Gregory A. Yanik

Background: Bronchiolitis obliterans syndrome (BOS) is a late-onset noninfectious pulmonary complication of allogeneic hematopoietic cell transplant (HCT) that is often diagnosed at an advanced stage with severe lung impairment. Increasing use of HCT for the treatment of hematologic diseases worldwide translates to an increasing burden of BOS, particularly for the community pulmonologist. Early recognition of BOS, which offers the best opportunity to mitigate morbidity and mortality, is hampered by incomplete knowledge of the clinical course and disease process. The goal of this research statement is to survey our current understanding of BOS and to define the research agenda for the early detection of BOS. Methods: We convened a multidisciplinary panel that included community representatives for an in-depth survey of the published literature followed by an online workshop. Results: Major knowledge gaps were identified within interrelated themes of natural history and pathogenesis, risk factors, and the clinical diagnostic approach. Conclusions: This statement reflects the detailed assessment of identified knowledge gaps with associated key research questions, as well as a proposed research road map to stimulate cross-disciplinary collaborations from preclinical to clinical investigations.

Supplementary Data from Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia

Coronavirus disease 2019 (COVID-19) is a heterogeneous clinical condition caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The initial stage of infection occurs at the time of respiratory viral invasion through angiotensin-converting enzyme 2 (ACE2) receptors in alveolar pneumocytes and macrophages. In the second stage of established pulmonary disease without and with hypoxia, viral multiplication and localized inflammation occurs. The third stage COVID-19 is the most severe, characterized by systemic hyperinflammation, acute respiratory distress syndrome (ARDS) and generalized microangiopathy, with significantly elevated biomarkers including IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1α, tumor necrosis factor-α, C-reactive protein, ferritin, D-dimer, von Willebrand factor (vWF) and thrombomodulin (TM). Evidence suggests that endothelial damage and activation play a key role in the pathobiology of the disease, and thus protecting endothelium and reversing endotheliitis may be a key therapeutic goal (Teuwen et al,Nat Rev Immunol2020). Defibrotide (DF), a complex mixture of poly-deoxyribonucleotides extracted from porcine mucosa, modulates expression of thrombogenic and inflammatory mediators produced in response to endothelial cell injury and/or leukocyte activation. DF increases tissue plasminogen activator (t-PA) and TM expression, thereby enhancing the enzymatic activity of plasmin to hydrolyze fibrin clot, while also decreasing vWF and plasminogen activator inhibitor-1 (PAI-1). Platelet adhesion is inhibited via increases in nitric oxide (NO), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) (Falanga A et al,Leukemia 2003). Anti-inflammatory properties via inhibition of p38 MAPK pathway have been demonstrated with DF, attenuating the release of inflammatory mediators including IL-6, thromboxane A2, leukotriene B4, tumor necrosis factor-alpha, and reactive oxygen species (Mitsiades et al,Clin Cancer Res2009). Additionally, DF inhibits both the expression and activity of heparanase, which in turn modulates heparan sulfate, a vital moiety for viral infection (Richardson et al,Blood Adv2018; Koganti et al,Cell Mol Life Sci2020). DF also modulates endothelial cell injury in murine models by down-regulating the expression of endothelial cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), that are critical to leukocyte adhesion and migration, and by increasing the endothelial cell release of anti-inflammatory cytokines, conferring survival benefit (Garcia-Bernal et al,J Cell Mol Med2020). DF is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) complicating stem cell transplantation and has demonstrated efficacy and safety in critically ill patients with multi-organ failure, underpinned by vasculopathy, endotheliitis, immune activation and hemorrhagic risk (Richardson et al,Blood2016). This multi-target and pleiotropic approach makes DF an attractive candidate for the treatment of advanced stage COVID 19 and the systemic endothelial complications underpinning both its pathobiology and ensuing mortality (Figure 1). Various clinical studies in Spain, Italy, Ireland, the UK and USA are underway, with the larger randomized placebo-controlled prospective phase 2 study in Spain (clinicaltrials.gov: NCT04348383) leading in accrual with promising early results, demonstrating safety to date with potential efficacy, as reflected by favorable outcome in a subset of intubated patients as part of an ongoing multi-center trial. Other studies within the group have focused on safety and particularly the therapeutic role of DF in advanced disease, including those patients requiring extracorporeal membrane oxygenation (ECMO) and full dose systemic anticoagulation. These trials include common in-depth biological correlatives, assessing biomarkers including heparanase, inflammatory cytokines, immune cell sub-populations, vWF and soluble TM, as well as other novel markers and pharmacokinetics. In aggregate, these studies will hopefully help demonstrate the effects of DF on the proposed targets in COVID-19 and successfully correlate these effects with improved clinical outcome. Disclosures: Moraleda: Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis, Sandoz, Takeda:Honoraria;Gilead:Honoraria, Other: Travel expenses.Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca:Honoraria;Boehringer Ingelheim and Sanofi:Consultancy;ADC Therapeutics and Rhizen Pharmaceuticals:Research Funding.Jara Rubio:Edwards Lifesciences, Getinge:Honoraria.Diaz-Ricart:Jazz Pharmaceuticals:Honoraria, Research Funding;German Jose Carreras Leukaemia Foundation:Research Funding.Carreras:Jazz Pharmaceuticals:Research Funding, Speakers Bureau;German Jose´ Carreras Leukaemia Foundation:Research Funding.Mo:Celgene/BMS:Membership on an entity's Board of Directors or advisory committees.Cooke:Jazz Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.Soiffer:Be the Match/ National Marrow Donor Program:Membership on an entity's Board of Directors or advisory committees;alexion:Consultancy;Celgene:Membership on an entity's Board of Directors or advisory committees;Juno:Membership on an entity's Board of Directors or advisory committees;Novartis:Consultancy;VOR Biopharma:Consultancy;Mana Therapeutics:Consultancy;Precision Bioscience:Consultancy;Cugene:Consultancy;Rheos Therapeutics:Consultancy;Gilead:Consultancy;Kiadis:Membership on an entity's Board of...

Rationale: “Noninfectious” pulmonary complications are significant causes of morbidity and mortality after allogeneic hematopoietic cell transplant. Early-onset viral reactivations or infections are common after transplant. Whether the first-onset viral infection causes noninfectious pulmonary complications is unknown. Objectives: To determine whether the first-onset viral infection within 100 days after transplant predisposes to development of noninfectious pulmonary complications. Methods: We performed a retrospective review of 738 allogeneic hematopoietic cell transplant patients enrolled from 2005 to 2011. We also established a novel bone marrow transplantation mouse model to test whether herpesviral reactivation after transplant causes organ injury. Measurements and Main Results: First-onset viral infections with human herpesvirus 6 or Epstein-Barr virus within 100 days after transplant increase the risk of developing idiopathic pneumonia syndrome (adjusted hazard ratio [aHR], 5.52; 95% confidence interval [CI], 1.61–18.96; P = 0.007; and aHR, 9.21; 95% CI, 2.63–32.18; P = 0.001, respectively). First infection with human cytomegalovirus increases risk of bronchiolitis obliterans syndrome (aHR, 2.88; 95% CI, 1.50–5.55; P = 0.002) and grade II–IV acute graft-versus-host disease (aHR, 1.59; 95% CI, 1.06–2.39; P = 0.02). Murine roseolovirus, a homolog of human herpesvirus 6, can also be reactivated in the lung and other organs after bone marrow transplantation. Reactivation of murine roseolovirus induced an idiopathic pneumonia syndrome–like phenotype and aggravated acute graft-versus-host disease. Conclusions: First-onset herpesviral infection within 100 days after allogeneic hematopoietic cell transplant increases risk of pulmonary complications. Experimentally reactivating murine roseolovirus causes organ injury similar to phenotypes seen in human transplant recipients.

A semi-quantitative metaiodobenzylguanidine (mIBG) scoring method (Curie scoring, CS) was previously examined in the Children’s Oncology Group (COG) high risk neuroblastoma trial, COG A3973 (A Randomized Study of Purged vs. Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma), with a post-induction CS>2 associated with poor event free survival (EFS). The validation of Curie scoring in an independent data set, High Risk Neuroblastoma1/International Society of Pediatric Oncology European Network (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of mIBG scans obtained from patients that had been prospectively enrolled on SIOPEN/HR-NBL1 was performed. All patients exhibited mIBG avid, International Neuroblastoma Staging System stage 4 neuroblastoma. mIBG scans were evaluated at two time points, diagnosis (n = 345) and post-induction (n = 330), prior to consolidation myeloablative therapy. Scans were evaluated in 10 different anatomic regions, each region scored 0-3 based upon disease extent, with a cumulative Curie score generated. Cut-points for outcome analysis were identified by Youden methodology. Curie scores from patients enrolled on COG A3973 were used for comparison. Results: The optimal cut-point for Curie score at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by Curie score noted [5-year EFS: 43.0 ±5.7 (CS≤12) vs. 21.4 ±3.6% (CS>12), p2 associated with inferior outcome [5-year EFS:39.2 ±4.7% (CS≤2) vs. 16.4 ±4.2% (CS>2), p2 associated with inferior outcome in two independent large, cooperative group trials.

10523 Background: The global ELIANA trial (NCT02435849) evaluates the efficacy and safety of CTL019, a single infusion of genetically modified autologous chimeric antigen receptor–expressing T cells targeting CD19+ cells in pediatric and young adult r/r B-ALL pts. Analyses show a complete response rate of 82% with or without complete blood count recovery ≤ 3 months. A serious adverse event rate of 71% was observed in ≤ 8 weeks of infusion, decreasing to 17% at > 8 weeks (Grupp S, et al. Blood. 2016;128(22) [abstract 221].). This analysis further evaluates the clinical benefit of CTL019. QOL was assessed before and after CTL019 infusion. Methods: Infused pts were 3-23 y/o with CD19+ B-ALL who were chemo refractory, relapsed after allogeneic stem cell transplant (SCT), or otherwise ineligible for SCT. Pts ≥ 8 y completed the Pediatric Quality of Life Inventory (PedsQL) and EuroQol EQ-5D at baseline and following CTL019 infusion. Minimal clinically important differences are estimated to be 4.4 and 7 to 10 for PedsQL and EQ-5D, respectively. Results: 62 of 81 enrolled pts were infused; 56% had relapsed after SCT with median of 3 prior therapies. At interim analysis, 50 pts were treated ≥ 3 months prior to data cutoff and eligible for primary efficacy analysis. A total of 39 pts were ≥ 8 y. Mean PedsQL total and EQ-5D VAS scores, respectively, were 58.4 and 69.4 at baseline. Mean changes from baseline for the PedsQL total and EQ VAS scores, respectively, were 13.9 and 13.7 at month 3 and 12.8 and 10.9 at month 6, supporting clinically meaningful improvements in QOL. Similar trends were observed with each PedsQL subscale. With EQ-5D, the proportions of pts reporting problems with mobility, self-care, usual activities, anxiety/depression, or pain/discomfort were notably decreased at months 3 and 6 compared with baseline. Conclusions: Clinically meaningful improvements in QOL were observed at 3 and 6 months after CTL019 therapy in pediatric and young adult r/r B-ALL pts, including fewer problems in each EQ-5D domain. These results suggest improved QOL after this one-time immunocellular therapy beyond the period of acute toxicities. Clinical trial information: NCT02435849.