Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab

OBJECTIVE: Zanubrutinib is a highly selective, next-generation Bruton\u27s tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted in significantly improved progression-free survival compared to bendamustine plus rituximab (BR) in adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) without del(17p). The current analysis compared the effects of zanubrutinib versus BR on patients\u27 health-related quality-of-life (HRQoL). METHODS: In the SEQUOIA trial, patient-reported outcomes (PROs) were assessed at baseline and every 12 weeks (3 cycles) using the EORTC QLQ-C30 and EQ-5D-5L. Descriptive analyses were performed on all the questionnaires\u27 scales and a mixed model for repeated measures was performed using the key QLQ-C30 endpoints of global health status/QoL (GHS/QoL), physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting at weeks 12 and 24. RESULTS: Compared with BR-treated patients, those in the zanubrutinib arm experienced greater improvements in HRQoL outcomes at both weeks 12 and 24. By week 24, mean change differences (95% confidence interval) between the arms were significant for GHS/QoL (4.9 [0.9, 9.0]), physical functioning (3.8 [0.8, 6.7]), diarrhea (-6.2 [-10.0, -2.5]), fatigue (-4.5 [-8.9, -0.1]), and nausea/vomiting (-4.5 [-8.9, -0.1]); role functioning (4.8 [-0.2, 9.7]) was marginally better in the zanubrutinib arm and there were no differences in pain symptoms (-0.4 [-4.3, 5.1]) between the arms. CONCLUSIONS: During the first 24 weeks of treatment, zanubrutinib was associated with better HRQoL outcomes in patients with treatment-naive CLL/SLL without del(17p) compared to BR. TRIAL REGISTRATION: The SEQUOIA trial is registered on clinicaltrials.gov as SEQUOIA trial (NCT03336333)

Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy

Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD) is an ultra-rare and aggressive condition that may occur following allogeneic hematopoietic cell transplant (HCT) due to immunosuppression. Approximately half of EBV+ PTLD cases are relapsed or refractory (R/R) to initial rituximab-containing therapy. There are limited treatment options and no standard of care for patients with R/R EBV+ PTLD, and little is known about their treatment history and outcomes. We performed a multinational, multicenter, retrospective chart review of patients with R/R EBV+ PTLD following HCT to describe patients' demographic and disease characteristics, treatment history, and overall survival (OS) from rituximab failure. Among 81 patients who received initial treatment with rituximab as monotherapy (84.0%) or in combination with chemotherapy (16.0%), median time from HCT to PTLD diagnosis was 3.0 months and median OS was 0.7 months. Thirty-six patients received a subsequent line of treatment. The most frequent causes of death were PTLD (56.8%), graft-versus-host disease (13.5%) and treatment-related mortality (10.8%). In multivariate analysis, early PTLD onset and lack of response to initial treatment were associated with mortality. This real-world study demonstrates that the prognosis of patients with R/R EBV+ PTLD following HCT remains poor, highlighting the urgent unmet medical need in this population.ACKNOWLEDGEMENTS. The authors gratefully acknowledge Benedetto Bruno, Federica Cavallo, Paul Chauvet, Sylvain Choquet, Vikas Dharnidharka, Daan Dierickx, Ulrich Jaeger, Charles Herbaux, Howard Huang, Periana Minga, Pietro Merli, Anthea Peters, Loretta Nastoupil, Josea Pérez Simón, John Reitan, Guillermo Rodríguez, Montserrat Rovira, Ahmed Sawas, Francesca Sismondi, Erin Sundaram, Ralph Ulrich Trappe, Jamie Wenke, and Heiner Zimmermann for their assistance with manuscript development. This study was funded by Atara Biotherapeutics. Medical writing assistance was provided by Folabomi Oladosu PhD, and Lee Blackburn MSc, from AMICULUM USA, funded by Atara Biotherapeutics

Outcome of Allogeneic Transplantation for Mature T-cell Lymphomas: Impact of Donor Source and Disease Characteristics

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamidebased haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD-). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD-). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD- cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT

Ultra-deep mutational landscape in chronic lymphocytic leukemia uncovers dynamics of resistance to targeted therapies

BTK inhibitors, Bcl-2 inhibitors, and other targeted therapies have significantly improved the outcomes of patients with chronic lymphocytic leukemia (CLL). With increased survivorship, monitoring disease and deciphering potential mechanisms of resistance to these agents are critical for devising effective treatment strategies. We used duplex sequencing, a technology that enables detection of mutations at ultra-low allelic frequencies, to identify mutations in five genes associated with drug resistance in CLL and followed their evolution in two patients who received multiple targeted therapies and ultimately developed disease progression on pirtobrutinib. In both patients we detected variants that expanded and reached significant cancer cell fractions (CCF). In patient R001, multiple known resistance mutations in both BTK and PLCG2 appeared following progression on zanubrutinib (BTK p.L528W, p.C481S; PLCG2 S707F, L845F, R665W, and D993H). In contrast, patient R002 developed multiple BTK mutations following acalabrutinib treatment, including known resistance mutations p.C481R, p.T474I and p.C481S. We found that pirtobrutinib was able to suppress, but not completely eradicate, BTK p.C481S mutations in both patients, but other resistance mutations such as mutations in PLCG2 and new BTK mutations increased while the patients were receiving pirtobrutinib. For example, BTK p.L528W in patient R001 increased in frequency more than 1,000-fold (from a CCF of 0.02% to 35%), and the CCF in p.T474I in patient R002 increased from 0.03% to 4.2% (more than 100-fold). Our data illuminate the evolutionary dynamics of resistant clones over the patients’ disease course and under selective pressure from different targeted treatments

Childhood trauma fatality and resource allocation in injury control programs in a developing country

BACKGROUND: Only a few studies have addressed the trimodal distribution of childhood trauma fatalities in lesser developed countries. We conducted this study to evaluate pre-hospital, Emergency Department (ED) and in-hospital distribution of childhood injury-related death for each mechanism of injury in Tehran, Iran. This information will be used for the efficient allocation of the limited injury control resources in the city. METHODS: We used Tehran's Legal Medicine Organization (LMO) database. This is the largest and the most complete database that receives information about trauma fatalities from more than 100 small and large hospitals in Tehran. We reviewed all the medical records and legal documents of the deceased registered in LMO from September 1999 to September 2000. Demographic and injury related characteristics of the children 15 years old or younger were extracted from the records. RESULTS: Ten percent of the 4,233 trauma deaths registered in LMO occurred among children 15 years old or younger. Motor vehicle crashes (MVCs) (50%), burns (18%), falls (6%) and poisonings (6%) were the most common mechanisms of unintentional fatal injuries. Prehospital, emergency department and hospital deaths comprised 42%, 20% and 37% of the trauma fatalities, respectively. While, more than 80% of fatal injuries due to poisoning and drowning occurred in prehospital setting, 92% of burn-related fatalities happened after hospital admission. CONCLUSION: Injury prevention is the single most important solution for controlling trauma fatalities due to poisoning and drowning. Improvements in the quality of care in hospitals and intensive care units might substantially alleviate the magnitude of the problem due to burns. Improvements in prehospital and ED care might significantly decrease MVC and falls-related fatalities

Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice.

PURPOSE: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice. EXPERIMENTAL DESIGN: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected. RESULTS: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose. CONCLUSIONS: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety

American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL