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La melioidosis es una enfermedad infecciosa causada por Burkholderia pseudomallei cuyo diagnóstico clínico puede ser difícil debido a su variada presentación clínica y a las dificultades del diagnóstico microbiológico, por lo cual pueden requerirse técnicas moleculares para su adecuada identificación una vez se sospecha su presencia.Son pocos los antibióticos disponibles para el tratamiento de esta enfermedad y, además, deben usarse durante un tiempo prolongado. Aunque se conoce por ser endémica en Tailandia, Malasia, Singapur, Vietnam y Australia, en Colombia se han reportado algunos pocos casos.Se presenta un caso de melioidosis en la región norte de Colombia, se hace una revisión de las características clínicas y el tratamiento, y se describe la epidemiología local de esta enfermedad.

In the present work, high-resolution molecular stratigraphy technique has been applied to the rock samples from Tumaco-1-ST-P well to investigate vertical variations of the deposited organic matter (O.M.) based on screening parameter and high-resolution biomarkers in both saturate and aromatic fractions in order to establish its origin, organic facies, depositional paleoenvironment, thermal maturity, biodegradation processes and to evaluate the exploratory potential in this frontier forearc basin. The O.M. is immature with a high concentration of biolipids (early diagenesis) and with poor to fair generation potential originated from a type II/III or III kerogen. Original total organic carbon (TOCo) and original hydrocarbon index (HIo) values for each formation and lithology are determined to evaluate the hydrocarbons potential in the basin. n-alkanes, isoprenoids, and tricyclic terpanes suggest an algal/bacterial and terrestrial input deposited on a marine-deltaic shale under oxic to suboxic conditions. The O.M. was deposited on siliciclastic rocks in a marine-continental (transitional) environment, although carbonate rocks were also deposited in the bottom of the column (late Oligocene). The molecular stratigraphic interpretation allows to conclude that organic facies and lithology in Tumaco-1-ST-P are characterized in Cascajal and Tangareal del Mira Fms. (1000–5000 ft) by a marine-deltaic paleoenvironment with an important terrestrial contribution and varying between deltaic plain and prodelta during the late Miocene. At the top of Tumaco Fm (5000–9000 ft) in the late to medium Miocene, the depositional environment was like the marine delta of the Tangareal del Mira Fm, changing to a marine platform environment at 8000 to 10,000 ft depth in the middle to early Miocene. Toward the bottom of the column (10,000–12,000 ft), Tumaco Fm was deposited in the late Oligocene under a marine shelf environment. In the present paper, we propose a modeling approach, based on the evolution of the thermal maturity through the stratigraphic column, that at 17,000 feet depth could exist rocks with O.M. in the hydrocarbon generation window for Tumaco Basin, Colombia.

Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.

Introduction: Dosing patterns of nilotinib (NIL) in chronic phase chronic myelogenous leukemia (CP-CML) patients (Pts) have not been well documented outside of clinical trials. SIMPLICITY (NCT01244750) is an ongoing observational study exploring tyrosine kinase inhibitor (TKI) use in routine clinical practice among CP-CML pts receiving TKIs in the US and Europe since 2010. This analysis reports NIL dosing patterns and explores predictors of dose reductions. A subset analysis focusing on the first-line (1L) approved dose of 300 mg twice daily (BID) will also be presented. Methods: Only SIMPLICITY pts receiving 1L NIL BID (n=349/408) were included. Baseline demographics and dosing patterns (starting dose, dose changes, time to dose reduction, and duration of therapy [DoT]) were analyzed descriptively. Statistical comparisons were made using t-tests, the Mann-Whitney U test for continuous variables, and chi-square for categorical variables. Logistic regression models were used to identify factors associated with dose reductions. Results: Of the 349 pts treated with 1L NIL, 281 (80.5%) started at the standard dose of 300 mg (BID) or the 400 mg (BID) dose for imatinib-resistance/intolerance, and 37 (10.6%) and 31 pts (8.9%) started on 150‒200 mg BID and 450‒800 mg BID. European pts were more likely to start on a dose >400 mg BID than US pts (P400 mg BID than those treated at community practices (PP=.021), but not in pts experiencing baseline fatigue (OR=1.799; P=0.072). Conclusions: Most pts treated with 1L NIL were started on 300 or 400 mg (BID); however, 1 in 4 pts required a dose reduction, most often due to intolerance. Physicians at academic centers were more likely to reduce the NIL dose than those in community practices. DoT with NIL for pts who received a dose reduction was shorter than that for those who did not. These findings will aid clinical decisions on dose optimization and maintaining response, whilst improving the patient quality of life.

Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22–90) and the median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)–naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. Significance: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305

Optimal power flow (OPF) problems are non-convex and large-scale optimization problems with important applications in power networks. This paper proposes the scheduled-asynchronous algorithm to solve a distributed semidefinite programming (SDP) formulation of the OPF problem. In this formulation, every agent seeks to solve a local optimization with its own cost function, physical constraints on its nodal power injection, voltage, and power flow of the lines it is connected to, and decision constraints on variables shared with neighbors to ensure consistency of the obtained solution. In the scheduled-asynchronous algorithm, every pair of connected nodes in the electrical network update their local variables in an alternating fashion. This strategy is asynchronous, in the sense that no clock synchronization is required, and relies on an orientation of the electrical network that prescribes the precise ordering of node updates. We establish the asymptotic convergence properties to the primal-dual optimizer when the orientation is acyclic. Given the dependence of the convergence rate on the network orientation, we also develop a distributed graph coloring algorithm that finds an orientation with diameter at most five for electrical networks with geometric degree distribution. Simulations illustrate our results on various IEEE bus test cases.

BACKGROUND Canonical Janus kinase 2 (JAK2) V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other JAK2 variants of potential clinical relevance. This study was designed to survey JAK2 variants in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) and to determine their contributions to disease pathogenesis. METHODS Next-generation sequencing of the coding region of JAK2 and 27 other genes was performed on bone marrow DNA samples. The study population was classified into 3 cohorts: chronic MPNs only (the MPN cohort); MPNs transformed into AML (the MPN>>AML cohort); and AML only, with MPN>>AML patients excluded (the AML cohort). RESULTS Testing was performed for 2154 patients, and non-V617F/non-exon 12 JAK2 sequence variants were identified in 114 (5.3%). They included 35 unique JAK2 variants across all functional domains. Sixteen of the 114 JAK2 variants occurred without somatic mutations in the remaining 27 genes. JAK2 variants were detected at a higher frequency in the MPN>>AML cohort (15.3%) in comparison with the MPN (4.6%; P

Summary Background Hypomethylating agents, such as decitabine, are the standard of care for older patients with newly diagnosed acute myeloid leukaemia. Single-arm studies have suggested that a 10-day schedule of decitabine cycles leads to better outcomes than the usual 5-day schedule. We compared the efficacy and safety of these two schedules. Methods Eligible patients were aged 60 years or older with acute myeloid leukaemia but unsuitable for intensive chemotherapy (or ClinicalTrials.gov , number NCT01786343 . Findings Between Feb 28, 2013, and April 12, 2018, 71 patients were enrolled. 28 received decitabine for 5 days and 43 for 10 days, and all were assessable for efficacy and safety. The primary endpoint was achieved in similar proportions of patients in the two treatment groups (12 [43%] of 28 in the 5-day schedule group, 95% credible interval 26–60, and 17 [40%] of 43 in the 10-day schedule group, 26–54, p=0·78; difference 3%, −21 to 27). Total follow-up was 38·2 months, during which the median duration of overall survival was 5·5 months (IQR 2·1–11·7) in the 5-day group and 6·0 months (1·9–11·7) in the 10-day group. 1-year overall survival was 25% in both groups. Complete remission, CRp, CRi, and overall survival did not differ between groups when stratified by cytogenetics, de-novo versus secondary or therapy-related acute myeloid leukaemia, or TP53mut status. The most common grade 3–4 adverse events were neutropenic fever (seven patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (five [18%] and 16 [37%], respectively). One patient (4%) died from sepsis in the context of neutropenic fever, infection, and haemorrhage in the 5-day group, and in the 10-day group six patients (14%) died from infection. Early mortality was similar in the two groups. Interpretation In older patients with newly diagnosed acute myeloid leukaemia, efficacy and safety did not differ by the 5-day or the 10-day decitabine schedule. Funding University of Texas MD Anderson Cancer Center and National Cancer Institute Specialized Programs of Research Excellence.

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity. FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.

7004 Background: Asciminib is the first BCR::ABL1 inhibitor to specifically target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL primary analysis, asciminib had superior efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. After a median follow-up of 2.3 years (16.5 months’ additional follow-up since primary analysis), we report efficacy and safety results (cutoff: October 6, 2021). Methods: Eligible pts were adults with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 European LeukemiaNet. Pts were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by major cytogenetic response (MCyR) status (Ph+ metaphases ≤35%) at baseline. The key secondary endpoint was major molecular response (MMR) rate at wk 96. Results: 233 pts were randomized to asciminib (n=157) or BOS (n=76). At cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) pts, respectively; the most common reason for discontinuation was lack of efficacy in 38 (24.2%) and 27 (35.5%) pts, respectively. MMR rate at wk 96 (per ITT) was higher on asciminib (37.6%) than BOS (15.8%). The difference, adjusting for baseline MCyR, was 21.7% (95% CI, 10.5%-33.0%; 2-sided P=.001). More pts on asciminib than BOS, respectively, had BCR::ABL1IS ≤1% (45.1% vs 19.4%) at wk 96. The probability of maintaining MMR and BCR::ABL1IS ≤1% for ≥72 wk was 96.7% (95% CI, 87.4%-99.2%) and 94.6% (95% CI, 86.2%-97.9%), respectively, on asciminib and 92.9% (95% CI, 59.1%-99.0%) and 95.0% (95% CI, 69.5%-99.3%), respectively, on BOS. Median duration of exposure was 103.1 (range, 0.1-201.1) wk on asciminib and 30.5 (range, 1.0-188.3) wk on BOS. Despite the longer duration of asciminib exposure, safety/tolerability of asciminib continued to be better than that of BOS (Table). No new on-treatment deaths were reported since the primary analysis. Most frequent (>10%) grade ≥3 adverse events (AEs) on asciminib vs BOS were thrombocytopenia (22.4%, 9.2%), neutropenia (18.6%, 14.5%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). Conclusions: After >2 years of follow-up, asciminib continued to show superior efficacy and better safety/tolerability vs BOS. Responses were durable, with more pts on asciminib in MMR. Additionally, more pts on asciminib had BCR::ABL1IS ≤1%, a milestone response in later lines associated with improved survival. These results continue to support the use of asciminib as a new CML therapy, with the potential to transform standard of care. Clinical trial information: NCT03106779. [Table: see text]

e19061 Background: The rapid spread of SARS-CoV-2 has elicited an equally rapid development of effective vaccines, leading to a reduction of COVID-19 severity and deaths. There is limited data on COVID-19-related immunity in chronic myeloid leukemia (CML) patients. Methods: SPARTA (SARS2 SeroPrevalence And Respiratory Tract Assessment) is an ongoing observational study for participants age ≥18 years to investigate immunity to SARS-CoV-2 after infection and/or vaccination. We included patients with CML and compared them with a non-cancer group. We collected saliva and peripheral blood to measure antigen levels by RT-PCR and antibodies (secretory IgG antibodies and neutralizing antibodies). Results: From October 1, 2021, to February 4, 2022, we prospectively enrolled 49 participants (23 CML, 26 non-cancer). Most were male (56.5%) in the CML group and female in the control group (61.5%), mean age 56.39 y vs. 51.96 y, respectively, and self-identified as white (87% vs. 76.9%). In the CML group, 11 (47.8%) had ≥1 comorbidities, vs 13 (50%) in the control group. Twenty-one (91.3%) CML patients were receiving tyrosine-kinase inhibitors; 4 (18.2%) non-cancer subjects reported taking any medication. Most participants in both groups had received at least one dose of COVID-19 vaccine (73.9% vs. 73.1%); 100% of CML patients received two doses vs. 84.2% of controls; the CML group had a higher percentage of subjects fully vaccinated (66.7% vs. 25%). The CML group had a lower percentage of patients previously diagnosed with COVID-19 (8.8% vs. 57.7%). However, there was no difference in the detection of SARS-CoV-2 antigen at the time of enrollment (0% vs. 4%). SARS-CoV-2 IgG antibodies were detected in most of the participants regardless of cancer status (78.3% in the CML cohort and 88% in the non-cancer cohort), and neutralizing antibodies were detected in 82.6% and 95.6%, respectively. The two groups had comparable IgG (mean 146.3 Ru/ml vs. 148.9 Ru/ml) and neutralizing (mean 1329.1 ng/ml vs. 1112 ng/ml) antibody levels. Conclusions: Our preliminary data comparing concomitant cohorts with similar socio-demographic characteristics and medical history indicate that a diagnosis of CML did not impact the development of antibodies against SARS-CoV-2. We are conducting continuous analysis of antibodies levels over time to assess the evolution of antibody immunity and functional studies including cellular immunity assessments.[Table: see text]

7049 Background: Efficacy and safety of BOS vs imatinib (IMA) in patients (pts) with newly diagnosed chronic phase CML was assessed in the phase 3 BFORE trial. Here we characterize the safety profile of BOS after 5 yrs follow-up, with a focus on GI, liver, effusion and renal treatment-emergent adverse events (TEAEs). Methods: Pts who received ≥1 dose of BOS (n=268) or IMA (n=265) 400 mg/d in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. Final database lock: June 12, 2020. Results: Median duration of treatment (Tx) was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of BOS- vs IMA-treated pts. Most common newly occurring TEAEs (any grade) after 12 mos were increased lipase (9.0%) with BOS, and diarrhea (8.3%) with IMA. In BOS- vs IMA-treated pts, 25.4% vs 14.3% had AEs leading to permanent Tx discontinuation; the majority discontinued in yr 1 (14.2% vs 10.6%). Most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; yr 1, 4.5%) with BOS vs thrombocytopenia (overall, 1.5%; yr 1, 1.5%) with IMA. GI, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of BOS- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) IMA-treated pts. One grade 5 renal TEAE occurred in the BOS arm and was not considered related to Tx. Cumulative rates per Tx yr are shown in the Table. Most common GI TEAEs were diarrhea (BOS vs IMA: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with BOS, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with IMA. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). GI, liver, effusion and renal TEAEs infrequently led to Tx discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Conclusions: The safety profiles of BOS and IMA in BFORE were distinct, with no new safety signals identified after 5 yrs follow-up. Onset of TEAEs occurred primarily during yr 1 (eg, GI and liver), with an increased incidence of some TEAEs (eg, effusion and renal) in later yrs. Discontinuations due to AEs generally occurred early into Tx, with few due to GI, liver, effusion and renal AEs. These safety results support the use of first-line BOS as a standard of care in pts with CP CML. Clinical trial information: NCT02130557. [Table: see text]

8043 Background: There are considerable outcome disparities among patients with multiple myeloma (MM). African-Americans have higher risk of developing MM, earlier age at diagnosis, and higher mortality compared to Whites. While outcomes have multifactorial socioeconomic etiologies, race and ethnicity (R&E) correlate with genomic ancestry, and any role of genetics should be explored. This requires equitable representation in biological databases like The Cancer Genome Atlas (TCGA). Here, we characterize disparities in MM cases of TCGA and clinical trials (CT). Methods: MM incidence was obtained from North American Association of Central Cancer Registries (NAACCR) for R&E, sex and age ( < 50, 50-64, 65+ years). Race includes White, Black, and Asian, along with Hispanic ethnicity, as TCGA MM is limited to these groups. Genes with oncogenic potential and > 5% mutation were stratified by R&E and age. TCGA MM cases are from USA, Canada, Italy, and Spain. On ClinicalTrials.gov, completed MM CT limited to these countries were identified. Student’s t-test and chi-square test were used to analyze disparities and gene mutations. Kaplan-Meier curve was generated to evaluate survival. Results: TCGA MM representation is in Table, calculated as (demographic TCGA cases divided by total TCGA cases) divided by (demographic incidence divided by total incidence). Race was not reported in 20% of TCGA, 4% of CT, and 3% of NAACCR. Of cases reporting R&E, Hispanics are underrepresented by 26% in TCGA and 47% in CT relative to incidence, Blacks by 22% in TCGA and 41% in CT, and Asians by 40% in TCGA and 10% in CT. Whites are overrepresented, by 8% in TCGA and 7% in CT. More men are in TCGA than women, in all R&E. Less than 25% of patients age < 50 relative to incidence are in TCGA, in all R&E. BCL7A is mutated more in Blacks age < 50 (n = 20, 50%) than Whites (n = 39, 10%) (p < 0.01). FAT4 is mutated in Whites age 65+ (n = 31, 10%) but not Blacks. In all ages, KRAS is mutated more in Blacks than Whites (31-35% vs. 20-25%, p < 0.05). Black patients have lower survival than Whites (p < 0.02). In patients age 65+, KRAS mutation is associated with 10% lower 4.5-year survival. Conclusions: Substantial disparities in Black, Hispanic, women, and age representation exist for MM cases in TCGA and CT. This stratification by R&E and age offers new insight on BCL7A, FAT4, and KRAS mutation in MM. Mutation status is associated with survival in older patients. Equitable demographic representation should be pursued to improve quality of available data and access to medical resources for all populations. [Table: see text]

6531 Background: There are significant inequities in cancer care and outcomes in the United States (US) and worldwide. Race, ethnicity, and sex all define sub-groups affected by these inequities. Randomized controlled trials (RCTs) provide new therapies in cancer care. Many new drugs have been recently approved for the management of lymphoma. We examined whether pivotal clinical trials included populations representative of those affected. Methods: Lymphoma clinical trials were collected from the US Food and Drug Administration (FDA) Databases ‘Oncology (cancer)/Hematologic Malignancies approval notifications’ and ‘Novel Drug Approvals’ between 2011 and 2021. Trials were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature related to the drug approval. Only studies for adult patients were included; one study was excluded due to inconsistencies in the total patients enrolled and the totals by race. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) RCTs were not included. The burden of diseases based on Surveillance, Epidemiology, and End Results (SEER) data was used as a comparison for US participants. Results: Thirty-three pivotal trials were identified from the FDA databases (2011-2021); 18 (54.5%) had available race data on CT.gov or in Primary Literature. Three trials focused on classical Hodgkin’s Lymphoma (cHL) and 15 on Non-Hodgkin’s Lymphoma (NHL). Two of the three trials for cHL with available data for race reported ethnicity data. Only 10 of 15 NHL trials that reported race demographics had available ethnicity data. Table 1 shows trials that had available data for race and ethnicity along with proportions from the SEER data. There was underrepresentation of Blacks and to some extent Hispanics in both cHL and NHL trials. Females were also underrepresented, particularly in NHL trials. Conclusions: There is racial, ethnic, and sex misrepresentation within clinical trials that led to approval of drugs for lymphomas in the US between 2011 and 2021. In addition, there was significant underreporting of racial and ethnic subgroups noted in the clinical trials.[Table: see text]

BACKGROUND The revised 2017 European LeukemiaNet (ELN) classification (ELN-2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as the fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN-2017 in comparison with ELN-2010 in younger patients with AML has not been validated to date. METHODS The authors performed a retrospective study on patients aged

Relapsed/refractory (R/R) Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) and lymphoid blast phase of chronic myeloid leukemia (LBP-CML) have poor outcomes. We designed a phase 1/2 study combining inotuzumab ozogamicin with bosutinib for this patient population. Patients with T315I mutation were excluded. Bosutinib was administered daily at three dose levels (300 mg/d, 400 mg/d, 500 mg/d) in a 3 + 3 design. Inotuzumab ozogamicin was dosed weekly during cycle one, and once every 4 weeks subsequently for a total of six cycles. The primary objective was to determine the safety and the maximum tolerated dose (MTD) of bosutinib in combination with inotuzumab ozogamicin. Eighteen patients were enrolled (Ph-positive ALL, n = 16; LBP-CML, n = 2). The median age was 62 years (range, 19-74) and the median number of prior therapies was one (range, 1-5). Dose limiting toxicities included grade 3 skin rash and bosutinib 400 mg daily was determined as the MTD. The most frequent grade 3/4 treatment-emergent adverse events were thrombocytopenia (60%) and neutropenia (38%). A complete response (CR) / CR with incomplete count recovery (CRi) was achieved in 15/18 (83%) patients; 11/18 (61%) patients achieved negative measurable residual disease by flow cytometry. Complete molecular response was noted in 10/18 (56%) patients. The 30-day mortality was 0%. After a median follow-up of 44 months, the median duration of response and overall survival were 7.7 months and 13.5 months, respectively. Six patients had a subsequent allogeneic stem cell transplant. No patient developed veno-occlusive disease. Inotuzumab ozogamicin with bosutinib was well tolerated in R/R Ph-positive ALL and LBP-CML.

This paper studies the problem of identifying finite-dimensional functional spaces that are close (within a predefined level of accuracy) to being invariant under the application of the Koopman operator. Given a dictionary of functions spanning a finite-dimensional functional space and a set of data snapshots gathered from a potentially nonlinear dynamical system, we define a measure of how close a functional space in the span of the dictionary is to being invariant under the Koopman operator. This measure provides a way of determining the prediction accuracy of the functional space. Given a desired level of accuracy, we propose a numerical algorithm, termed Tunable Symmetric Subspace Decomposition (T-SSD), to find a dictionary of functions with elements in the span of the original dictionary that satisfies it. Starting from the original dictionary, the T-SSD algorithm proceeds by iteratively removing the functions that violate the accuracy bound. We prove that T-SSD converges to a dictionary satisfying the accuracy criteria after a finite number of iterations.

In this letter, we provide a detailed characterization of the equilibria and bifurcations of two-dimensional linear-threshold models. Using the input to the system as the bifurcation parameter, we characterize the location of the admissible equilibria, show that bifurcations can arise only when equilibria lie on the boundary of well-defined regions of the state space, and prove that (codimension-one) bifurcations can only be of three different types: persistent, non-smooth fold, and Hopf. We show how these bifurcations change the qualitative properties of the system trajectories, and how these behaviors resemble prototypical patterns of EEG activity observed before, during, and after seizure events in the human brain. Our findings suggest that low-dimensional linear threshold models can effectively be used to model, analyze, predict, and ultimately regulate the interactions of neuronal populations in the human brain.

