Acute myeloid leukemia: current progress and future directions

Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.Subject terms: Prognosis, Health services     

Incidence and mortality rates of selected infection-related cancers in Puerto Rico and in the United States

Background  

In 2002, 17.8% of the global cancer burden was attributable to infections. This study assessed the age-standardized incidence and mortality rates of stomach, liver, and cervical cancer in Puerto Rico (PR) for the period 1992-2003 and compared them to those of Hispanics (USH), non-Hispanic Whites (NHW), and non-Hispanic Blacks (NHB) in the United States (US).     

Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or without chemotherapy or chemotherapy alone

BACKGROUND: The optimal management of patients with splenic marginal zone lymphoma/marginal zone lymphoma (SMZL) is controversial. The objective of this retrospective study was to compare the outcomes of patients with SMZL who received treatment with rituximab, rituximab plus chemotherapy, or chemotherapy alone. METHODS: The Leukemia Service database was searched for patients with splenic lymphoma who were registered between May 1995 and October 2004. The indications for treatment were the same as those used for patients with chronic lymphocytic leukemia. RESULTS: SMZL was confirmed in 70 patients. The median age was 64 years. The median number of CD20 molecules per cell was 69 x 10(3). Forty-three patients required systemic therapy; rituximab in 26 patients, chemotherapy plus rituximab in 6 patients, and chemotherapy alone in 11 patients. Ten additional patients underwent splenectomy, and 17 patients were in the observation group. The overall response rates were 88% with rituximab, 83% with rituximab plus chemotherapy, and 55% with chemotherapy alone; the 3-year survival rates were 95%, 100%, and 55%, respectively. The 3-year failure-free survival (FFS) rates were 86%, 100%, and 45% in the rituximab, rituximab plus chemotherapy, and chemotherapy alone groups, respectively. Rituximab treatments resulted in longer survival and FFS compared with chemotherapy. Rituximab alone resulted in disappearance of splenomegaly in 92% of patients and normalization of absolute lymphocyte counts. In univariate analysis, younger age and rituximab-based therapy were predictive of longer FFS. CONCLUSIONS: Rituximab with or without chemotherapy was found to have major activity in patients with SMZL. These results may be associated with high levels of cellular CD20 antigen sites. Rituximab should be the treatment of choice, at least in older patients with SMZL who have comorbid diseases.     

The long-term effects of childhood maltreatment experiences on subsequent illicit drug use and drug-related problems in young adulthood

ObjectivesThe objective of this study was to examine the associations between (a) childhood maltreatment (i.e., physical abuse, sexual abuse, and neglect) and subsequent illicit drug use and (b) childhood maltreatment and drug-related problems in young adulthood.MethodsWave 1 and Wave 3 public-use data from the National Longitudinal Study of Adolescent Health were used. Logistic regressions, controlling for adolescent drug use and other important family and peer contextual processes, were estimated to determine the associations between (a) childhood maltreatment experiences and subsequent illicit drug use and (b) childhood maltreatment and drug-related problems in young adulthood.ResultsAmong the participants, 31.9% reported some form of childhood maltreatment. Childhood physical abuse was associated with a 37% (OR = 1.37; 95% CI = 1.04, 1.80) increase in illicit drug use during the 30 days prior to the Wave 3 survey, a 48% (OR = 1.48; 95% CI = 1.16, 1.89) increase in illicit drug use during the year prior to the Wave 3 survey, and a 96% (OR = 1.96; 95% CI = 1.40, 2.76) increase in drug-related problems in young adulthood. The latter two associations persisted even after controlling for illicit drug use in adolescence. Neglect among females was associated with a higher likelihood of past year illicit drug use in young adulthood (OR = 1.31; 95% CI = 1.002, 1.71). However, this association was not significant once the effect of illicit drug use in adolescence was statistically controlled for.ConclusionsThe present findings suggest that childhood maltreatment is related to subsequent illicit drug use and drug-related problems in young adulthood and that some of these associations differ by gender. Implications for preventive intervention are discussed.     

Tetracycline compounds with non-antimicrobial organ protective properties: Possible mechanisms of action

Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The first^t of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad-spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the “beneficial” actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline's multiple mechanisms of action as a means to understand their beneficial effects.     

A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase

Imatinib is the single most effective agent in chronic myelogenous leukemia (CML) in blast phase (BP), inducing hematologic responses in 30 - 50% of patients. However, only a few of these are complete (CHR) and durable. Imatinib is synergistic with idarubicin and cytarabine. We administered imatinib 600 mg/day, cytarabine 10 mg/day subcutaneous, and idarubicin 12 mg/m² intravenous every 14 days in 19 patients with CML in myeloid BP. Fourteen patients (74%) achieved a hematologic response: CHR in 9 (47%) (3 with complete and 1 with minor cytogenetic responses) and return to chronic phase (RTC) in 5 (26%). Median duration of response was 10 weeks (range, 2 - 89). Six patients received allogeneic stem cell transplantation: 4 CHR, 1 chronic phase and 1 BP. Median survival was 5 months (range, 2 - 20 months). This outpatient regimen is effective and well tolerated and perhaps superior to single-agent imatinib for patients in myeloid BP.     

Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia

BACKGROUND: Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP). METHODS: Patients received decitabine 15 mg/m(2) intravenously daily, 5 days a week for 2 weeks, and imatinib 600 mg orally daily. Global DNA methylation was measured by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing. RESULTS: Twenty-eight patients were enrolled (25 with imatinib resistance; 18 in AP, 10 in BP). A total of 91 cycles (median, 2.5 cycles per patient) was administered. Complete hematologic responses, partial hematologic responses, and hematologic improvement were observed in 9 (32%), 1 (4%), and 2 (7%) patients. Major and minor cytogenetic responses were observed in 5 (18%) and 3 (11%) patients. The hematologic response rate was higher in patients without BCR-ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%). Median duration of hematologic response was 18 (range, 4 to 107+) weeks. Myelosuppression was the major adverse effect, with neutropenic fever in 9 patients (32%). LINE methylation decreased from 71.6% +/- 0.9% (mean +/- standard error of the mean) to 60.4% +/- 2.0% on Day 5, 60.5% +/- 1.8% on Day 12, and returned to 68.8% +/- 1.4% at peripheral blood recovery. A decrease in LINE methylation tended to be greater in nonresponders than in responders on Days 5 and 12. CONCLUSIONS: Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations.