Cellulose-Based Laser-Induced Graphene Devices for Electrochemical Monitoring of Bacterial Phenazine Production and Viability.

As an easily disposable substrate with a microporous texture, paper is a well-suited, generic substrate to build analytical devices for studying bacteria. Using a multi-pass lasing process, cellulose-based laser-induced graphene (cLIG) with a sheet resistance of 43.7 ± 2.3 Ωsq-1 is developed and utilized in the fabrication of low-cost and environmentally-friendly paper sensor arrays. Two case studies with Pseudomonas aeruginosa and Escherichia coli demonstrate the practicality of the cLIG sensors for the electrochemical analysis of bacteria. The first study measures the time-dependent profile of phenazines released from both planktonic (up to 60 h) and on-chip-grown (up to 22 h) Pseudomonas aeruginosa cultures. While similarities do exist, marked differences in phenazine production are seen with cells grown directly on cLIG compared to the planktonic culture. Moreover, in planktonic cultures, pyocyanin levels increase early on and plateau around 20 h, while optical density measurements increase monotonically over the duration of testing. The second study monitors the viability and metabolic activity of Escherichia coli using a resazurin-based electrochemical assay. These results demonstrate the utility of cLIG paper sensors as an inexpensive and versatile platform for monitoring bacteria and could enable new opportunities in high-throughput antibiotic susceptibility testing, ecological studies, and biofilm studies.

Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat.

In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number, NCT01243073. N Engl J Med 2015; 373:920-928, DOI: 10.1056/NEJMoa1503479.).

CML Chapter.

The discovery of the tyrosine kinase inhibitor (TKI) imatinib in the early 2000's revolutionized the treatment and prognosis of patients with chronic myeloid leukemia (CML) [Hochhaus et al. in N Engl J Med 376:917-927, 2017]. The treatment of patients with CML has changed dramatically since the approval of imatinib and other TKIs. Before the TKI era, newly diagnosed patients would undergo HLA typing to try to identify a well-matched donor, and then proceed quickly to allogeneic hematopoietic cell transplantation (HCT). With the introduction of imatinib followed a few years later by dasatinib, nilotinib, then bosutinib, treatment approaches changed in a dramatic way. Transplantation is no longer an upfront treatment option for newly diagnosed CML patients, and in fact, it is very rarely used in the management of a patient with CML currently. The management of CML patients has been a model of personalized medicine or targeted therapy that is being emulated in the treatment of many other hematologic malignancies and solid tumors such as lung cancer [Soverini et al. in Mol Cancer 17:49, 2018]. The Philadelphia Chromosome (Ph) which leads to the formation of the BCR-ABL fusion gene and its product the BCR-ABL protein is the cause of CML. With effective targeting of this protein with the available TKIs, the disease is completely controllable if not curable for most patients. Life expectancy for patients with CML is essentially normal. Quality of life becomes an important goal including the potential for pregnancy, and ultimately the chance to discontinue all TKI therapy permanently. The three cases outlined below serve to highlight some of the important issues in the management of patients with CML in the post-TKI era.

Biology and Current Treatment of Myeloproliferative Neoplasms.

The classical myeloproliferative neoplasms (MPN) are characterized by clonal expansion of one or more hematopoietic cell lineages and are driven by mutations that activate constitutive signaling via JAK2 pathway. The criteria for diagnosis have now been defined by the World Health Organization (WHO) and the term MPN as is currently used encompasses the entities of primary myelofibrosis, polycythemia vera, and essential thrombocytosis. There is imperfect correlation between the genotype and disease phenotype in MPN and the latter is determined by a variety of patient factors that are independent of the driver mutation. The disease course in MPN can span decades and accurate risk assessment is critical in the choice of therapy and treatment is largely geared toward prevention of complications and providing symptomatic relief. Although new agents have been approved in recent years, no therapy has been convincingly shown to alter disease progression and allogeneic hematopoietic stem cell transplantation (HCT) remains the only curative therapy known to date.

Growth Kinetics and Atomistic Mechanisms of Native Oxidation of ZrSxSe2-x and MoS2 Crystals.

A thorough understanding of native oxides is essential for designing semiconductor devices. Here, we report a study of the rate and mechanisms of spontaneous oxidation of bulk single crystals of ZrSxSe2-x alloys and MoS2. ZrSxSe2-x alloys oxidize rapidly, and the oxidation rate increases with Se content. Oxidation of basal surfaces is initiated by favorable O2 adsorption and proceeds by a mechanism of Zr-O bond switching, that collapses the van der Waals gaps, and is facilitated by progressive redox transitions of the chalcogen. The rate-limiting process is the formation and out-diffusion of SO2. In contrast, MoS2 basal surfaces are stable due to unfavorable oxygen adsorption. Our results provide insight and quantitative guidance for designing and processing semiconductor devices based on ZrSxSe2-x and MoS2 and identify the atomistic-scale mechanisms of bonding and phase transformations in layered materials with competing anions.

Patterns in Protein Flexibility: A Comparison of NMR "Ensembles", MD Trajectories, and Crystallographic B-Factors.

Proteins are molecular machines requiring flexibility to function. Crystallographic B-factors and Molecular Dynamics (MD) simulations both provide insights into protein flexibility on an atomic scale. Nuclear Magnetic Resonance (NMR) lacks a universally accepted analog of the B-factor. However, a lack of convergence in atomic coordinates in an NMR-based structure calculation also suggests atomic mobility. This paper describes a pattern in the coordinate uncertainties of backbone heavy atoms in NMR-derived structural "ensembles" first noted in the development of FindCore2 (previously called Expanded FindCore: DA Snyder, J Grullon, YJ Huang, R Tejero, GT Montelione, Proteins: Structure, Function, and Bioinformatics 82 (S2), 219-230) and demonstrates that this pattern exists in coordinate variances across MD trajectories but not in crystallographic B-factors. This either suggests that MD trajectories and NMR "ensembles" capture motional behavior of peptide bond units not captured by B-factors or indicates a deficiency common to force fields used in both NMR and MD calculations.

Iron Overload Is Associated with Delayed Engraftment and Increased Nonrelapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation.

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P = .005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P = .025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P = .034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P = .044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.

Outcome of Allogeneic Hematopoietic Cell Transplantation after Venetoclax and Hypomethylating Agent Therapy for Acute Myelogenous Leukemia.

The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML.

Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.

Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT.

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome-positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.

Developing and Monitoring a Standard-of-Care Chimeric Antigen Receptor (CAR) T Cell Clinical Quality and Regulatory Program.

As the world of cellular therapy expands to include immune effector cell (IEC) products such as commercial chimeric antigen receptor (CAR) T cells, quality management (QM) professionals are faced with creating either new IEC stand-alone programs or expand existing hematopoietic cell transplantation (HCT) programs to promote patient safety and be aligned with quality, regulatory, and accreditation requirements. The team professionals at City of Hope (COH) recently expanded the quality HCT program to include IEC products and, in doing so, implemented new regulatory infrastructure while maintaining high quality patient care. At COH, we developed the quality structure of our cellular therapy program through collaborations between quality, regulatory, and CAR T patient care committees, which included physicians and nurse coordinators. To ensure the quality of our program, we monitor data collection and reporting, perform quarterly proactive audits of, for example, outcome analysis, and measure selected end-points for benchmarking purposes. QM professionals play a critical role in the monitoring and evaluation processes and provide guidance on how to implement accreditation requirements and what impact the requirements may have on care management. Here we describe the process by which COH expanded our HCT QM program to include IEC therapy. We share examples of how we developed our overall program structure and other key items such as how we addressed patient care management and accreditation to apprise other programs that wish to create and/or expand existing programs.

Long-Term Outcomes of Patients with Acute Myelogenous Leukemia Treated with Myeloablative Fractionated Total Body Irradiation TBI-Based Conditioning with a Tacrolimus- and Sirolimus-Based Graft-versus-Host Disease Prophylaxis Regimen: 6-Year Follow-Up from a Single Center.

Cyclophosphamide (Cy)/etoposide combined with fractionated total body irradiation (FTBI) or i.v. busulfan (Bu) has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myelogenous leukemia (AML) eligible for a myeloablative conditioning (MAC) regimen. Recent data has suggested that i.v. Bu could be the preferred myeloablative regimen in patients with myeloid malignancies. However, Bu-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here we report long-term survival outcomes of patients with AML receiving FTBI combined with Cy or etoposide before undergoing alloHCT at City of Hope (COH). We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 patients (median age, 41 years; range, 18 to 57 years) with AML in first or second complete remission who underwent alloHCT at COH between 2005 and 2015. Eligible patients received a MAC regimen with FTBI (1320 cGy) and Cy (120 mg/kg) for unrelated donor transplantation or etoposide (60 mg/kg) for related donor transplantation. Graft-versus-host disease (GVHD) prophylaxis was provided with tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60% and nonrelapse mortality was 15%. The GRFS rate was 45% at 1 year and 39% at 2 years. We also describe late metabolic effects and report the cumulative incidence of secondary malignancies (9.5%). Overall, in this young adult patient population, our results compare favorably to chemotherapy-based (i.v. Bu) conditioning regimens without significant long-term toxicity arising from TBI-based regimens.

Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia: A Center for International Blood and Marrow Transplant Research Study.

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, P = .03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.

Protein structure prediction assisted with sparse NMR data in CASP13.

CASP13 has investigated the impact of sparse NMR data on the accuracy of protein structure prediction. NOESY and 15 N-1 H residual dipolar coupling data, typical of that obtained for 15 N,13 C-enriched, perdeuterated proteins up to about 40 kDa, were simulated for 11 CASP13 targets ranging in size from 80 to 326 residues. For several targets, two prediction groups generated models that are more accurate than those produced using baseline methods. Real NMR data collected for a de novo designed protein were also provided to predictors, including one data set in which only backbone resonance assignments were available. Some NMR-assisted prediction groups also did very well with these data. CASP13 also assessed whether incorporation of sparse NMR data improves the accuracy of protein structure prediction relative to nonassisted regular methods. In most cases, incorporation of sparse, noisy NMR data results in models with higher accuracy. The best NMR-assisted models were also compared with the best regular predictions of any CASP13 group for the same target. For six of 13 targets, the most accurate model provided by any NMR-assisted prediction group was more accurate than the most accurate model provided by any regular prediction group; however, for the remaining seven targets, one or more regular prediction method provided a more accurate model than even the best NMR-assisted model. These results suggest a novel approach for protein structure determination, in which advanced prediction methods are first used to generate structural models, and sparse NMR data is then used to validate and/or refine these models.

Post-Allogeneic Hematopoietic Stem Cell Transplantation Eculizumab as Prophylaxis Against Hemolysis and Thrombosis for Patients with Hematologic Disorders Associated with Paroxysmal Nocturnal Hemoglobinuria Clones.

Paroxysmal nocturnal hemoglobinuria (PNH) is frequently seen in the context of other aplastic anemia and myelodysplastic syndromes and is associated with hemolysis and increased thromboembolic events. Allogeneic hematopoietic stem cell transplantation (alloHCT) is the sole curative treatment but is associated with significant morbidity. The terminal complement inhibitor eculizumab reduces hemolysis and thromboembolic events and is the sole Food and Drug Administration-approved therapy for PNH. Prophylactic administration of this agent in the early post-transplantation setting to prevent hemolysis and thrombosis has not been described in the literature. We describe our institutional experience of 8 patients with PNH who underwent alloHCT and who received at least 1 dose of eculizumab within 30 days of alloHCT for prevention of thrombosis and hemolysis. One patient with underlying aplastic anemia who received bone marrow stem cells failed to engraft. Another patient experienced steroid-refractory grade IV acute graft-versus-host disease and died of a fungal infection. The other patients engrafted well; no hemolysis, thrombotic events, or infections associated with encapsulated bacteria occurred in any of the 8 patients.

Late mortality after bone marrow transplant for chronic myelogenous leukemia in the context of prior tyrosine kinase inhibitor exposure: A Blood or Marrow Transplant Survivor Study (BMTSS) report.

BACKGROUND: Late mortality was investigated in patients with chronic myelogenous leukemia (CML) who underwent blood or bone marrow transplant (BMT) with or without prior tyrosine kinase inhibitor (TKI) therapy. METHODS: By using data from the Blood or Marrow Transplant Survivor Study, the authors examined late mortality in 447 patients with CML who underwent BMT between 1974 and 2010, conditional on surviving ≥2 years post-BMT. For vital status information, the medical records, the National Death Index, and the Accurint database were used. Standardized mortality ratios (SMRs) were calculated using general population age-specific, sex-specific, and calendar-specific mortality rates. Kaplan-Meier techniques and Cox regression were used for all-cause mortality analyses. Cumulative incidence and proportional subdistribution hazards models for competing risks were used for cause-specific mortality analyses. RESULTS: The 10-year overall survival rate was 65.7% and 73% for those who underwent transplant with and without pre-BMT exposure to TKI therapy, respectively. Patients who underwent transplant with and without pre-BMT TKI experienced SMRs of 6.4 and 6.4, respectively (P = .8); and the SMRs were 11.6 and 8.1, respectively, for those with high-risk disease (P = .2). Independent predictors of non-CML-related mortality included chronic graft-versus-host disease (hazard ratio [HR], 2.8; 95% CI, 1.8-4.4) and busulfan/cyclophosphamide conditioning (HR, 0.5; 95% CI, 0.3-0.9; reference, total body irradiation/cyclophosphamide conditioning). The 20-year cumulative incidence of CML-related and non-CML-related mortality was 6% and 36%, respectively, for the entire cohort. Both CML-related mortality (HR, 1.0; 95% CI, 0.1-12.6) and non-CML-related mortality (HR, 1.3; 95% CI, 0.6-3.1) were comparable for those with and without pre-BMT TKI therapy. CONCLUSIONS: The similar late mortality experienced by patients with CML who undergo transplantation with or without pre-BMT TKIs suggests that allogeneic BMT can be considered in the context of TKI intolerance or nonadherence. The prevention of post-BMT non-CML-related mortality could favorably affect long-term survival.

Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia.

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, both as first-line therapy and after imatinib intolerance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034/Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034/Dose-optimization). In this largest assessment of patients across the dasatinib clinical trial program (N=2712), pleural effusion developed in 6-9% of patients at risk annually in DASISION, and in 5-15% of patients at risk annually in 034/Dose-optimization. With a minimum follow up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034/Dose-optimization, respectively. A significant risk factor identified for developing pleural effusion by a multivariate analysis was age. We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not. clinicaltrials.gov identifier 00481247; 00123474.