Search

Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate that was first evaluated in B-cell lymphomas but was subsequently shown to be highly effective in acute lymphoblastic leukemia (ALL). INO improved response rates and survival in a randomized study in adults with relapsed/refractory B-cell ALL, leading to its regulatory approval in the United States in 2017. While the formal approval for INO is as monotherapy in relapsed/refractory ALL, subsequent studies with INO administered in combination with chemotherapy and/or blinatumomab both in the frontline and salvage settings have yielded promising results. In this review, we discuss the clinical development of INO in ALL, highlighting lessons learned from the initial clinical trials of INO, as well as the many ongoing studies that are seeking to expand the role of INO in ALL. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia/lymphoma (ALL) is the most common pediatric cancer and is a malignancy of T or B lineage lymphoblasts. Dysregulation of intracellular Ca2+ levels has been observed in patients with ALL, leading to improper activation of downstream signaling. Here we describe a new zebrafish model of B ALL, generated by expressing human constitutively active CaMKII (CA-CaMKII) in tp53 mutant lymphocytes. In this model, B cell hyperplasia in the kidney marrow and spleen progresses to overt leukemia/lymphoma, with only 29% of zebrafish surviving the first year of life. Leukemic fish have reduced productive genomic VDJ recombination in addition to reduced expression and improper splicing of ikaros1, a gene often deleted or mutated in patients with B ALL. Inhibiting CaMKII in human pre-B ALL cells induced cell death, further supporting a role for CaMKII in leukemogenesis. This research provides novel insight into the role of Ca2+-directed signaling in lymphoid malignancy and will be useful in understanding disease development and progression. Author summary: Acute lymphoblastic leukemia/lymphoma (ALL) is the most common pediatric cancer, representing approximately 3,000 new cases annually in patients under the age of 20 in the United States. Although survival rates for ALL are approximately 92%, there still remains a subset of cases that have poor outcomes that require novel model systems to understand disease etiology and identify novel targets for drug discovery. Our research identified calcium/calmodulin-dependent protein kinase, CaMKII, as a critical mediator of B cell ALL maturation. We found that zebrafish expressing activated CaMKII on a tp53 mutant background developed B cell ALL, with cancer cells visible in the marrow, spleen, and blood. These fish incorrectly expressed a key gene, ikaros1, which is often mutated or deleted in patients with B cell ALL. We also determined that treating human B ALL cells in culture with a drug targeting CaMKII caused the malignant cells to die. These results identified CaMKII as a key gene in B ALL development and a possible target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis.Methods: This qualitative study utilized in-depth semi-structured interviews. Parents and/or patients within two years of receiving a new acute leukemia diagnosis were asked to reflect upon their family's experiences preceding the patient's diagnosis. Subjects were purposively sampled for maximum variation in race, ethnicity, income, and language. Interviews were analyzed using inductive theory-building and the constant comparative method to understand the process of diagnosis. Chart review was conducted to complement qualitative data.Results: Thirty-two interviews were conducted with a diverse population of English and Spanish speaking participants from two tertiary care pediatric cancer centers. Parents reported feeling frustrated when their intuition conflicted with providers' management decisions. Many felt laboratory testing was not performed soon enough. Additional contributors to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining appointments, and financial disincentives to seek urgent or emergent care. Reports of difficulty obtaining timely appointments and financial concerns were disproportionately raised among low-income Black and Hispanic participants. Comparatively, parents with prior healthcare experiences felt better able to navigate the system and advocate for additional testing at symptom onset.Conclusions: While there are disease-related factors contributing to delays in diagnosis, it is important to recognize there are multiple non-disease-related factors that also contribute to delays. Evidence-based approaches to reduce outcome disparities in pediatric cancer likely need to start in the primary care setting where timeliness of diagnosis can be addressed. [ABSTRACT FROM AUTHOR]

Acute Lymphocytic Leukemia (ALL) is a malignancy that originates from immature lymphoid cells and is clinically established with flow cytometry through disease‐specific markers. Variation between ethnic groups is an epidemiological aspect of ALL. Higher incidence rates have been observed in Latin American patients and ALL in Latinos carries a dismal prognosis. The cell of origin in ALL is derived from immature cells of either the B or T lineage. Most reported data among Latinos either exclusively looks at B cell precursor ALL or do not distinguish between subtypes. We used the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database to delineate the differences in incidence rates of B‐ALL and T‐ALL across ethnic groups in the United States. Data from SEER‐18 was used to compare incidence rates of T‐ALL and B‐ALL. Due to the utilization of cytogenetics and subsequent changes in ICD coding over the years examined the most recent data reported from 2002 to 2017. We compared rates in Non‐Hispanic Whites (NHWs), Latinos, Blacks and Asian‐Pacific Islanders (API). Age‐adjusted incidence rates per 100,000 person‐years were calculated. The incidence rate of B‐ALL in the Latino population was consistently higher than other race/ethnicities throughout the years, ranging from 1.0 per 100,000 in 2002 to 2.5 per 100,000 in 2017. Blacks had the lowest age adjusted incidence rate (AAIR) of B‐ALL overall, with rates approximately one third of those found in Latinos and the highest AAIR of T‐ALL with an AAIR of 0.5 per 100,000. [ABSTRACT FROM AUTHOR]

Background: Hereditary cancer susceptibility syndrome (HCSS) contributes to the cancer predisposition at an early age, therefore, identification of HCSS has found to be crucial for surveillance, managing therapeutic interventions and refer the patients and their families for genetic counselling. The study aimed to identify ALL patients who meet the American College of Medical Genetics (ACMG) criteria and refer them for the genetic testing for HCSS as hereditary leukemia and hematologic malignancy syndrome, and to elucidate the significance of high consanguinity with the prevalence of inherited leukemia in Pakistani population.Methods: A total of 300 acute lymphoblastic leukemia patients were recruited from the Children's Hospital, Lahore, Pakistan from December 2018 to September 2019. A structured self-reporting questionnaire based on family and medical history of the disease was utilized for the data collection.Results: In our cohort, 60.40% of ALL patients were identified to meet ACMG criteria. Among them, a large number of patients (40.65%) solely fulfil the criteria due to the presence of parental consanguinity. However, parental consanguinity showed protective impact on the onset at early age of disease [OD = 0.44 (0.25-0.77), p-value = 0.00] while, a family history of cancer increased the risk of cardiotoxicity [OD = 2.46 (1.15-5.24), p-value = 0.02]. Parental consanguinity shows no significant impact on the family history of cancer and the number of relatives with cancer.Conclusions: More than 50% of the ALL patients were considered the strong candidates' for genetic testing of HCSS in the Pakistani population, and parental consanguinity was the leading criteria fulfilled by the individuals when assessed through ACMG guidelines. Our study suggests revisiting ACMG guidelines, especially for the criterion of parental consanguinity, and formulating the score based criteria based on; genetic research, the toxicology profile, physical features, personal and family history of cancer for the identification of patients for the genetic testing. [ABSTRACT FROM AUTHOR]

Higher incidence and poorer outcomes of acute lymphoblastic leukemia (ALL) in Hispanic Americans have been attributed to high-risk molecular markers associated with Native American (NA) ancestry. However, the diverse Hispanic populations in the United States differ substantially in ancestry. Continental Hispanics have a high proportion of NA ancestry while Caribbean Hispanics have a lower proportion of NA ancestry. Here, we analyzed mortality data of 2428 children and adults with ALL. Mortality rates were age-adjusted and compared by race and ethnicity using negative binomial regression with particular attention to distinct Hispanic populations. While both Continental (mortality rate ratio (MRR) 2.09, 95% CI 1.82–2.39) and Caribbean (MRR 1.27, 95% CI 1.05–1.54) Hispanics had higher mortality rates than other racial and ethnic groups, Continental Hispanics had significantly higher mortality rates than Caribbean Hispanics. This is the first study to demonstrate a clear difference in ALL mortality by Hispanic group on a population basis. [ABSTRACT FROM AUTHOR]

B-cell acute lymphoblastic lymphoma (B-ALL) is a disease found mainly in children and in young adults. B-ALL is characterized by the rapid proliferation of poorly differentiated lymphoid progenitor cells inside the bone marrow. In the United States, ~4,000 of these patients are diagnosed each year, accounting for ~30% of childhood cancer types. The tumorigenesis of the disease involves a number of abnormal gene expressions (including TEL-AML1, BCR-ABL-1, RAS and PI3K) leading to dysregulated cell cycle. Risk factors of B-ALL are the history of parvovirus B 19 infection, high birth weight and exposure to environmental toxins. These risk factors can induce abnormal DNA methylation and DNA damages. Treatment procedures are divided into three phases: Induction, consolidation and maintenance. The goal of treatment is complete remission without relapses. Apart from traditional treatments, newly developed approaches include gene targeting therapy, with the aim of wiping out leukemic cells through the inhibition of mitogen-activated protein kinases and via c-Myb inhibition enhancing sensitivity to chemotherapy. To evaluate the efficacy of ongoing treatments, several indicators are currently used. The indicators include the expression levels of microRNAs (miRs) miR-146a, miR-155, miR-181a and miR-195, and soluble interleukin 2 receptor. Multiple drug resistance and levels of glutathione reductase can affect treatment efficacy through the increased efflux of anti-cancer drugs and weakening the effect of chemotherapy through the reduction of intracellular reactive oxygen species. The present review appraised recent studies on B-ALL regarding its pathogenesis, risk factors, treatments, treatment evaluation and causes of disease relapse. Understanding the mechanisms of B-ALL initiation and causes of treatment failure can help physicians improve disease management and reduce relapses. [ABSTRACT FROM AUTHOR]

Background and Objective: The TOWER and INO-VATE-ALL trials demonstrated the efficacy and safety of blinatumomab and inotuzumab ozogamicin (inotuzumab), respectively, versus standard-of-care (SOC) chemotherapy in adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). The cost effectiveness of blinatumomab versus inotuzumab has not previously been examined.Methods: Cost effectiveness of blinatumomab versus inotuzumab in R/R B-cell precursor ALL patients with one or no prior salvage therapy from a United States (US) payer perspective was estimated using a partitioned survival model. Health outcomes were estimated based on published aggregate data from INO-VATE-ALL and individual patient data from TOWER weighted to match patients in INO-VATE-ALL using matching adjusted indirect comparison (MAIC). Analyses were conducted using five approaches relating to use of anchored versus unanchored comparisons of health outcomes and, for the anchored comparisons, the reference treatment to which treatment effects on health outcomes were applied. Estimates from TOWER including the probabilities of complete remission and allogeneic stem-cell transplant (allo-SCT), overall and event-free survival, utilities, duration of therapy, and use of subsequent therapies were MAIC adjusted to match INO-VATE-ALL. Costs of treatment, adverse events, allo-SCT, subsequent therapies, and terminal care were from published sources. A 50-year time horizon and 3% annual discount rate were used.Results: Incremental costs for blinatumomab versus inotuzumab ranged from US$7023 to US$36,244, depending on the approach used for estimating relative effectiveness. Incremental quality-adjusted life-years (QALYs) ranged from 0.54 to 1.78. Cost effectiveness for blinatumomab versus inotuzumab ranged from US$4006 to US$20,737 per QALY gained.Conclusions: Blinatumomab is estimated to be cost effective versus inotuzumab in R/R B-cell precursor ALL adults who have received one or no prior salvage therapy from a US payer perspective. [ABSTRACT FROM AUTHOR]

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a relatively rare cancer in the United States. The treatment of relapsed or refractory ALL, in adult and pediatric patients, remains a therapeutic challenge. Historically, salvage chemotherapy has been used as a bridge for patients eligible for an allogeneic hematopoietic stem-cell transplant (HSCT), which remains the only known cure for ALL. OBJECTIVE: To review the use of blinatumomab in the treatment of relapsed or refractory B-cell precursor ALL (B-ALL), focusing on its unique mechanism of action, pharmacokinetics, evidence in clinical trials, adverse-event profile, and its ability to bridge to an allogeneic HSCT. DISCUSSION: Blinatumomab uniquely harnesses the patient's own lymphocytes to attack B-ALL. Blinatumomab binds to CD3 to activate the patient's T-lymphocytes and CD19 on B-ALL. Based on the results of phase 2 clinical trial data conducted by Topp and colleagues, in December 2014 the US Food and Drug Administration (FDA) granted accelerated approval for blinatumomab for the treatment of relapsed or refractory Philadelphia chromosome (Ph)-negative B-ALL in adults and pediatric patients. In a follow-up phase 3 clinical trial (the TOWER trial), blinatumomab demonstrated a significant increase in overall survival and event-free survival, as well as in the ability to bridge eligible patients to an allogeneic HSCT versus salvage chemotherapy. In addition, in July 2017 blinatumomab received FDA approval for the treatment of relapsed or refractory Ph-positive B-ALL, based on the results of the phase 2 clinical trial ALCANTARA. Blinatumomab, although generally well-tolerated by patients, with an adverse-event profile different from conventional chemotherapy, has 2 significant warnings in its prescribing information, including the risk for cytokine release syndrome and for neurologic toxicities. CONCLUSION: Blinatumomab represents a significant step forward in the treatment of relapsed or refractory Ph-positive and Ph-negative B-ALL in adults and pediatric patients, as a result of its significant improvement of overall survival and event-free survival versus conventional chemotherapy. Blinatumomab serves as an effective bridge to patients eligible for an allogeneic HSCT. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia (T-ALL) is a curable malignancy in the pediatric population. However, population-level data on its incidence and outcomes among adults is sparse. Using SEER database, we identified 1141 patients aged ≥20 years with pathologically confirmed T-ALL diagnosed between the years 2001 and 2014 and actively followed. Incidence of T-ALL was 0.13 cases/100,000 population with significant variations by age, gender, race, and period. The 5-year overall survival (OS) declined significantly with increasing age (age <40, 51.9%; age 40–59, 37.3%; age 60–79, 19.2%; age ≥80, 0%; p <.001) and varied by race (whites – 45.7%, blacks – 25.1%, others – 40.3%; p <.001). Over time, OS has improved significantly in patients <60 years (2001–2007, 42.8% vs 2008–2014, 53.1%; p =.005), but not in patients older than 60 years (2001–2007, 18% vs 2008–2014, 22.8%; p =.71), highlighting the need for effective and safe treatments in this population. [ABSTRACT FROM AUTHOR]