Purpose: Breast cancer survivors may experience worse social, physical, and emotional function compared to the general population, although symptoms often improve over time. Data on problems in living can help to improve interventions and supportive care for breast cancer survivors. Symptoms such as fatigue, pain, difficulties with sleep, and sexual problems may have an adverse effect on the quality of life of breast cancer survivors. Methods: We examined problems in living using data from a survey of 164 breast cancer survivors who had completed primary therapy for the disease. Results: A total of 164 women completed the study questions (response rate 16.4%). The mean age of the women was 67 years. Among all participants, 66.7% were white, 29.5% were African-American, and the remainder were of other races. Almost all of the symptoms were more likely to be reported by participants who were < 55 years of age. Other important correlates of symptoms included non-white race, marital status, and having a household income of less than $50,000 per year. Conclusion: The results of this study highlight the need for caregivers to emphasize screening for and discussion of symptoms, including sleep difficulties, fatigue, loss of strength, aches and pains, and muscle or joint stiffness. Of particular concern are younger survivors and those who are African American or low-income.

In an effort to assess our determination to continue transplant activity in Colombia during the Covid-19/pandemic, this study seeks to describe the risk of infection and mortality of transplanted patients versus those on waiting list. Therefore, a descriptive study of SARS-CoV-2/COVID-19 infection in transplant recipients and patients on waiting list was conducted. The data sources were the information systems of the Instituto Nacional de Salud of Colombia: National Donation and Transplant Information System, the National Public Health Surveillance System and the National COVID-19 Data Repository. Characteristics of the patients who tested positive were analyzed and the mortality rate was determined. An RT-PCR test for SARS-CoV-2/COVID-19 was performed in 7% of the transplant recipients included in this study, and 14.8% of them tested positive. Among patients on the waiting list, 15.2% were tested and 16.7% showed positive results. Overall, 1% (84/8,108) of the transplant recipients and 2.5% (74/2,926) of patients on waiting list were infected with SARS-CoV-2/COVID-19. There were no differences in mortality between these groups (p=0.8748). In conclusion, with the data obtained so far, the hospital availability, and the adoption of safety protocols in the institutions, our findings can support the continuity of the transplant activities in this country., HIGHLIGHTS • As on July 31, 2020, a total of 1,011 patients including transplant recipients and those on the organ transplant waiting list were tested for SARS-CoV-2. Confirmed infection was seen in 158 cases • The results as on July 31, 2020 in Colombia indicate a statistically lower incidence of infection in transplant recipients (1.03%) compared to that in patients on the waiting list (2.52%) who were mostly (94.6%) on dialysis, and probably could not adhere to the strict quarantine due to this condition. • The case mortality rate in the study population (transplant recipients and patients on the organ transplant waiting list) was 3 times higher than that in the general population (13.3% and 3.9%, respectively). • There were no statistically significant differences in mortality among transplant recipients and those on the waiting list for transplant (p=0.8980).

Patients with chemotherapy-induced febrile neutropenia (CIFN) may have changes in the pharmacokinetics (PK) compared to patients without malignancies or neutropenia. Those changes in antibiotic PK could lead to negative outcomes for patients if the therapy is not adequately adjusted to this. In this, open-label, non-randomized, prospective, observational, and descriptive study, a PK model of cefepime was developed for patients with hematological neoplasms and post-chemotherapy febrile neutropenia. This study was conducted at a cancer referral center, and study participants were receiving 2 g IV doses of cefepime every 8 h as 30-min infusions. Cefepime PK was well described by a two compartment model with a clearance dependent on a serum creatinine level. Using Monte Carlo simulations, it was shown that continuous infusions of 6g q24h could have a good achievement of PK/PD targets for MIC levels below the resistance cut-off point of Enterobacteriaceae. According to the simulations, it is unnecessary to increase the daily dose of cefepime (above 6 g daily) to increase the probability of target attainment (PTA). Cumulative fraction of response (CFR) using interment dosing was suboptimal for empirical therapy regimens against K. pneumoniae and P. aeruginosa, and continuous infusions could be used in this setting to maximize exposure. Patients with high serum creatinine levels were more likely to achieve predefined PK/PD targets than patients with low levels.

The aim of the study was to describe the microbiology and susceptibility profile of candidemia and to identify the risk factors associated with mortality in Colombia. A cohort of patients was followed for 30 days during 2008 to 2010. Microbiological identification and susceptibility assessments were performed in a reference centre. Demographic, clinical and treatment variables were evaluated for their associations with mortality. A parametric survival regression analysis was used to identify the risk factors associated with mortality. A total of 109 patients with candidemia in four hospitals in Colombia were identified, with a median age of 30 years old. C. parapsilosis was the most frequently identified microorganism (38.5%), the susceptibility of all isolates was high to fluconazole and anidulafungin, except for C. glabrata isolates. The overall mortality was 35.7%, and the risk factors associated with mortality included lack of antifungal treatment (HR 5.5, 95% CI 3.6–11.4), cancer (HR 3.9, 95% CI 2.3–8.0), diabetes (HR 2.5, 95% CI 1.03–6.4), and age (HR 1.13 per every 10 years, 95% CI 1.02–1.24). Catheter removal was associated with a low mortality rate (HR 0.06, 95% CI 0.00–0.49). Prompt antifungal treatment, better glycemic control and catheter removal should be prioritized in the management of candidemia.

Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.

Background: Five-year follow-up of the open-label, phase 3 DASISION study (NCT00481247) demonstrated faster and deeper molecular responses with dasatinib versus imatinib as first-line therapy for CML-CP. NCCN guidelines recommend considering comorbidities when selecting first-line TKI therapy. This exploratory post hoc analysis of DASISION investigates the effect of comorbidities on responses with dasatinib versus imatinib. Design: Patients with newly diagnosed CML-CP were randomized to 100mg dasatinib (n=259) or 400mg imatinib (n=260) QD. Charlson Comorbidity Index (CCI) was retrospectively calculated for each patient at diagnosis; data were retrospectively stratified by CCI categories (2-4, 5-6, and ≥7 [high burden]). Major molecular response (MMR) and MR4.5 were compared between treatments using unstratified Cochran-Mantel-Haenszel tests. Time to response was evaluated using Kaplan-Meier methodology with HRs based on Cox proportional hazards models and P-values from unstratified log-rank tests. Results: Baseline characteristics were mostly balanced between treatments. Fourteen (3%) patients had CCI 2-4, 260 (50%) had 5-6, and 245 (47%) had ≥7. Responses were numerically greater with dasatinib versus imatinib for CCI 2-4 (MMR: 85.7% versus 57.1%, P=0.2542; MR4.5: 71.4% versus 14.3%, P=0.0374) and ≥7 (MMR: 70.8% versus 64.0%, P=0.2552; MR4.5: 45.0% versus 39.2%, P=0.3589), and significantly higher for CCI 5-6 (MMR: 81.1% versus 64.8%, P=0.0033; MR4.5: 42.4% versus 29.7%, P=0.0329). Median time to MMR (months) was significantly shorter with dasatinib than imatinib for CCI 5-6 (15.0 versus 24.0; HR, 1.64; P=0.0006) and ≥7 (12.0 versus 21.4; HR, 1.41; P=0.0279). Grade 3/4 treatment-related adverse events (TRAEs; dasatinib versus imatinib): 0% versus 14% (CCI 2-4), 8% versus 9% (CCI 5-6), 24% versus 13% (CCI ≥7). Frequency of grade 3/4 TRAEs leading to discontinuation was similar: 0% versus 0%, 1% versus 1%, 8% versus 7%. No deaths occurred for CCI 2-4; similar percentage of patients died between treatments for CCI 5-6 and ≥7. Conclusions: Dasatinib was effective across all CCI groups, consistent with previous findings, suggesting that comorbidities do not negatively affect TKI activity. These findings highlight the benefits of first-line dasatinib in patients with CML-CP and elevated comorbidity burden. Funding: Bristol Myers Squibb. Previous presentation: 62nd ASH Annual Meeting, December 5-8, 2020; republished with permission of Elsevier Inc.

An amendment to this paper has been published and can be accessed via the original article.

Introduction: Long-term follow-up (≥4years) demonstrated a low incidence of cardiac and vascular treatment-emergent adverse events (TEAEs) with bosutinib treatment. We evaluated cardiac, vascular, hypertension, and effusion TEAEs after≥7years of follow-up in patients with Philadelphia chromosome–positive (Ph+) leukemia. Methods: This retrospective analysis of a phase I/II study and its ongoing extension study included data from patients with chronic phase chronic myeloid leukemia (CML) treated with bosutinib after resistance/intolerance to imatinib (CP2L) or to imatinib plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after treatment with, at a minimum, imatinib (ADV). Results: In all, 570 patients were treated with bosutinib; median treatment duration was 11.1months (range: 0.03-133.1). The incidence of cardiac, vascular, hypertension, and effusion-related TEAEs was 10.9%, 8.8%, 9.1%, and 13.3%, respectively. Few patients had maximum grade 3-4 TEAEs (cardiac, 3.9%; vascular, 4.0%; hypertension, 3.0%; effusion, 4.6%). Grade 5 TEAEs occurred in the cardiac (0.7%) and vascular (1.8%) clusters only. In years 5-7, fewer than 5% of patients each year had newly occurring cardiac, vascular, hypertension, or effusion TEAEs. The exposure-adjusted TEAE rates (patients with TEAEs/total patient-year) pooled across CP2L, CP3L, and ADV cohorts were as follows: cardiac, 0.044; vascular, 0.035; hypertension, 0.038; and effusion, 0.056, of which, correspondingly, 0.9%, 1.2%, 0%, and 2.1% required treatment discontinuation. Conclusions: The incidence of cardiac, hypertension, vascular, and effusion events was low in patients with Ph+CML resistant or intolerant to prior therapy who were treated with bosutinib.

Glasdegib, in combination with low-dose cytarabine (LDAC), is the first smoothened inhibitor approved for treatment of acute myeloid leukemia. Glasdegib plus LDAC is indicated for patients in whom therapy options are limited, e.g. older patients and those ineligible for intensive chemotherapy due to preexisting comorbidities. This review summarizes the recommendations of a panel of hemato-oncologists regarding the selection of patients best suited for treatment with glasdegib plus LDAC and the management during therapy with this combination. The panel considered the impact of concomitant medications and comorbidities during treatment with glasdegib plus LDAC, and discussed common adverse events (AEs) associated with glasdegib plus LDAC. Management strategies for AEs discussed by the panel included dose modifications, supportive care therapies, and prophylactic treatments. Finally, the panel highlighted the importance of patient communication and education regarding the possible AEs that may occur during treatment.

Background Dasatinib monotherapy has demonstrated modest clinical activity in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP). The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has dramatically improved with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with tyrosine kinase inhibitors (TKIs). Methods The authors reviewed 85 patients (23 with CML-LBP and 62 with newly diagnosed Ph-positive ALL) who received hyper-CVAD plus dasatinib. Results In the CML-LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML-LBP. The BCR-ABL1 transcript was p210 in 22 patients (96%) and p190 in 1 patient (4%). In the Ph-positive ALL cohort, p210 and p190 transcripts were detected in 13 patients (21%) and 48 patients (77%), respectively. Patients with CML-LBP were less likely to achieve deep molecular remission than patients with Ph-positive ALL: the major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). Survival outcomes were similar for CML-LBP and Ph-positive ALL: the 5-year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML-LBP (5-year OS rate, 88% vs 57%; P = .04). In Ph-positive ALL, the outcome was driven by deeper molecular remission: the 5-year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). Conclusions The outcome of CML-LBP has improved with hyper-CVAD plus dasatinib therapy with survival comparable to that of Ph-positive ALL. Further improvement may be achieved with the use of novel TKIs and targeted agents.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038., Open Access funding enabled and organized by Projekt DEAL. This study was funded by Pfizer.

