Study Steering Committee Research Articles

Burden of Migraine and Migraine-Associated Symptoms in People with Differing Ethnic and Racial Backgrounds: Results of the OVERCOME (US) Study (S41.003)

Burden of Migraine and Migraine-Associated Symptoms in People with Differing Ethnic and Racial Backgrounds: Results of the OVERCOME (US) Study (S41.003)

Effective Control of Advance Systemic Mastocytosis with Avapritinib: Mutational Analysis from the Explorer Clinical Study

Effective Control of Advance Systemic Mastocytosis with Avapritinib: Mutational Analysis from the Explorer Clinical Study

Low Frequency of T Cell and Antibody Responses to Vaccination Against Sars-Cov-2 in Patients Post Allogeneic Stem Cell Transplantation in Comparison with Chronic Myeloid Malignancy Patients

Low Frequency of T Cell and Antibody Responses to Vaccination Against Sars-Cov-2 in Patients Post Allogeneic Stem Cell Transplantation in Comparison with Chronic Myeloid Malignancy Patients

Immune Checkpoint Analysis of T Effectors and Regulatory T Cells in Patients with CML Reveals Increased Expression at Diagnosis and with Refractory Disease

Immune Checkpoint Analysis of T Effectors and Regulatory T Cells in Patients with CML Reveals Increased Expression at Diagnosis and with Refractory Disease

Efficacy of Avapritinib in Patients with Advanced Systemic Mastocytosis: Hematologic and Bone Marrow Responses from the Phase 2 Open-Label, Single-Arm, Pathfinder Study

Efficacy of Avapritinib in Patients with Advanced Systemic Mastocytosis: Hematologic and Bone Marrow Responses from the Phase 2 Open-Label, Single-Arm, Pathfinder Study

‘Application of Prognostic Scoring in Systemic Mastocytosis Patients within a UK Centre of Excellence: Guys and St Thomas’ NHS Foundation Trust.‘

‘Application of Prognostic Scoring in Systemic Mastocytosis Patients within a UK Centre of Excellence: Guys and St Thomas’ NHS Foundation Trust.‘

Decreased Early Mortality in Young Adults with Acute Lymphoblastic Leukemia Treated at Specialized Cancer Centers in California

BackgroundA population-based study suggested that adolescent and young adults with acute lymphoblastic leukemia (ALL) have superior survival when treated at specialized cancer centers (SCC; versus community hospitals). However, the association of location of initial care with early mortality (death within 60 days) has not yet been evaluated in children and adolescents and young adults with ALL. Therefore, we examined the impact of location of initial care, sociodemographic factors and complications on early mortality in children (0-18 years) and adolescent and young adults (AYAs; 19-39 years) with ALL.MethodsUsing the California Cancer Registry linked to a hospitalization database in California, we identified children and AYAs with first primary diagnosis of ALL who received inpatient treatment within 60-days of diagnosis between 1991 and 2014. SCCs were defined as Children's Oncology Group or National Cancer Institute (NCI)-designated cancer centers for children and NCI-designated cancer center for AYAs. Children and AYAs were classified as receiving all or part/none of their care at a SCC within 60-days of diagnosis. Mulitple logistic regression was used to identify factors associated with receiving all initial care at a SCC and to build a propensity score separately for children and AYAs. Inverse probability-weighted, multivariable logistic regression models estimated the associations between location of care, sociodemographic characteristics, clinical factors and complications with early mortality. Results are presented as odds ratios (ORs) and 95% confidence intervals (CI).ResultsOf the 6,531 patients with ALL in our study, the overall early mortality rate for was 2.1% in children and 6.3% in AYAs. The majority of children received all of their care at an SCC (n=4752, 85.4%) compared to only 36.1% of AYAs (n=1779). Rates of early mortality varied significantly by location of care and age (children: all care at an SCC 1.9% vs part/none 3.2%, p=0.04; AYAs: all care at an SCC 3.9% vs part/none 7.7%, p=0.002). Among children, factors associated with receiving all care at a SCC were younger age, Hispanic race/ethnicity (vs non-Hispanic white), more recent diagnosis and having public/no insurance (vs private). Factors associated with receiving all care at a SCC among AYAs were younger age, non-Hispanic white race/ethnicity (vs Hispanic), public/no insurance, and living in a lower socioeconomic status (SES) neighborhood. In multivariable, inverse probability weighted models, receiving all care at a SCC (versus part/no care) was associated with significantly lower early mortality in AYAs (OR 0.44, CI 0.27-0.74), but not in children (OR 0.61, CI 0.34-1.08). Higher early mortality in children was associated with complications of bleeding (OR 5.73, CI 2.76-11.90), sepsis (OR 2.02, CI 1.01-4.04), renal (OR 4.1, CI 2.17-7.76) and respiratory failure (OR 5.48, CI 2.66-11.29). In AYAs, higher early mortality was associated with older age (>29), having a comorbidity (OR 1.83, CI 1.08-3.10) and complications of liver failure (OR 8.03, CI 2.41-26.76), renal failure (OR 2.45, CI 1.33-4.52) and respiratory failure (OR 11.89, CI 5.87-24.09). Early mortality was not associated with race/ethnicity, neighborhood SES or health insurance for either age group. Rates of complications were similar by location of care in children and AYAs except for thrombosis in children (all: 0.40% vs part/none: 1.00% p=0.03) and renal failure in AYAs (all: 14.3% vs part/none: 10.7% p=0.03).ConclusionsOur results suggest that treatment at a SCC is associated with a significantly lower early mortality for AYA patients after adjusting for sociodemographic and clinical factors. We observed a borderline difference in mortality by location of care in children, likely because, in contrast to AYAs, the vast majority of children are seen at SCCs. The reduction in mortality at SCCs may be due to access to clinical trials and other specialized services available at these types of institutions. DisclosuresWun:Janssen: Other: Study steering committee and research support (site PI); Pfizer: Other: Study steering committee and research support (site PI).

Complications and Early Mortality in Patients with Acute Promyelocytic Leukemia Treated in California

Background: Treatment advances, such as all-trans retinoic acid, have improved outcomes in acute promyelocytic leukemia (APL), but early mortality (defined here as death ≤7 and <30 days from diagnosis) continues to be a barrier to improving overall survival, especially in older patients. Few population-based studies have evaluated the impact of complications on early mortality by age in APL patients.Methods: Using a retrospective observational study design, we analyzed linked data from the California Cancer Registry and hospital discharge records in California from 1999-2014. We identified patients ≥15 years of age diagnosed with APL who were hospitalized within 30 days of diagnosis (N =980). Multivariable logistic regression analyses were used to determine the association of complications with early mortality (overall and by age group), adjusting for sociodemographic factors, comorbidities and hospital type. Results are presented as adjusted odds ratios (OR) and 95% confidence intervals (CI).Results: Of 980 patients hospitalized with APL, 17.0% (n=167) died in the first 7 days and 28.0% (n=274) died within 30 days of diagnosis. 7-day mortality decreased over time (19.7%, 1999-2002; 14.3%, 2011-2014). There was consistent positive association of 7-day mortality with increasing age (12.4%, 15-39 years, 17.1%, 40-59 years, and 22.5%, >60 years). Major complications in those that died at 7 days included bleeding, hemorrhagic stroke and respiratory failure, with significantly higher rates of bleeding and hemorrhagic stroke seen in those aged 15-39 compared with those >60 years. 30-day mortality also decreased over time (33.2%, 1999-2002; 24.8%, 2011-2014), with a positive association with increasing age (17.7%, 15-39 years, 25.8%, 40-59 years, and 43.0%, >60 years). (Figure) Complications did not vary substantially by age, except that older patients (>60 years) had higher rates of ischemic stroke, renal failure and respiratory failure than those aged 15-39. (Table) In multivariable models, major bleeding (OR 2.13, CI 1.20-3.78), hemorrhagic stroke (OR 5.48, CI 2.78-10.80), renal failure (OR 1.88, CI 1.18-2.99), and respiratory failure (OR 7.82, CI 4.89-12.52) were associated with 30-day mortality. Higher 30-day mortality also was associated with older age (>60 vs 15-59 years) and having >3 comorbidities (vs 0). Race/ethnicity, marital status, neighborhood socioeconomic status, health insurance and hospital type was not significantly associated with early mortality.Conclusions: Almost one third of APL patients die within 30 days of diagnosis, the majority within the first 7 days, with older patients having the highest 30-day mortality. Complications of bleeding, hemorrhagic stroke and respiratory failure continue to drive early mortality, but socioeconomic factors and hospital type did not impact early mortality. Because early mortality, not drug resistance, continues to be a major cause of treatment failure in APL patients, more robust initiatives to address these complications, including more aggressive supportive measures and universal prophylaxis of differentiation syndrome, may lead to better outcomes. [Display omitted] DisclosuresJonas:AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy. Wun:Janssen: Other: Study steering committee and research support (site PI); Pfizer: Other: Study steering committee and research support (site PI).

The Wire Study\u2014a protocol for a multi-stage feasibility study evaluating K-wire fixation of hand fractures in the UK

BackgroundHand fractures are common and sometimes require surgery to restore function. Placement of Kirschner wires (K-wires) is the most common form of surgical fixation. After placement, a key decision is whether to bury the end of a K-wire or leave it protruding from the skin (exposed). A recent systematic review found no evidence to support either approach and a national clinician and surgeon survey demonstrated further uncertainty. We aim to determine the design of a definitive randomised controlled trial assessing the cost and clinical effectiveness of buried versus exposed Kirschner wires for adults with metacarpal or phalangeal fractures.MethodsWe will employ three methodologies: a national service evaluation of current clinical practice, patient and surgeon focus groups and a consensus meeting to finalise the protocol for a randomised controlled trial. For the service evaluation, all outcomes will be summarised using descriptive statistics overall and split by group (buried versus exposed K-wires). Information collected in the patient focus groups will be analysed thematically. The surgeon consensus meeting will address each part of the design in turn and through discussion agree a final protocol.DiscussionThe study may be monitored, or audited in accordance with the current approved protocol, Good Clinical Practice (GCP), relevant regulations and standard operating procedures. The Chief Investigator will submit and, where necessary, obtain approval from the above parties for all substantial amendments to the original approved documents. A feasibility study report will be published by the Wire Study Steering committee. Additional members of the steering group and citable collaborators will be listed within the manuscript and their roles identified.

First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing Antibodies

First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing Antibodies

Study Design and Initial Baseline Characteristics in Solace-Kids: Crizanlizumab in Pediatric Patients with Sickle Cell Disease

Study Design and Initial Baseline Characteristics in Solace-Kids: Crizanlizumab in Pediatric Patients with Sickle Cell Disease

Early Initiation of Treatment with Rivipansel for Acute Vaso-Occlusive Crisis in Sickle Cell Disease (SCD) Achieves Earlier Discontinuation of IV Opioids and Shorter Hospital Stay: Reset Clinical Trial Analysis

Early Initiation of Treatment with Rivipansel for Acute Vaso-Occlusive Crisis in Sickle Cell Disease (SCD) Achieves Earlier Discontinuation of IV Opioids and Shorter Hospital Stay: Reset Clinical Trial Analysis

Red Hair Color Is Associated with Elevated CRP Levels among US Women

Red Hair Color Is Associated with Elevated CRP Levels among US Women

The development of a regional referral pathway for locally recurrent rectal cancer: A Delphi consensus study

BackgroundThe management of patients with locally recurrent rectal cancer (LRRC) is often complex and requires multidisciplinary input whereas only few patients are referred to a specialist centre. The aim of this study was to design a regional referral pathway for LRRC, in Nouvelle Aquitaine (South-West, France). MethodsIn 2016, we conducted with a Study Steering Committee (SC) a three phase mixed-methods study including identification of key factors, identification of key stakeholders and Delphi voting consensus. During three rounds of Delphi voting, a consensus was defined as favorable, if at least 80% of participating experts rate the factor, below or equal to 3/10 using a Likert scale, or consider it as “useful” using a binary scale (third round only). Finally, the SC drafted guidelines. ResultsAmong the 423 physicians involved in 29 regional digestive Multi-Disciplinary Team (MDT) meeting, 59 participants (from 26 MDT meeting) completed all three rounds of Delphi voting. Thirteen out of twenty initially selected factors reached a favorable consensus. All patients with a LRRC need to be included into a referral pathway. Patients with a central pelvic recurrence offered curative treatment in their local hospital and patients with unresectable metastatic disease were excluded of the referral. Key performance indicators were also agreed including the time to referral and completion of pelvic MRI-, CT-, PET-scan prior to MDT referral. ConclusionThe development of this referral pathway represents an innovative health service, which will improve the management of patients with LRRC in France.

Incidence, Natural History and Outcomes of Transient and Persistent Antiphospholipid Antibodies in Children and Young Adults with Provoked Venous Thromboembolism: Analysis of the Kids-DOTT Trial

Background: Antiphospholipid syndrome (APS) is characterized by the development of thromboembolic events in the setting of persistent antiphospholipid antibodies (APA). While several studies have investigated the clinical characteristics and venous thromboembolic (VTE) outcomes of pediatric patients with a diagnosis of APS, there is a scarcity of published data describing the incidence, natural history and VTE outcomes of children who present with positive APA at the time of an acute VTE episode. Objective: To describe the incidence, natural history and outcomes of transient and persistent APA in patients ≤21 years old with a first episode of provoked VTE. Methods: Patients with positive APA at the time of enrollment in an ongoing NHLBI-sponsored multicenter, parallel-cohort randomized controlled trial (RCT) on duration of anticoagulation therapy in provoked VTE (the Kids-DOTT Trial; NCT00687882) were included in this analysis. APA testing was obtained at the time of enrollment in all patients, and at 6 weeks post-VTE diagnosis in those with an initial positive APA result. Subsequent follow-up testing in patients whose APA persisted at 6 weeks post-VTE was performed at the discretion of the enrolling site's treating hematologist. Patients with persistent APA at 6 weeks were treated in a non-randomized parallel-cohort of the trial in which patients received at least a 3-month therapeutic course of anticoagulation. Those without persistent APA at 6 weeks were retained in the RCT and randomized to shortened-duration (no further therapy) versus conventional duration (total duration = 3 months) of therapy. Measured APA included lupus anticoagulant-sensitive activated partial thromboplastin time (LAS-aPTT), dilute Russell viper venom time (DRVVT), hexagonal phase phospholipid assay (STACLOT LA), anti-cardiolipin (ACL) IgM, and anti-beta-2-glycoprotein-1 (aß2GPI) IgG and IgM. Data were prospectively collected. Descriptive statistics were used to summarize data on demographic characteristics, VTE presentation, and outcomes of interest (persistent thrombus occlusion at 6 weeks post-VTE, post-thrombotic syndrome [PTS], recurrent VTE and clinically-relevant bleeding [CRB]). The blind was maintained in the Kids-DOTT trial throughout data transfer and analysis. Results: APA testing was performed in 476 patients at the time of enrollment. Twenty-one percent of patients (n=100) had at least one positive APA and were included in the present analysis. Demographics, VTE characteristics, and laboratory findings at enrollment are summarized in Table 1. Median age was 9.6 years (range 0.05-19). The most common thrombosis site was the lower extremity (43%). Presence of a central venous catheter was the provoking factor in 44% of cases. LA was the most common APA detected at the time of enrollment (36%, 35% and 13% of patients by STACLOT, DRVVT and LAS-aPTT, respectively). Twenty-four percent of patients had a persistent APA at 6 weeks post-VTE (Figure 1). Of these, 16 (66.7%) had repeat APA testing at least 12 weeks from first positive APA. Persistent APA at ≥12 weeks (i.e., APS) was determined in 12 of the 16 patients. Most of these children with APS had a single positive APA (aß2GPI IgG/IgM, n=4, LA, n=4, ACL IgM, n=2) while only 1 patient had triple-positive APA (Table 2). Rates of recurrent VTE, complete venous occlusion at 6 weeks post-VTE, development of PTS, and CRB were higher in APS patients as compared to those without APS (Table 3). Conclusions: This Kids-DOTT analysis reports for the first time that positive APA are found in nearly one quarter of children and young adults with provoked VTE at the time of the acute VTE episode, and that approximately 75% of these are transient (negative at 6 weeks post-VTE diagnosis). Patients with provoked VTE who have APS tended to have increased risk of adverse VTE outcomes when compared to those without APS; however, the size of these subgroups does not permit a definitively-powered comparison in outcomes. The putative role of persistently positive APAs as a prognostic factor for adverse VTE outcomes should be formally tested upon completion of the Kids-DOTT trial. Disclosures Tarango: Shire: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: Study steering committee. Goldenberg:NIH: Other: research support and salary support.

Incidence of Venous Thromboembolism and Impact on Mortality in Patients with Primary CNS Lymphoma: A Population Based Study

Background: Venous thromboembolism (VTE) is a known complication of cancer, with a high incidence in patients with both gliomas and lymphoma. Recent studies have shown a high risk of intracranial bleeding in glioma patients treated for VTE with anticoagulation. To date, there are no large, population-based studies describing the incidence of VTE in patients with primary central nervous system lymphoma (PCNSL).Methods: Using the California Cancer Registry, we identified patients with a first histologic diagnosis of PCNSL from 2005-2014 and linked these cases to the California hospitalization and emergency department databases. Patients with a VTE within 6 months prior to PCNSL diagnosis were excluded (n=11). We calculated cumulative incidence of VTE and major bleeding and associated 95% confidence intervals (CI), adjusted for the competing risk of death. Multivariable Cox proportional hazards regression models, using the methods of Fine and Gray to adjust for competing risk of death, were used to analyze factors associated with VTE and major bleeding. Models included sex, race/ethnicity, age at diagnosis, neighborhood sociodemographic status, health insurance at diagnosis, Elixhauser comorbidities, HIV status, initial treatment (chemotherapy, radiation, or CNS procedure), and prior VTE (> 6 months prior to diagnosis). The major bleeding model additionally included VTE type as a time dependent covariate. The association of VTE and major bleeding with PCNSL-specific mortality was analyzed using multivariable Cox proportional hazards regression models; VTE and major bleeding were included as time dependent covariates. Results are presented as adjusted hazard ratios (HR) and 95% CI.Results: There were 992 patients with a PCNSL identified. VTE occurred in 143 patients (14.4%). Of the VTE events, 52% were pulmonary emboli [(PE +/- deep vein thrombosis (DVT)], 23% proximal DVT and 22% distal DVT. The 3- and 12-month cumulative incidences of VTE were 10.2% (CI: 8.4-12.2%) and 13.6% (CI: 11.5-15.8%), respectively (Figure 1). Patients who received chemotherapy had over 2-fold increased risk of developing VTE (HR=2.42, CI: 1.33-4.42) compared to those who did not receive chemotherapy, and those who received radiation were also at increased risk of VTE (HR=1.56 CI: 1.07-2.27). Asian/Pacific Islanders had a decreased risk of VTE compared to non-Hispanic Whites (HR=0.37, CI: 0.21-0.66).Major bleeding occurred in 156 patients (15.7%). Of the major bleeding events, 53% were intracranial hemorrhage, 33% were gastrointestinal bleeds, 12% of patients required a transfusion and 3% had unspecified bleeding. The 3- and 12-month cumulative incidences of major bleeding were 9.8% (CI: 8.1-11.8%) and 13.2% (CI: 11.1-15.3%), respectively (Figure 2). PE and proximal DVT were associated with increased risk of major bleeding (HR=4.57, CI: 2.43-8.60 and HR=5.95, CI: 2.47-14.34, respectively).In the PCNSL specific mortality models, PE was associated with increased risk of death (HR=1.81, CI: 1.14-2.87), though DVT (proximal or distal) was not. Patients with major bleeding were at over 2-fold increased risk of PCNSL death compared to those without major bleeding (HR=2.34, CI: 1.71-3.19).Conclusions: The incidence of VTE in this large population-based study of patients with PCNSL was high at 14.4%, with most VTE events occurring within the first 3 months after diagnosis. Risk factors associated with VTE included treatment with either chemotherapy or radiation. PE and proximal DVT were associated with increased risk of major bleeding, suggesting these patients may have received anticoagulation, and as recently shown in glioma patients, are at a high risk of intracranial hemorrhage. In addition, PE and major bleeding were both independently associated with higher PCNSL mortality. [Display omitted] DisclosuresWun:Janssen: Other: Study steering committee and research support (site PI); Pfizer: Other: Study steering committee and research support (site PI).

Analysis of a Global Registration Trial of the Efficacy and Safety of CTL019 in Pediatric and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

▪A single-center trial of CD19 directed, lentiviral transduced chimeric antigen receptor (CAR) T cells (CTL019) for relapsed and refractory (r/r) B-ALL pediatric patients showed rates of CR >90% with prolonged CAR T cell persistence/CR without further therapy in the majority of patients infused (Maude NEJM 2014).We report here the feasibility, safety and efficacy of the first multicenter global pivotal registration CAR T cell trial. Features of this trial include: i) the first trial in which industry-manufactured cells were provided to all patients; ii) enrollment across 25 centers in the US, EU, Canada, Australia, and Japan; iii) successful transfer and manufacturing of cells in a global supply chain; and iv) successful implementation of cytokine release syndrome (CRS) management across a global trial. All patients had CD19 positive B-ALL with morphologic marrow tumor involvement at registration (>5% blasts), and were either primary refractory; chemo-refractory after first relapse, relapsed after second line therapy; or ineligible for allogeneic SCT. CTL019 was manufactured from patient PBMC under GMP conditions in the US, at a centralized "sponsor-owned" manufacturing facility, and supplied to all sites. The primary endpoint of overall remission rate (CR+CRi) within 3 months and secondary endpoints (EFS, DOR, OS and safety) were assessed by an independent review committee.Based on preliminary data as of March 2016, 57 patients were enrolled. There were 3 manufacturing failures (5%), 5 patients were not infused due to death or adverse events (9%), and 15 patients were pending infusion at the data cut off. Following fludarabine/cyclophosphamide lymphodepleting chemotherapy in the majority of the patients, 34 patients (median age 11 [3-23], 50% with prior HSCT) were infused with a single dose of CTL019 at a median dose of 2.9 x106 transduced CTL019 cells/kg (0.2 to 4). Among 29 patients reaching D28 prior to the data cutoff, 83% (24/29) achieved CR or CRi by local investigator assessment, all of which were MRD-negative. Two early deaths occurred prior to initial disease assessment, one due to disease progression and one due to intracranial hemorrhage. Two patients did not respond. One patient was in CR by BM at D28, but CSF was not assessed, therefore this patient was classified as "incomplete" assessment.Safety was managed by a protocol-specified CRS algorithm with no cases of refractory CRS. Using the Penn CRS grading scale, 82% of patients experienced CRS, with 7 grade 3 (21%) and 8 grade 4 (24%) events. 44% patients with CRS required anti-cytokine therapy; all received tocilizumab with or without other anti-cytokine therapy, with complete resolution of CRS. Besides CRS, the most common grade 3 and 4 non-hematologic AEs were febrile neutropenia (29%), increased bilirubin (21%), increased AST (21%), and hypotension (21%). 21% of patients experienced grade 3 or 4 neuropsychiatric events including confusion, delirium, encephalopathy, agitation and seizure; no cerebral edema was reported. CTL019 in vivo cellular kinetics by qPCR demonstrated transgene persistence in blood in responding patients at and beyond 6 months. Overall exposure (AUC 0-28d) and maximal expansion (Cmax) of CTL019 DNA measured by qPCR was higher in responding compared with non-responding patients.In summary, this pivotal global study in pediatric and young adult patients with r/r B-ALL receiving CTL019, confirms a high level of efficacy and a similar safety profile to that shown in the prior single center experience. Safety was effectively and reproducibly managed by appropriately trained investigators. The study has completed accrual. At the meeting, updated data from a planned formal interim analysis including safety, efficacy (primary and selected secondary endpoints), cellular kinetics, and impact of anti-cytokine therapy will be presented for more than 50 patients infused at 25 global sites. DisclosuresGrupp:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Laetsch:Novartis: Consultancy; Loxo Oncology: Consultancy. Bittencourt:Seattle Genetics: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Educational Grant. Maude:Novartis: Consultancy. Myers:Novartis Pharmaceuticals: Consultancy. Rives:Novartis: Consultancy; Jazz Pharma: Consultancy. Nemecek:Medac, GmbH: Research Funding; Novartis: Consultancy; National Marrow Donor Program: Membership on an entity’s Board of Directors or advisory committees. Schlis:Novartis: Honoraria. Martin:Jazz Pharmaceuticals: Other: One time discussion panel; Novartis: Other: Support of clinical trials. Bader:Medac: Consultancy, Research Funding; Riemser: Research Funding; Neovii Biotech: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Peters:Novartis: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy; Medac: Consultancy. Biondi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board; BMS: Membership on an entity’s Board of Directors or advisory committees. Baruchel:Servier: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Jazz: Consultancy; Baxalta: Research Funding. June:University of Pennsylvania: Patents & Royalties; Johnson & Johnson: Research Funding; Celldex: Consultancy, Equity Ownership; Pfizer: Honoraria; Immune Design: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; Tmunity: Equity Ownership, Other: Founder, stockholder . Sen:Novartis: Employment. Zhang:Novartis: Employment. Thudium:Novartis: Employment. Wood:Novartis Pharmaceuticals: Employment, Other: Stock. Taran:Novartis: Employment. Pulsipher:Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee; Medac: Other: Housing support for conference.

A Pilot Trial of Unmatched Human Placenta-Derived Stem Cells (HPDSCs) in Conjunction with Unrelated Cord Blood Transplantation (UCBT) in Children and Young Adults with Malignant and Non-Malignant Disease (IND 14949)

Background: Myeloablative conditioning (MAC) and reduced toxicity conditioning (RTC) followed by UCBT (matched at 4-6/6 HLA loci) in children with malignant and non-malignant diseases is safe and effective (Wagner/Cairo et al, Blood, 1996; Geyer/Cairo et al, BJH, 2011). However, there is a low concentration of CD34+ hematopoietic progenitor cells (HPCs) in banked UCB (Cairo/Kurtzberg et al, Transfusion, 2005) compared to bone marrow or peripheral blood, leading to delayed hematopoietic reconstitution and 10-20% incidence of graft failure (Cairo et al, Blood, 1997; Cairo et al, Transfusion, 2005; Satwani/Cairo et al, BBMT, 2013). Human placenta-derived stem cells (HPDSCs) are rich in HPCs and HPC colony forming unit capabilities, low in HLA Class I and II expression, low in T-cell content, and have regenerative, anti-inflammatory, and immunosuppressive properties (Cairo et al, BMT, 2015). Mendez-Ferrer et al have demonstrated that HPDSCs enhance in-vivo engraftment when combined with UCBT in NOD-SCID animals (Mendez-Ferrero et al, Nature, 2010).Objective: To determine the safety of administering unrelated donor HPDSC in conjunction with unrelated single or double UCBT following MAC or RTC in children and adults with malignant and non-malignant diseases and to determine the time to hematopoietic engraftment, immune reconstitution and probability of donor chimerism.Methods: Patients ≤55 years of age with malignant and non-malignant diseases with a single UCB 5-6/6 HLA match and TNC ≥ 3.5x 107/kg, or double UCB 4-6/6 HLA match and combined TNC >5.0 x 107/kg are eligible. HLA typing was performed by serology for Class I A and B and by high resolution DNA typing of DRB1. Patients received either fully myeloablative or reduced toxicity pre-UCBT conditioning as indicated for the targeted disease followed by single or double UCB plus HPDSC infusion. All patients received filgrastim (G-CSF) starting at least 24 hours after the HPDSC infusion until myeloid engraftment and GVHD prophylaxis with tacrolimus or cyclosporine plus mycophenolate mofetil.Results: Twenty one patients have been enrolled to date: mean age 11 (0.31-34.9) years, 11 males, 10 females. Fourteen subjects had malignancies (relapsed/refractory or hypodiploid precursor B-ALL (n=7), relapsed/refractory or high risk AML (n=5), T-cell ALL induction failure (n=1), and T-cell lymphoblastic lymphoma (n=1)) and seven had non-malignant disorders (adrenoleukodystrophy (n=1), chronic granulomatous disease (n=1), congenital amegakaryocytic thrombocytopenia (n=1), bone marrow failure (n=1), SCID (n=1), severe aplastic anemia (n=1), and dyskeratosis congenita (n=1)). Fourteen patients received single UCBT followed by HPDSC infusion, and seven patients received double UCBT followed by HPDSC infusion. There were no severe adverse events associated with the HPDSC infusions. Median time to neutrophil and platelet engraftment were 22 (13-53) and 45 (20-98) days post UCBT, respectively. Mean percent of whole blood donor chimerism at days 30, 60, 100 and 180 were 97% (SEM 1.25), 99%, (SEM 0.36), 99% (SEM 0.39), and 97.9 (SEM 1.31), respectively. Average percent of whole blood HPDSC chimerism was <1% at day 30. Average absolute CD3/4/8 at days 100, 180, 270, and 365 were 150/107/43, 411/ 256/154, 1020/630/371, and 1207/728/458, respectively, per mcl. Average absolute CD56 and CD19 at days 100, 180, 270 and 365 were 478/654, 190/713, 308/2225 and 361/1215 respectively. The probability of NRM at day 100 was 0%. Of patients with malignant disease, the incidence of relapse was 0/14 (0%) at day 100 and 1/14 (7.1%) at day 180 post-transplant. For the full cohort, the probability of Grade II-IV aGVHD was 14.8% (CI95 0.0-28.9) (Figure 1) and the probability of 12 month overall survival was78.6% (CI95 62.0-99.6) (Figure 2). OS at day 100 and day 180 are 19/19 (100%) and 15/19 (78.9%) respectively. 2/21 patients have not yet reached day 100. Sixteen of twenty-one patients are alive at a median of 535 (53-1175) days post UCBT.Conclusions: These preliminary results suggest that single or double UCBT combined with unrelated HPDSC is safe, well tolerated, and has a lower than expected probability of Grade II-IV aGVHD. A larger cohort and longer follow-up is required to determine the safety and clinical significance of these early findings. [Display omitted] [Display omitted] DisclosuresPulsipher:Novartis: Consultancy, Other: Study Steering Committee; Jazz Pharmaceutical: Consultancy; Chimerix: Consultancy; Medac: Other: Housing support for conference. Zhang:Celgene: Employment, Equity Ownership, Patents & Royalties. Gurney:Celgene: Employment, Equity Ownership. Cairo:Celgene: Research Funding.

Monitoring of Minimal Residual Disease before and after Allogeneic Stem Cell Transplantation Childhood ALL - a Retrospective Assessment on Behalf of the PDWP of the EBMT, the COG, PBMTC, the I-BFM and the Westhafen-Intercontinental-Group

▪Objectives: A small number of previous studies have demonstrated prognostic significance of MRD detection before and after allogeneic transplantation in children ALL. A major challenge of studies has been low patient numbers that were insufficient for multivariate analysis and assessment of specific post-transplant time points. To address this, the Westhafen Intercontinental Group (WIG) performed a retrospective analysis to investigate the impact of pre- and post-transplant MRD assessment in children with ALL.Patients and Methods:Patients (pts) treated in Europe (France, Germany, Italy, and Netherlands), North America (COG/PBMTC, Seattle, Minnesota, and Johns Hopkins) and Australia were included. All pts were registered either in local or national trials. Pts were transplantations between 09/99 and 05/16; analysis was performed in 06/16. Altogether 747 pts were included on whom 2960 MRD measurements were performed in bone marrow. MRD prior to transplant was available in 650 pts. MRD was assessed in bone marrow prior to transplant and on days +30, +60, +100, +180, +365 and beyond day +365 post-transplant either by flow cytometry or by RQ-PCR of TCR and IG gene rearrangements.Of these 747 pts, 466 (62%) were male and 281 (38%) were female. Pts received their transplant in CR1 (n=275, 37% ), CR2 (n=410, 55%), >CR3 (n=55, 7%), or non-remission (NR) (n=7, 1%). 586 patients (78%) had pre-B ALL, 145 pts (20%) had T-cell phenotype and 16 pts (2%) had bi-lineage or bi-phenotype AL. Grafts were matched sibling donors (MSD; n=227, 30%), matched unrelated donors (MUD; n=314, 42%), from mismatched donors (MMD, n=75, 10%), cord blood (n=128, 17%) or no data (n=3, 1%). 31 patients (4%) were younger than 2, 365 pts (49%) were ≥2 and ≤ 10, and 351 pts (47%) were older than 10 years at the time of transplant.After MRD assessment, pts were grouped for analysis according to the level of MRD in three groups: pts in whom no MRD was detectable were categorized "MRD negative", pts with MRD <10E-4 (0.01% by flow) were "MRD low positive", and finally pts with MRD ≥10E-4(≥0.01% by flow) as "MRD high positive".Results:The total group of pts showed a 4y-pEFS and a 4y-pOS of 55.0% and 60%; cumulative incidence (CI) of relapse (CIR) and CI of treatment related mortality (CI TRM) were 31% and 13%. The following pre transplant factors did not influence outcome: age, gender, relapse site, cytogenetics, donor, and stem cell source.MRD prior to transplant was available in 648 pts. MRD high, low and negative, patients showed a 4y-pEFS of 37%, 67%, and 62% (p<0.0005). Pts with a high MRD load prior to transplant had a 2.47 fold increased hazard ratio to develop relapse and a 1.67 increased risk to develop TRM (p<0.0005). Multivariate Cox regression analysis revealed that level of pre transplant MRD and remission status at transplant also significantly influenced survival.MRD values post-transplant were analysed as time-dependent covariates. 4y-pEFS at day +30 for MRD high, MRD low and MRD negative pts were: 43%, 65%, and 59%, respectively (p=0.002). At Day +60 for MRD high, low and MRD negative pts: 36%, 47%, and 64%, respectively (p<0.008). At day +90 for MRD high, MRD low and MRD negative pts: 44%, 69%, and 65%, respectively (p<0.003). At day +180 for MRD high, MRD low and MRD negative pts: 12%, 40%, and 79%, respectively. And at day +365 for MRD high, low and MRD negative patients: 25%, 36, and 87% respectively. High MRD at all time points post-transplant led to a higher relapse and an increased TRM rate.There was an interaction between MRD and aGVHD at all time-points investigated after transplantation. At day +30, patients with high MRD had a 2.54 fold increased risk to develop an event which is defined as relapse or TRM, where the risk for high MRD pts with aGVHD was 0.64. This was due to a lower relapse risk compared to MRD positive patients without aGVHD.Summary and Conclusion:This world wide study confirmed in the largest patient population investigated so far, MRD prior to transplant is a powerful predictor for survival after transplant. When analysed either for the different time points or for the highest MRD value post- transplant, MRD results were always significantly associated with pEFS. All pts who showed an MRD load of >10E-4 (0.01% by flow) at any time after transplant had an increased risk. Occurrence of aGVHD in MRD positive pts reduced the risk of relapse. Serial MRD detection after transplantation allows for the prediction of relapse. DisclosuresBader:Medac: Consultancy, Research Funding; Servier: Consultancy, Honoraria; Neovii Biotech: Research Funding; Riemser: Research Funding; Novartis: Consultancy, Honoraria. Verneris:Bimogen: Other: Advisory Board. Borowitz:Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; BD Biosciences: Research Funding; HTG Molecular: Consultancy. Peters:Medac: Consultancy; Novartis: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy. Grupp:Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Pulsipher:Novartis: Consultancy, Other: Study Steering Committee; Jazz Pharmaceutical: Consultancy; Chimerix: Consultancy; Medac: Other: Housing support for conference.

Comparison of Total Body Irradiation-Based with Intravenous Busulfan-Based Chemotherapy-Only Conditioning Regimens for Myeloablative Hematopoietic Cell Transplantation (HCT) in Adults with Acute Lymphoblastic Leukemia

Total body irradiation (TBI)-based conditioning regimens are considered the standard of care for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic cell transplantation (HCT). However, due to concerns regarding acute and long-term toxicities, non-TBI regimens, commonly including busulfan (BU), have been increasingly explored. We performed a retrospective cohort analysis with the hypothesis that there would be equivalence of these two myeloablative approaches by reviewing outcomes for adult patients (pts), aged 18-60 years, undergoing a first, well-matched sibling, related or unrelated donor HCT in CR1 or CR2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005-2014. Eight hundred nineteen pts received TBI (63% 9-12 Gy, 37% ≥13 Gy) combined with etoposide (25%) or cyclophosphamide (Cy) (75%) and 299 pts received intravenous BU combined with a second alkylator Cy (15%) or melphalan (Mel) (13%), or a nucleoside analogue fludarabine (Flu) (41%) or clofarabine (Clo)(30%). The majority of the BU-based pts were treated at the Moffitt or MD Anderson Cancer Center. The BU-based regimens were grouped together for analyses since no significant differences in basic outcomes among the different chemotherapy-only regimens were noted. Patients in the BU-containing group were older but had better performance status, took longer to achieve CR1 and longer to receive HCT; more received peripheral blood than marrow grafts, peri-HCT ATG, pre- and post HCT tyrosine kinase inhibitors ( TKI), and were treated more recently than pts in the TBI-based group (Table 1). With median follow-up of 3.6 years for the BU-based group and 5.3 years for the TBI-based group, adjusted 3 year outcomes showed treatment-related mortality (TRM) BU 19% vs. TBI 25% (p=.04); relapse BU 37% vs. TBI 28% (p=.007); disease-free survival (DFS) Bu 45% vs. TBI 48% (p=.35); and overall survival (OS) BU 57% vs. TBI 53% (p=.35) (Figures A-B). Patients in the BU group had significantly more grade II-IV acute GVHD (47% vs. 40%, p=.025), but marginally less chronic GVHD (49% vs. 55% at 3 years, p=.073). In multivariate analysis, the BU group had a significantly higher rate of acute GVHD after day 50 (RR 1.75, 95% CI 1.19-2.58, p=.004), but marginally less chronic GVHD (RR 0.83, 95% CI 0.68-1.01 p=.059) and higher risk of relapse (RR 1.46, 95% CI 1.15-1.85 p=.002) compared with TBI-based regimens. Despite the observed higher risks of acute GVHD and relapse, BU-based conditioning led to similar TRM, OS, and DFS following HCT for ALL. [Display omitted] [Display omitted] [Display omitted] DisclosuresCiurea:Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Seftel:Otsuka: Research Funding. Pulsipher:Medac: Other: Housing support for conference; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.