Through the years gemtuzumab ozogamicin (GO) has moved from a panacea in the treatment of acute myeloid leukemia (AML) to a pariah and back again. Early promise of targeted therapy with accelerated approval in the United States in 2000 gave way to fear over increased toxicity in the absence of efficacy, which subsequently resulted in the drug manufacturer voluntarily withdrawing GO from the market in 2010. We outline the history of GO in terms of initial drug development and early clinical trials that ultimately led the way to GO frontline use in AML based on a series of Phase III studies. Among these studies, we discuss the similarities and differences in terms of dosing, frequency, response rates, and toxicities that ultimately led to the re-approval of GO in 2017 based on efficacy, particularly in patients with core-binding factor (CBF) leukemia. Herein, we also review the clinical efficacy of GO in the frontline treatment of acute promyelocytic leukemia, which is based on either initial patient high-risk disease or potential co-morbidities that preclude the use of arsenic trioxide (ATO). Finally, we assess the current evidence for biomarkers aside from initial cytogenetics that may predict a favorable response to GO. [ABSTRACT FROM AUTHOR]

BACKGROUND: Data suggest that acute leukemia survivors experience moderate to severe distress that does not significantly decline from diagnosis through survivorship. OBJECTIVES: The purpose of this study is to assess acute leukemia survivors' level and source of self-reported distress from active cancer treatment through six months post-treatment. METHODS: A cross-sectional group-comparison design was used. Male (n = 60) and female (n = 40) survivors aged 19-84 years were accrued from a National Cancer Institute-designated cancer center. Patients were sampled at four time points: during induction therapy, at completion, and at three and six months after the end of induction therapy. Distress was self-reported using the Distress Thermometer and its 38-item Problem List (PL). Analysis of variance and chi-square determined relationships among distress scores, PL endorsements, subscale scores, and time groups. FINDINGS: Self-reported distress was elevated for all groups. Highest distress scores were found during induction therapy. [ABSTRACT FROM AUTHOR]

Background: Transfusion of blood products is a key component of the supportive management in patients with acute leukemia (AL). However high-quality trial evidence and clinical outcome data to support specific transfusion goals for blood products for patients with AL remain limited leading to diverse transfusion practices. The primary objective of this study was to determine the spectrum of transfusion patterns in a variety of care settings among providers who treat AL patients.Study Design and Methods: A 31-question survey queried providers caring for AL patients about the existence of institutional guidelines for transfusion of blood products, transfusion triggers for hemoglobin (Hb), platelets (PLTs), and fibrinogen in various settings including inpatient and outpatient and before procedures.Results: We analyzed 130 responses and identified divergent transfusion Hb goals in hospitalized and ambulatory patients, fibrinogen goals for cryoprecipitate transfusions, and variation in practice for use of certain PLTs and red blood cell products. The least variable transfusion patterns were reported for PLT goals in thrombocytopenia and in the setting of invasive procedures such as bone marrow biopsy and lumbar punctures.Conclusions: This survey confirmed wide variations in blood product transfusion practices across several clinical scenarios in patients with AL. The findings emphasized the need for large prospective randomized trials to develop standardized evidence-based guidelines for blood product transfusions in patients with AL with the goal of limiting unnecessary transfusions without compromising outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To determine the risk of venous thromboembolism (VTE), stroke, ischemic heart disease, and myelodysplastic syndrome (MDS) in association with the receipt of colony-stimulating factors (CSFs) and/or erythropoiesis-stimulating agents (ESAs) in women with breast cancer.Methods: We studied 77,233 women with breast cancer aged ≥65 in 1992-2009 from the Surveillance, Epidemiology, and End Results-Medicare linked data with up to 19 years of follow-up.Results: Incidence of VTE increased from 9 cases in women receiving no chemotherapy and no CSFs/ESAs to 22.79 cases per 1,000 person-years in those receiving chemotherapy with CSFs and ESAs. Women with chemotherapy who received both CSFs and ESAs (adjusted hazard ratio and 95 % confidence interval 2.01, 1.80-2.25) or received ESAs without CSFs (2.03, 1.74-2.36) were twice as likely to develop VTE than those receiving no chemotherapy and no CSFs/ESAs, whereas those receiving CSF alone without ESA were 64 % more likely to have VTE (1.64, 1.45-1.85). Risk of MDS was significantly increased by fivefold in patients receiving ESA following chemotherapy.Conclusions: Receipts of CSFs and ESAs were significantly associated with an increased risk of VTE in women with breast cancer. Use of ESAs was significantly associated with substantially increased risks of MDS. These findings support those of previous studies. [ABSTRACT FROM AUTHOR]

Background Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. Patients and methods Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome ( n = 12), or chronic myelomonocytic leukaemia ( n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. Results Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. Conclusions Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML. [ABSTRACT FROM AUTHOR]

Purpose: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. Patients and methods: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. Results: Patients had AML ( n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. Conclusion: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed. [ABSTRACT FROM AUTHOR]

To investigate the risk factors for acute GVHD (aGVHD), based on NIH consensus criteria (NCC), we evaluated 775 patients who underwent allogeneic transplantation. Of them, 346 patients developed aGVHD by NCC, in whom we also analyzed factors affecting aGVHD-specific survival. The cumulative incidence of aGVHD was 44.7%, consisting of classic aGVHD (n=320) and late-onset (n=26). Multivariate analyses revealed that younger age (P=0.015), unrelated donors (P=0.004) and acute leukemia compared with other hematologic malignancies (P=0.005) were significant risk factors for aGVHD, whereas PBSCs showed no association (P=0.720). Multivariate analyses, with only aGVHD patients, revealed that late-onset aGVHD had superior aGVHD-specific survival to classic aGVHD (P=0.044), and identified the association of visceral organ involvement (P=0.002), severity of aGVHD at onset (P=0.035) and advanced disease status (P<0.001) with inferior aGVHD-specific survival. In conclusion, this study demonstrates the risk and prognostic factors for aGVHD by NCC with some differences with the previous reports that were based on old criteria. The difference in the risk factors according to different criteria will give insights about the pathophysiology of GVHD. The better prognosis of late-onset aGVHD than of classic aGVHD raises the necessity for prospective trials with a large cohort focusing on the onset time. [ABSTRACT FROM AUTHOR]

Abstract: Between 1997 and 2002, 16 cases of acute childhood leukemia were diagnosed in children who either lived in Churchill County, Nevada at the time of diagnosis or had lived in the county before their diagnosis. The cases were characterized as a cluster of like illnesses and the probability of having such a cluster occur by chance was estimated to be very small (approximately one in 2.33×108). This suggested that the cluster could be linked to one or more physical, limnological, chemical, or biological agents. This review discusses the setting in which the cluster took place, the epidemiological investigations carried out by the Nevada Bureau of Health Protection Services, the National Center for Environmental Health Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry, and subsequent investigations supported by a special allocation of federal funds through the US Environmental Protection Agency’s Region IX office in San Francisco, CA. This review is meant as background for the papers in this special issue that report results from multi- and interdisciplinary research into environmental and biological factors potentially related to the Churchill County leukemia cluster. [Copyright &y& Elsevier]

Since 2001, the World Health Organization classification for hematopoietic and lymphoid neoplasms has provided a framework for defining acute leukemia (AL) subtypes, although few population-based studies have assessed incidence patterns and patient survival accordingly. We assessed AL incidence rates (IRs), IR ratios (IRRs), and relative survival in the United States (2001-2007) in one of the first population-based, comprehensive assessments. Most subtypes of acute myeloid leukemia (AML) and acute lymphoblastic leukemia/lymphoma (ALL/L) predominated among males, from twice higher incidence of T-cell ALL/L among males than among females (IRR = 2.20) to nearly equal IRs of acute promyelocytic leukemia (APL; IRR = 1.08). Compared with non-Hispanic whites, Hispanics had significantly higher incidence of B-cell ALL/L (IRR = 1.64) and APL (IRR = 1.28); blacks had lower IRs of nearly all AL subtypes. All ALL/L but only some AML subtypes were associated with a bimodal age pattern. Among AML subtypes, survival was highest for APL and AML with inv(16). B-cell ALL/L had more favorable survival than T-cell ALL/L among the young; the converse occurred at older ages. Limitations of cancer registry data must be acknowledged, but the distinct AL incidence and survival patterns based on the World Health Organization classification support biologic diversity that should facilitate etiologic discovery, prognostication, and treatment advances. [ABSTRACT FROM AUTHOR]

The article reports on a population-based comparative study regarding incidences of hematological malignancies between Taiwan and the U.S. It presents several bar-graphs and pie-charts related to hematological malignancies incidences in both the countries. It mentions that according to lymphoid malignancies the incidences of acute lymphoblastic leukemia (ALL) is lower in Taiwan.

The article presents a study which is aimed at identifying predictors of outcome and rates of successful discharge for patients with acute leukemia admitted to intensive care units (ICUs) in the U.S. Accordingly, it analyzes 90 patients with acute leukemia who were admitted to an ICU from 2001 to 2004. It mentions respiratory compromise as the most common reason for ICU transfer for all patients. Meanwhile, it concludes that a diagnosis of acute leukemia should not disquality patients from an ICU admission.

Myelodysplastic syndromes (MDS) are a group of disorders characterized by progressive cytopenias and transformation to acute leukemia. Over the last four years, we have experienced a revolution in the treatment of MDS. Three drugs were approved in the U.S. Two of them, 5-azacitidine and 5-aza-2'-deoxycitidine, induce DNA hypomethylation. The third agent, lenalidomide, is a thalidomide analogue with significant activity in a subset of patients with low-risk MDS, anemia and chromosome 5 alterations. Several other agents are being evaluated in MDS. In this short review, we will summarize our current approach to the therapy of patients with MDS. [ABSTRACT FROM AUTHOR]

Work on one haplotype-mismatched transplants has been proceeding for over 20 years all over the world and novel transplant techniques have been developed. Some centres have focused on the conditioning regimens and post transplant immune suppression; others have concentrated on manipulating the graft. Haploidentical transplant modalities are based mainly on high-intensity conditioning regimen, but reduced intensity regimens have recently been introduced. The graft may be a megadose of extensively T cell-depleted or unmanipulated progenitor cells. Excellent engraftment rates are associated with a very low incidence of GVHD- and regimen-related mortality even in patients who are over 50 years old. Overall, event-free survival and transplant-related mortality compare favourably with reports on transplants from sources of stem cells other than the matched sibling. Improvements will come with successful implementation of strategies to accelerate and strengthen post transplant immune reconstitution as well as transplantation of patients in early stage disease.Bone Marrow Transplantation (2008) 41, 473–481; doi:10.1038/sj.bmt.1705966; published online 7 January 2008 [ABSTRACT FROM AUTHOR]

Gemtuzumab Ozogamicin (GO) is an antibody-targeted chemotherapy agent consisting of the humanized murine CD33 antibody (clone P67.6) to which the calicheamicin-g1 derivative is attached via a hydrolysable bifunctional linker. GO is able to induce apoptosis in vitro in CD33-expressing cells and it has been approved in USA and in Europe as monotherapy for the treatment of elderly patients (older than 60 years) with relapsed acute myeloid leukemia (AML). GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adults AML patients (including also with incomplete platelet recovery). Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimens in adults and children. As for adverse events, veno-occlusive syndrome characterizes its tolerability profile, but GO is comparatively well tolerated by most patients.Oncogene (2007) 26, 3679–3690. doi:10.1038/sj.onc.1210364 [ABSTRACT FROM AUTHOR]

Measurable (minimal) residual disease (MRD) in B-acute lymphoblastic leukemia (B-ALL), as assessed by flow cytometry, is an established prognostic factor used to adjust treatment in most pediatric therapeutic protocols. MRD in B-ALL has been standardized by the Children's Oncology Group in North America and more recently in a multicenter Foundation for the National Institutes of Health-funded study. This article outlines the reagents, instrument setup, and analysis protocols required for the reproducible detection of residual leukemic cells in patients following induction therapy for B-ALL. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Staining and flow cytometry for B-acute lymphoblastic leukemia (B-ALL) measurable residual disease detection Support Protocol: Specimen collection, handling, storage, and shipping Basic Protocol 2: Analysis and interpretation of data for B-ALL measurable residual disease detection Basic Protocol 3: Analysis of samples lacking sufficient CD19+ events., (© 2022 Wiley Periodicals LLC.)

Cyclosporine A (CSA) and methotrexate (MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplantation cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients treated with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myelogenous leukemia. In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2 years compared with CSA/MTX (41.1% versus 21.3%; P = .039). The incidences of day +180 grade II-IV acute GVHD and 2-year chronic GVHD were comparable in the PTCy and CSA/MTX arms (25.2% versus 25.4% [P = .90] and 42.6% versus 42.6% [P = .84], respectively). Similarly, 2-year leukemia-free survival (LFS; 54.4% versus 74.32%; P = .052), overall survival (OS; 70.6% versus 79.7%; P = .15), and GVHD-free relapse-free survival (GRFS; 38.1% versus 52.5%; P = .49) were not statistically different in the 2 arms. Our data show that GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS as seen with conventional CSA/MTX in patients undergoing allo-HCT from an MSD. The higher rate of relapse observed with PTCy needs further evaluation in a prospective study. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to disclose., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The clinical development of antibody–drug conjugates (ADCs) has gained momentum in recent years and these agents are gradually moving into frontline regimens for pediatric acute leukemias. ADCs consist of a monoclonal antibody attached to a cytotoxic payload by a cleavable linker. This structure allows for highly cytotoxic agents to be directly delivered to leukemia cells leading to cell death and avoids excessive off-tumor toxicity. Near universal expression on B-cell acute lymphoblastic leukemia (ALL) blasts and the ability of rapid internalization has rendered CD22 an ideal target for ADC in B-ALL. Inotuzumab ozogamicin, the anti-CD22 antibody linked to calicheamicin led to complete remission rates of 60–80% in patients with relapsed/refractory B-ALL. In acute myeloid leukemia (AML), the CD33 targeting gemtuzumab ozogamicin has demonstrated modest improvements in survival and is the only ADC currently licensed in the United States for pediatric patients with de novo AML. Several other ADCs have been developed and tested clinically for leukemia but have achieved limited success to date. The search for additional leukemia-specific targets and optimization of ADC structure and specificity are ongoing efforts to improve their therapeutic window. This review provides a comprehensive overview of ADCs in acute leukemias, with a focus on pediatric ALL and AML. [ABSTRACT FROM AUTHOR]

Evaluable karyotypes were available in 776 of 1148 adult patients who were entered on acute myeloid leukemia (AML) treatment protocols of the Eastern Cooperative Oncology Group. Among these, we found seven patients (0.9%) with t(9;22)(q34;q11), the Philadelphia (Ph) chromosome, in bone marrow metaphases. All fulfilled the FAB criteria for AML (three M0, two M1, two M2), although one patient presented with an additional, distinct lymphoid blast cell population. Chromosomal aberrations in addition to the Ph chromosome were seen in four patients (including two cases of monosomy 7). Molecular analysis by polymerase chain reaction in four patients tested revealed variable BCR/ABL transcript forms (ela2, b2a2, b3a2, b2a3+ela2). By immunophenotyping, all seven patients were myeloid based on the overall antigen expression pattern. However, all but one demonstrated lymphoid-associated antigens on the myeloid blast cells. The six evaluable patients failed to respond to treatment with a standard anthracycline/cytosine arabinoside-containing regimen. We conclude that the incidence of the Ph chromosome in AML is very low. Although both genotypically and phenotypically heterogenous, Ph chromosome-positive AML, represents a clinically distinct entity with poor outcome. [ABSTRACT FROM AUTHOR]

Discusses the management of acute childhood leukemia in the United States. Chemotherapy; Management of remission; Blood transfusions; Psychotherapy.

Trivalent arsenic [As(III)] is currently approved by the FDA for the treatment of chronic and acute leukemias. However, As(III) has also demonstrated damaging effects on human health, including development of cardiovascular disease, diabetes, and cancer. Further, As(III) is a potent angiogenic agent. In this context, curcumin, an active ingredient in the dietary agent turmeric, has demonstrated potent antiproliferative, antiinflammatory, and antiangiogenic properties. In this report, we have shown that both curcumin and turmeric inhibit expression of vascular endothelial growth factor in HCT-116 human colon cancer cells exposed to As(III). Further, in the chicken chorioallantoic membrane assay model, treatment with low As(III) concentrations results in extensive increase in blood vessel density, which, however, is reduced in the presence of curcumin or turmeric. Collectively, the findings reported here strongly suggest that turmeric and curcumin can dramatically attenuate the process of angiogenesis induced by low As(III) concentrations. [ABSTRACT FROM AUTHOR]

Among 58 black children with leukemia, seven had sickle cell trait and one was homozygous for Hb-S. Both of these rates are similar to those for the black population of the United States in general. The presence of sickle cell trait did not appear to influence the median age of onset, the median survival time, or the quality of survival in black children with acute leukemia. The single patient with sickle cell anemia died a sudden, unexpected death with massive intravascular erythrocytic sickling secondary to viremia while in a leukemic remission. [ABSTRACT FROM AUTHOR]

Examines the transfer of lymphocytes on bone marrow transplantation of patients with acute leukemia in Seattle, Washington District of Columbia. Use of cyclosporin A for the graft control reaction; Influence of allergy to foods on the occurrence of atopic disease; Mechanism of food allergy.

Purpose: To determine the relationship between the receipt of colony-stimulating factors (CSFs) with erythropoiesis-stimulating agents (ESAs) and the risk of developing venous thromboembolism (VTE), stroke, heart disease, and myelodysplastic syndrome (MDS) in patients with colorectal cancer., Methods: We studied 80,925 patients diagnosed with colorectal cancer at age ≥ 65 years in 1992-2009 from the nationwide 16 areas of the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. Cumulative incidence and the time to events Cox hazard regressions were used to explore the risks of outcomes in association with the receipt of CSFs and ESAs., Results: Patients who received chemotherapy (CT) with both CSF and ESA were 58% more likely to develop VTE than those who received CT without CSF and ESA (hazard ratio, 1.58; 95% confidence interval, 1.43-1.76). The risk of stroke appeared to be not associated with the use of CSF and ESA, whereas the risk of heart disease was only significantly elevated in those patients who did not receive CT but received ESA. The risk of acute myeloid leukemia or MDS was significantly increased 4- to 9-fold in patients who received ESA, regardless of receipt of CT or CSF., Conclusion: The use of ESAs was significantly associated with a substantially increased risk of MDS in patients with colorectal cancer. The use of CSFs and ESAs was also significantly associated with a moderately increased risk of VTE and a slightly elevated risk of heart disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) occurs in 2% to 12% of patients with acute leukemia (AL) despite disease- and therapy-associated thrombocytopenia, and it can be associated with significant morbidity and mortality. Because of the few high-quality studies, there are no evidence-based guidelines for VTE prophylaxis in this patient population. We sought to determine the spectrum of practice regarding prevention of VTE in patients with AL during induction and consolidation therapies., Methods: We conducted a 19-question Web-based survey directed at North American providers caring for these patients. One hundred fifty-one of 215 responses received were eligible for analysis, with a response rate of 20.9% among physicians who treated leukemias., Results: Overall, 47% and 45% of providers reported using pharmacologic VTE prophylaxis during induction and consolidation phases, respectively. Approximately 15% of providers did not provide any VTE prophylaxis, while 36% used mechanical methods and ambulation. Among providers who did not recommend pharmacologic prophylaxis, the most commonly cited reasons were the perceived high risk of bleeding (51%), absence of data supporting use (38%), and perceived low risk of VTE (11%)., Conclusion: Large, prospective studies are needed to define the safest and most effective approach to VTE prevention in patients with AL., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome. Methods: 61 index cases with NF1 clinical diagnosis but no identifiable NF1 mutation were screened for SPRED1 mutation. Results: We describe one known SPRED1 mutation (c.190C>T leading to p.Arg64Stop) and four novel mutations (c.637C>T leading to p.Gln213Stop, c.2T>C leading to p.Met1Thr, c.46C>T leading to p.Arg16Stop, and c.1048_1060del leading to p.Gly350fs) in five French families. Their NF1-like phenotype was characterised by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description. However, we did not observe Noonan-like dysmorphy. It is noteworthy that one patient with the p.Arg16Stop mutation developed a monoblastic acute leukaemia. Conclusions: In our series, SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying an NF1-like phenotype. SPRED1 mutated patients did not display any specific dermatologic features that were not present in NF1 patients, except for the absence of neurofibromas that seem to be a specific clinical feature of NF1. The exact phenotypic spectrum and the putative complications of this NF1 overlapping syndrome, in particular haematological malignancies, remain to be further characterised. NIH diagnostic criteria for NF1 must be revised in view of this newly characterised Legius syndrome in order to establish a specific genetic counselling. [ABSTRACT FROM AUTHOR]

The article pays tribute to David W Golde, who was an academic physician and was deeply committed to his patients'care. He was one of the world's leading expert on hairy cell leukemia, on the 'histiocytic disorders' and on unusual diseases such as pulmonary alveolar proteinosis. He also researched acute leukemia, polycythemia vera and other diseases. He was a leader, a mentor, a scientist and a skilled and compassionate clinician. The American Society of Hematology Executive Committee has approved the naming of a clinical research training institute fellowship in his memory.

Focuses on Acute Leukemia Forum 2000 held on March 31, 2000 in San Francisco, California. Effort to expand understanding of the pathogenesis of stem cell in leukemia; Participants of the symposium; Lectures presented in the symposium by medical practitioner Ernest Beutler.

Purpose/objectives: To evaluate the current knowledge of symptoms experienced by adults with acute leukemia (AL) and provide evidence to inform practice and research., Data Sources: Literature review using an electronic search supplemented by a hand search of current literature reporting the physiologic and/or psychological symptoms of patients with AL was conducted., Data Synthesis: Because of the variability found in the methods and specific aims of the articles, a rating system was applied to score how strongly the findings contributed to meeting the aims of the research. This rating system was applied to assist the authors in analyzing the findings. Therefore, the articles that scored lower ultimately contributed less during the analysis phase., Conclusions: Knowledge regarding the symptoms experienced by adults undergoing treatment is being slowly evaluated. However, to better understand and subsequently manage these symptoms, longitudinal research examining the symptom trajectories in this population is needed., Implications for Nursing: Additional investigation into symptom characteristics will facilitate the development of tailored interventions to manage the temporal characteristics of symptoms for this population.