This paper investigates the problem of regulating in real time a linear dynamical system to the solution trajectory of a time-varying constrained convex optimization problem. The proposed feedback controller is based on an adaptation of the saddle-flow dynamics, modified to take into account projections on constraint sets and output-feedback from the plant. We derive sufficient conditions on the tunable parameters of the controller (inherently related to the time-scale separation between plant and controller dynamics) to guarantee exponential and input-to-state stability of the closed-loop system. The analysis is tailored to the case of time-varying strongly convex cost functions and polytopic output constraints. The theoretical results are further validated in a ramp metering control problem in a network of traffic highways.

Chronic myeloid leukemia (CML) represents 15% of newly diagnosed leukemia cases. In the United States, about 9000 new CML cases are diagnosed annually [1]. BCR-ABL1-targeted tyrosine kinase inhibitors (TKIs) have vastly changed the treatment and prognosis of CML. Before the introduction of TKIs, allogeneic hematopoietic stem cell transplantation (SCT) was the only known cure for CML. However, due to the advanced age of most patients with CML, this treatment modality was utilized in a small proportion of patients and mortality remained high. The TKIs have transformed CML into a manageable chronic disease state and have decreased the annual mortality to less than 2%. Thus, the prevalence of CML will continue to increase annually until the annual incidence equals the annual mortality, with an estimated potential plateau prevalence of 300,000–500,000 cases in the United States. There are currently five approved TKIs in the United States and in Europe. These include imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. While imatinib changed the landscape of CML treatment drastically, the low rates of molecular response in addition to the high rates of discontinuation due to adverse effects led to the development of second- and third-generation TKIs. These TKIs are more potent than imatinib, have unique adverse effect profiles, and have activity against different molecular mutations, all of which must be considered when choosing a therapeutic agent. This chapter discusses the second- and third-generation TKIs and their role in CML therapy.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated acute myeloid leukemia (AML) treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next-generation sequencing (NGS) at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1 and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS-mutated patients, pretreatment cohort-level variant allelic frequencies for RAS were higher in nonresponders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i. Significance: Sequential NGS-based mutational analysis at relapse after FLT3i-based therapies showed distinct pathways of secondary resistance between type I and II FLT3i. FLT3 mutations may be lost at relapse after FLT3i-based therapies. Pretreatment RAS/MAPK mutations may also be associated with primary resistance in patients treated with type I FLT3i. See related commentary by Shastri et al., p. 113.

Treatment of acute leukemia has been delivered predominantly in academic and larger leukemia treatment centers with the infrastructure and staff needed to manage patients receiving complex therapeutic regimens and supportive care. However, in recent years, several oral agents and less-myelosuppressive regimens were approved, making it possible for these patients to receive therapy in smaller community hospitals and oncology office practices. In this review, we discuss the optimum community setting, type of patient who can be treated, agents that can be applied, and an appropriate clinical circumstance in which a referral to a tertiary center should be made.

Treatment of acute leukemia with intensive chemotherapy leads to an increased risk of myelosuppression. Luteinizing hormone (LH) blockade improves hematopoietic recovery in mice after radiation or chemotherapy, through protection of the hematopoietic stem cells which express the LH receptor. We hypothesized that LH blockade improves hematopoietic recovery following intensive chemotherapy in patients with leukemia. We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received intensive chemotherapy and leuprolide given for abnormal uterine bleeding prevention or treatment. Given that leuprolide was more commonly administered in younger patients, we performed propensity score matching between the leuprolide (AML N=64; ALL N=49) and control groups (AML N=128; ALL N=98 patients). Patients with AML who received leuprolide had an additional increase of 13.8 x 109/L/year in their platelet count, and a 0.19 x 109/L/year increase in their lymphocyte count after chemotherapy compared to control (P=0.02; P=0.03 respectively). Those with ALL who received leuprolide had an additional increase of 0.37 x 109/L/year in their absolute neutrophil count (P=0.02). In AML, leuprolide was associated with higher long-term hemoglobin levels (P

Extreme gradient boosting methods outperform conventional machine-learning models. Here, we have developed the LEukemia Artificial intelligence Program (LEAP) with the extreme gradient boosting decision tree method for the optimal treatment recommendation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in chronic phase (CML-CP). A cohort of CML-CP patients was randomly divided into training/validation (N = 504) and test cohorts (N = 126). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum TKI treatment was suggested for each patient. The area under the curve in the test cohort was 0.81899.Backward multivariate analysis identified age at diagnosis, the degree of comorbidities, and TKI recommended therapy by the LEAP CML-CP model as independent prognostic factors for overall survival. The bootstrapping method internally validated the association of the LEAP CML-CP recommendation with overall survival as an independent prognostic for overall survival. Selecting treatment according to the LEAP CML-CP personalized recommendations, in this model, is associated with better survival probability compared to treatment with a LEAP CML-CP non-recommended therapy. This approach may pave a way of new era of personalized treatment recommendations for patients with cancer.

