusion criteria (710 patients). For RIC regimens, pooled analysis of 9 studies (n=507) showed an EFS/PFS rate of 47% (95%CI=32-61%) and an OS rate of 53% (95%CI=39-67%). NRM rate for RIC regimens from a pooled analysis of 9 studies (n=507) was 24% (95%CI=16-33%). Incidences of acute (grade 2-4) and chronic GVHD (all grades) following a RIC regimen were 31% (95%CI=20-45%, pooled from 6 studies (n=299)) and 42% (95%CI=30-54%, pooled from 7 studies (n=369)), respectively. For MAC regimens, pooled analysis of 4 studies (n=124) showed an EFS/PFS rate of 34% (95%CI=21-50%). The OS rate was 40% (95%CI=28-52%) from a pooled analysis of 5 studies (n=138). NRM rate for MAC regimens was 37% (95%CI=23-51%) based on a pooled analysis of 4 studies (n=119); only 1 study reported incidence of acute (grade 2-4) and chronic GVHD (all grades) of 36% (95%CI=23-50%) and 35% (95%CI=22-48%), respectively. When analysis was restricted to the late/salvage setting, we analyzed aforementioned outcomes regardless of regimen intensity (RIC+MAC) as well as specifically to RIC or MAC. When RIC and MAC regimens were combined, the pooled analysis of 12 studies (n=578) showed an EFS/PFS rate of 34% (95%=23-46%) and OS rate of 43% (95%CI=32-53%). The NRM rate was 30% (95%CI=20-41%, pooled analysis of 11 studies (n=563)). For RIC regimens in the late/salvage setting, the pooled analysis of 7 studies (n=436) showed an EFS/PFS rate of 40% (95%CI=26-56%) and OS rate of 48% (95%CI=33-62%). For MAC regimens in the late/salvage setting, the pooled analysis of 3 studies (n=105) showed an EFS/PFS rate of 35% (95%CI=17-55%) and OS rate of 38% (95%CI=22-56%). The observed heterogeneity was statistically significant among RIC studies for outcome of OS (p 〈 0.0001) but not for MAC (p= 0.1315). Conclusion: These results demonstrate that allo-HCT is an effective strategy for treatment of MCL even in the late/salvage setting. On the basis of a relatively lower NRM and a slightly better EFS/PFS and OS, RIC regimens may be the preferred choice when an allo-HCT is being considered for MCL. However, a prospective comparative study in this setting is necessary to generate more conclusive evidence. Disclosures No relevant conflicts of interest to declare.

Description: Background: No prospective randomized trials exist comparing high-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) against conventional therapy for management of peripheral T-cell lymphomas (PTCL) as upfront consolidation or in the relapsed/refractory (R/R) settings. Available data supporting this approach is limited to single-arm prospective or retrospective studies only. Accordingly, we performed a systematic review/meta-analysis of the published literature using PUBMED/MEDLINE from date of inception until March 4, 2015. Patients and methods: Our search identified 1586 publications, but only 27 (n=1368) met our inclusion criteria. Data were collected on treatment benefits (progression-free (PFS) and overall survival (OS)) and harms (transplant-related mortality (TRM) and secondary malignancies). Results: Specifically pertaining to HDT/auto-HCT as front-line consolidation data were available from 3 single-arm prospective (n=179) and 16 retrospective (n=599) studies. Moreover, for HDT/auto-HCT for R/R disease, 14 eligible retrospective (n=581) studies were identified. Pooled analysis of only prospective studies showed rates of PFS (2 studies, n=158) 33% (95%CI=14-56%), OS (3 studies, n=179) 54% (95%CI=32-75%), and TRM (2 studies, n=136) 2% (0.3-5%) for HDT/auto-HCT as front-line consolidation. When only retrospective studies were analyzed, pooled analysis showed rates of PFS (12 studies, n=518) 55% (95%CI=40-69%), OS (16 studies, n=599) 68% (95%CI=56-78%), TRM (7 studies, n=226) 6% (95%CI=2-11%), and incidence of secondary malignancies (4 studies, n=153) of 7% (95%CI=2-14%) with HDT/auto-HCT as front-line consolidation. Alternatively, pooled analysis of retrospective studies evaluating HDT/auto-HCT in the R/R setting showed rates of PFS (11 studies, n=511) 36% (95%CI=32-40%), OS (14 studies, n=581) 47% (95%CI=43-51%), TRM (5 studies, n=338) 10% (95%CI=5-17%), and incidence of secondary malignancies (1 study, n=29) of 3.4%. Additionally, we evaluated the efficacy of HDT/auto-HCT in various histologic subtypes both as front-line consolidation and in R/R disease. Only 1 prospective study using HDT/auto-HCT as front-line consolidation showed an apparently higher 5-year PFS and OS for ALK-negative anaplastic large cell lymphoma (ALK-neg-ALCL) (PFS=61%, OS=70%) compared to PTCL-NOS (PFS=38%, OS=47%) or angioimmunoblastic (AILT) (PFS=49%, OS=52%). Moreover, 2 retrospective studies using HDT/auto-HCT as front-line consolidation also showed higher rates of PFS and OS for ALCL (PFS=68%, OS=78%) compared to PTCL-NOS (PFS=64%, OS=75%) or AILT (PFS=48%, OS=63%). Finally, in the R/R setting, outcomes following HDT/auto-HCT from one retrospective study showed higher PFS for ALCL (67%) vs. PTCL-NOS (23%). The observed heterogeneity was statistically significant for PFS and OS among prospective (p=0.008 and p=0.0009) and retrospective (p

Description: Background Conservative treatment which typically includes phlebotomy or hydroxyurea or other cytoreductive therapy (plus aspirin) (ConsRxAsa) is effective treatment with acceptable complications for management of polycythemia Vera (PV) but is not considered curative [thus resulting in a shorter life expectancy (LE) in comparison to LE in the general population]. On the other hand, an allogeneic hematopoietic cell transplantation (allo-HCT) from a HLA compatible donor is considered a curative treatment option, but is potentially associated with high-risk of life-threatening complications. We sought to answer the question of which of these two treatment options results in better survival. Methods Because there are no direct randomized controlled trials (RCT) addressing the question if ConsRxAsa is superior to allo-HCT, we resorted to a decision-analysis to answer this question. We constructed a Markov model to represent and analyze the decision of ConsRxAsa vs. Allo-HCT.  The results of the model were expressed in terms of life expectancy (LE) and survival probabilities. We performed a systematic review (and when possible a meta-analysis) to inform parameters in the model. ConsRxAsa arm was modeled by simulating the natural history of PV. For Allo-HCT arm, we adopted our previously published model (Biol Blood Marrow Transplant 2009;15:1415-21) but modified it to evaluate the effect of both conventional and reduced-intensity allo-HCT performed in chronic phase of PV. Results We identified 165 relevant articles of which only 7 described testing various treatments for PV in RCTs. However, most data used to populate the decision model came from one RCT and one cohort study. Using base case of age of 45 years, we estimated a probability of survival at 10 and 20 years of 86% and 67% for ConsRxAsa versus 55% and 32% for allo-HCT (Fig).  This translates into an average LE of 17.1 years for ConsRxAsa vs. 11.6 years for allo-HCT, respectively. Sensitivity analysis according to age, early transplant-related mortality, risk of bleeding or thrombosis did not affect the results. Adopting median age of 65 years and comparing reduced-intensity allo-HCT vs. ConsRxAsa, we found that the average LE was 8.6 years for allo-HCT vs. 12.5 in the conservative treatment arm. Again, conservative treatment remained superior under a wide range of assumptions. Conclusions integration of current best existing evidence into the decision model shows that conservative management of PV appears to provide a better survival compared to offering  an allo-HCT in chronic phase of P. Vera. Disclosures: No relevant conflicts of interest to declare.

Description: Background: High-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) has been offered to patients with chronic lymphocytic leukemia (CLL), both as front-line consolidation and in the relapsed setting. Uncertainty remains in regards to the role of HDT in the front-line consolidation setting in CLL. Accordingly, we performed a systematic review and meta-analysis aiming at evaluating the totality of evidence pertaining to the efficacy (or lack thereof) of HDT and auto-HCT as front-line consolidation in subjects with CLL. Materials and methods: A total of 475 references were identified through a systematic search of PUBMED/MEDLINE and Cochrane through June 26, 2014. Only four randomized controlled trials which included a total of 600 subjects were eligible for inclusion in this meta-analysis. Data was meta-analyzed for benefits: progression-free survival (PFS) (data from 2 studies (total n=178)), event-free survival (EFS) (data from 2 studies (total n=422)), PFS or EFS (data from 4 studies (total n=600)), and overall survival (OS) (data from 4 studies (total n=600)); and harms: treatment related mortality (TRM) (data from 2 studies (total n=276)), development of any secondary malignancy ((data from 4 studies (total n=581)), or development of secondary MDS/AML in particular (data from 4 studies (total n=581)). Results: These results are reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Four studies enrolled a total of 301 subjects in the HDT/auto-HCT arm and 299 subjects in the control arm. Offering front-line HDT/auto-HCT did not improve PFS [Hazard ratio (HR)=0.70 (95%CI= 0.32, 1.52), p=0.37] or OS [HR=0.91 (95%CI= 0.62, 1.33), p=0.64]. An advantage favoring HDT/auto-HCT was observed in terms of EFS (HR=0.46 (95%CI= 0.26, 0.83), p=0.01] or when analysis included PFS or EFS [HR=0.54 (95%CI= 0.35, 0.82), p=0.004]. Moreover, HDT/auto-HCT did not result in higher TRM (Risk ratio (RR)=1.32 (95%CI= 0.43, 4.06), p=0.63]. When analyzing development of any secondary malignancy, no difference was observed whether subjects were offered HDT/auto-HCT or not [RR=1.06 (95%CI=0.55, 2.05), p=0.86]. A two-fold higher incidence of secondary MDS/AML, albeit not statistically significant, was observed with the HDT/auto-HCT approach [RR=1.95 (95%CI=0.60, 6.34), p=0.27]. Conclusion: Offering HDT/auto-HCT as front-line consolidation in patients with CLL does not improve OS. At the present time, this approach should be offered only in the context of a clinical trial. Disclosures No relevant conflicts of interest to declare.

Description: Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy which affects over 300,000 children born each year worldwide. In spite of improvement in supportive care in recent years, there is still a lack of effective treatment options. SCD leads to debilitating and cyclic episodes of erythrocyte sickling with progressive organ injury, contributing to lifetime morbidity and shortened life expectancy. Allogeneic HCT (allo-HCT) is a potentially curative therapy for SCD because engraftment is associated with resolution of the clinical phenotype of the disease and abrogation of its complications. Medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated the efficacy of allo-HCT in the adult population. Here, we conduct a systematic review/meta-analysis to assess the totality of evidence pertaining to the efficacy (or lack thereof) of allo-HCT in children and adults. Materials and methods: We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane library on July 3rd, 2019. We extracted data on clinical outcomes related to benefits (overall [OS] and disease free/event free survival [EFS/DFS]) and harms (non-relapse mortality [NRM] and graft failure [GF]), independently by two authors. Our search strategy identified 1001 references but only 30 studies (n= 1995 patients) were included in this systematic review/meta-analysis. We also performed a sub analysis on clinical outcomes for studies that included only pediatric patients (defined as

Description: Introduction: The decision-making process during clinical recommendations development is central for producing high-quality hematology clinical practice guidelines, but little is known about how the activity roles of guidelines panelists (e.g., chair, methodologist, content expert, etc.) and the use of decision-making frameworks influence evidence-informed decisions when making clinical recommendations. Objective: To explore and describe the activity roles of panelists in hematology guidelines panels, the application of a structured decision-making framework, and the factors being considered by panels when making clinical recommendations. Methods: We conducted conventional and summative qualitative analyses on the decision-making process of 9 audio-recorded panels convened by the American Society of Hematology (ASH) to develop guidelines for the management of the following conditions: heparin-induced thrombocytopenia, thrombophilia, optimal management of anticoagulation therapy, venous thromboembolism (VTE) in pregnancy, in pediatric populations, in patients with cancer, in non-surgical patients, in surgical patients, and treatment in VTE. Each panel developed final recommendations through group consensus during face-to-face meetings using GRADE (Grading of Recommendations Assessment, Development, and Evaluation)'s Evidence-to-Decision (EtD) framework. For each recommendation, panels made explicit judgments for each criterion in the framework. We analyzed GRADE and non-GRADE criteria that were used to make each recommendation, as well as the activity roles of each panelist. Results: GRADE criteria occupied 95% of all deliberations. Over half (51.1%) of the panel deliberations concerned research evidence related to the clinical effects of a treatment or practice, followed by discussion on resource use and costs (16.7%), feasibility and acceptability (13.5%), risks of benefits and harms (8.8%), equity (4.0%), and values and preferences (1.0%). Non-GRADE criteria represented the remaining 5% of the discussions (transparent communication on the decision-making process when making recommendations, legal implications, political context, and clinical experience). Chairs and co-chairs actively led and facilitated all discussion topics; they contributed to over half of the deliberations (55.2%). The remaining deliberations were from panelists (38.1%), systematic review team members (5.0%), and patient representatives (1.0%). Conclusions: The application of the EtD framework provided a highly structured decision-making process when making clinical recommendations for hematologic conditions. Chairs and co-chairs tend to actively lead the panel discussions, which contributed to framework adherence. The optimal role of chairs and co-chairs versus other panelists need to be further investigated. Future studies should examine how the decision-making process of treatment and interventions for hematologic conditions differ between guidelines panels that use and do not use a structured framework to develop clinical practice recommendations. Disclosures Cuker: Genzyme: Consultancy; Synergy: Consultancy; Spark Therapeutics: Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 673 Background: Informed decision making in health care requires balancing of information related to benefit and harms of treatments. However, it is shown that the amount of space dedicated for presenting information on harms in randomized trials is less than that used to list authors' names and affiliations. Poor or absent reporting of treatment-related harms can mislead decision makers at all levels (public, researchers, funding agencies). Several efforts have been made to improve the quality of data collection and reporting of treatment-related harms. In oncology, after recognizing that many cancer treatments are toxic, and not infrequently result in severe morbidity and even death, the National Cancer Institute's (NCI) lead the way to standardize terminology and data collection on treatment-related harms. The first standards for collection of harms data in cancer known as Common Toxicity Criteria (CTC) were developed in 1982 followed by three revisions. Here we investigate the impact of NCI CTC and NCI common terminology criteria for adverse events (CTCAE) on quality of reporting of treatment-related harms in a cohort of NCI cooperative group (NCI-COG) trials. Methods: We extracted data on elements addressing assessment of treatment-related harms from protocols and matching publications from all consecutive phase III NCI-COG randomized controlled trials (RCTs) for the years 1955 to 2006. RCTs reporting treatment-related mortality data as deaths per arm and treatment-related morbidity data as per patient per arm were categorized to have good quality. RCTs reporting treatment-related morbidity data in the aggregate method such as % of events per arm were categorized as intermediate quality while RCTs which did not report any treatment-related harms data were classified as poor quality. Results: We reviewed 429 RCTs enrolling 157,337 patients. Twenty seven percent (115/429) of RCTs had good quality of reporting of treatment-related harms while 63% (271/429) of RCTs were of intermediate quality. Only 10% (43/429) of RCTs had poor quality of reporting of treatment-related harms. Quality of treatment-related harms reporting did not improved with time. Nine percent (37/429) of RCTs were published before introduction of NCI CTC v1.0 while 66% (284/392) were published after NCI CTC v1.0 but before introduction of NCI v2.0 and 85% (92/108) of RCTs were published after NCI CTC v2.0 but before NCI CTCAE (figure). The quality of treatment-related harms reporting improved after introduction of NCI CTC v1.0 (p-value=0.002) while NCI CTC v2.0 (p-value= 0.78) and NCI CTACE (p-value=0.001) did not have positive impact on treatment-related harms reporting (figure). The NCI CTC/NCI CTCAE or similar standardized treatment-related harms assessment instrument was explicitly referred to in 55% (235/429) of protocols vs. 47% (203/429) of publications. Forty five percent (193/429) of protocols mentioned seriousness of treatment-related harms compared to 33% (142/429) of publications. Severity of treatment-related harms was mentioned in 63% (272/429) of protocols versus 71% (303/429) of publications. Conclusion: Quality of treatment-related harms reporting in NCI-COG RCTs did not improved with time. The introduction of NCI CTC initially did improve quality of treatment-related harms reporting. However, NCI CTC V2.0 and NCI CTCAE did not subsequently appear to impact reporting of quality of treatment-related harms in NCI-COG RCTs. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Clinical practice guidelines (CPGs) represent a key mechanism for optimizing health care decision making. CPGs are a product of discussion by a group of, typically, 10-20 individuals with varying expertise. Little is known how CPG panels actually make their recommendations. Objective: In a study of real-life decision making, we investigated the factors considered by members of panels convened by the American Society of Hematology (ASH) to develop guidelines, when using the widely accepted formal GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. Methods: To account for panel level factors and individual level factors, we employed two level hierarchical, random-effect, multivariate logistic and ordered logistic regression analysis. Results: 101 participants taking part in 8 CPGs panels issued 1,289 recommendations. Association of GRADE (normative) factors with the strength of recommendations (SOR) dominated the findings over the non-GRADE (descriptive) factors. In the main analysis certainty in evidence (regardless of direction for or against intervention) [OR=1.83 (95CI% 1.45 to 2.31;p