Highlights • Shortage of facemask respirators is a challenge during the SARS-CoV-2 pandemic • Decontamination and reuse are valid options for meeting the massive demand • Biocidal efficacy, functioning, and residual toxicity are the aspects to consider • UVGI and VHP seem to be the most promising decontamination methods for respirators, Introduction As has happened in other emerging respiratory pandemics, demand for N95 filtering facemask respirators (FFRs) has far exceeded their manufacturing production and availability in the context of the SARS-CoV-2 pandemic. One of the proposed strategies for mitigating the massive demand for N95 FFRs is their reuse after a process of decontamination that allows the inactivation of any potentially infectious material on their surfaces. This article aims to summarize all of the available evidence on the different decontamination methods that might allow disposable N95 FFRs to be reused, with emphasis on decontamination from SARS-CoV-2. Methods We performed a systematic review of the literature in order to identify studies reporting outcomes of at least one decontamination method for inactivating or removing any potentially infectious material from the surface of N95 FFRs, specifically addressing issues related to reduction of the microbial threat (including SARS-CoV-2 when available), maintaining the function of N95 FFRs and a lack of residual toxicity. Results We identified a total of 14 studies reporting on the different decontamination methods that might allow disposable N95 FFRs to be reused, including small-scale energetic methods and disinfecting solutions/spray/wipes. Among these decontamination methods, ultraviolet germicidal irradiation (UVGI) and vaporized hydrogen peroxide (VHP) seem to be the most promising decontamination methods for N95 FFRs, based on their biocidal efficacy, filtration performance, fitting characteristics, and residual chemical toxicity, as well as other practical aspects such as the equipment required for their implementation and the maximum number of decontamination cycles. Conclusions Although all the methods for the decontamination and reuse of N95 FFRs have advantages and disadvantages, UVGI and VHP seem to be the most promising methods.

This review reflects the presentations and discussion at the 14th post-ASH International Workshop on Chronic Myeloproliferative Malignancies, which took place on the 10th-11th December 2019, immediately after the 61st American Society of Hematology (ASH) Annual Meeting in Orlando, Florida. Rather than present a resume of the proceedings, we address some of the topical translational science research and clinically relevant topics in detail. We consider how recent studies using single-cell genomics and other molecular methods reveal novel aspects of hematopoiesis which in turn raise the possibility of new therapeutic approaches for patients with myeloproliferative neoplasms (MPNs). We discuss how alternative therapies could benefit patients with chronic myeloid leukemia (CML) who develop BCR-ABL1 mutant subclones following ABL1-tyrosine kinase inhibitor therapy (TKIs). In MPNs, we focus on efforts beyond JAK-STAT and the merits of integrating activin receptor ligand traps, interferon-α, and allografting in the current treatment algorithm for patients with myelofibrosis (MF). This article is protected by copyright. All rights reserved.

Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML.The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020.Discontinuation of TKIs.Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR).Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs.In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies.ClinicalTrials.gov Identifier: NCT02269267.

Background Acquisition of additional cytogenetic abnormalities (ACAs) in addition to Philadelphia chromosome is frequently observed in patients with chronic myeloid leukemia (CML) in advanced phase. The presence of core binding factor (CBF) translocations determines the diagnosis of acute myeloid leukemia regardless of blast percentage, and CBF rearrangements are rarely identified as ACAs. Patients and Methods A retrospective chart review of patients with CML who had CBF rearrangement, t(8;21) or inv(16), in Philadelphia chromosome-positive clones was conducted. Additional cases of CML with CBF rearrangements were identified through literature review. Results Between August 1997 and December 2014, we identified 11 patients who had Philadelphia chromosome and CBF rearrangement in the same clones: 1 (9%) with t(8;21) and 10 (91%) with inv(16). Nine (82%) patients were in blast phase, and 2 (18%) in second chronic phase. Four (36%) patients received tyrosine kinase inhibitor monotherapy, 2 (18%) received tyrosine kinase inhibitor and chemotherapy, and 5 (45%) received chemotherapy only. Three (27%) patients achieved complete remission with incomplete count recovery, and 4 (36%) had no response after the initial therapy. Three (27%) patients underwent allogeneic stem cell transplantation. The median event-free survival and overall survival for the 11 patients were 2 months and 6 months, respectively. Literature review identified 14 patients with CML with CBF rearrangement with a median overall survival of 14 months. Conclusion Acquisition of CBF rearrangement in addition to Philadelphia chromosome is a rare phenomenon associated with poor prognosis. CBF rearrangements as ACAs in patients with CML can be considered high-risk features.

PURPOSE: Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths. METHODS: In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place. RESULTS: Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%. CONCLUSION: Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.

Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin, is approved for the treatment of newly-diagnosed CD33 + AML in adults and children ≥ 1 month old, and relapsed or refractory CD33 + AML in adults and children ≥ 2 years old. GO treatment has been associated with an increased risk of hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), especially following hematopoietic stem cell transplantation. Other non-specific serious adverse events (SAEs) associated with GO treatment are myelosuppression, bleeding/thrombocytopenia, infusion-related reaction, and tumor lysis syndrome. This report summarizes an expert panel of physicians’ recommendations for the evaluation and management of SAEs following GO, emphasizing the prevention and management of VOD/SOS.

The recurring translocation t(1;19) (q23;p13) with TCF3-PBX1 rearrangements are uncommon in adult acute lymphoblastic leukemia (ALL), and their prognostic impact remains to be described in the era of modern chemotherapies. We investigated 427 adult patients with newly diagnosed pre-B ALL, 16 (4%) had t(1;19)(q23;p13) at diagnosis. All 16 patients achieved complete remission after induction with intensive chemotherapy, and with a median of 7-year follow-up, 2 relapsed. The 5-year cumulative incidence of relapse and overall survival rates were 14% and 82%, respectively. Our analysis showed that adult patients with t(1;19)(q23;p13) positive ALL had favorable prognosis with intensive chemotherapy regimens.

Background CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML. Methods Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23). Results BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts. Conclusions The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia.