Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.

A Novel Type of Monocytic Leukemia Stem Cell Revealed by the Clinical Use of Venetoclax-Based Therapy.

The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens. SIGNIFICANCE: These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass. This article is featured in Selected Articles from This Issue, p. 1949.

Venetoclax is safe and tolerable as post-transplant maintenance therapy for AML patients at high risk for relapse.

Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among high relapse risk patients. Between February 2019 and December 2021, we administered post-SCT ven maintenance to 49 AML patients at high-risk for relapse as a prospectively defined off-label practice at our institution. Ven was planned to be administered until 1-year post-SCT. While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively. Our experience demonstrates single agent ven is a safe, tolerable, and feasible maintenance therapy that may improve RFS and OS in high relapse risk post-SCT patients.

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia.

Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: i) higher doses of venetoclax are tolerable and more effective, and ii) azacitidine can be discontinued after deep remissions. Forty-two newly diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine+Venetoclax (HiDDAV) Study (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital polymerase chain recation. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400 mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.

Machine Learning-Based Exploratory Clinical Decision Support for Newly Diagnosed Patients With Acute Myeloid Leukemia Treated With 7 + 3 Type Chemotherapy or Venetoclax/Azacitidine.

PURPOSE: There are currently limited objective criteria to help assist physicians in determining whether an individual patient with acute myeloid leukemia (AML) is likely to do better with induction with either standard 7 + 3 chemotherapy or targeted therapy with venetoclax plus azacitidine. The study goal was to address this need by developing exploratory clinical decision support methods. PATIENTS AND METHODS: Univariable and multivariable analysis as well as comparison of a range of machine learning (ML) predictors were performed using cohorts of 120 newly diagnosed 7 + 3-treated AML patients compared with 101 venetoclax plus azacitidine-treated patients. RESULTS: A variety of features in the two patient cohorts were identified that may potentially correlate with short- and long-term outcomes, toxicities, and other considerations. A subset of these diagnostic features was then used to develop ML-based predictors with relatively high areas under the curve of short- and long-term outcomes, hospital stays, transfusion requirements, and toxicities for individual patients treated with either venetoclax/azacitidine or 7 + 3. CONCLUSION: Potential ML-based approaches to clinical decision support to help guide individual patients with newly diagnosed AML to either 7 + 3 or venetoclax plus azacitidine induction therapy were identified. Larger cohorts with separate test and validation studies are necessary to confirm these initial findings.

Atraumatic Splenic Rupture due to Chronic Myelomonocytic Leukemia Treated with Partial Splenic Artery Embolization.

Splenic rupture can be categorized into two groups: traumatic and atraumatic. Traumatic rupture is frequently associated with blunt abdominal trauma, while atraumatic splenic rupture (ASR) is more uncommon and has been associated with both benign and malignant hematological disorders. In general, most cases of splenic rupture are managed with splenectomy, which carries significant mortality and morbidity; more recently, splenic artery embolization (SAE) has become a mainstay of management particularly after traumatic rupture. We describe a patient with chronic myelomonocytic leukemia (CMML) who presented to the emergency department for acute abdominal pain and was found to have an ASR. He underwent partial SAE, with postoperative complications of leukocytosis and tumor lysis syndrome (TLS) requiring rasburicase and allopurinol. On follow-up in clinic 2 months post-discharge, the patient was doing well on hydroxyurea, without need for further intervention at that time. In patients with hematologic malignancies presenting with abdominal pain and splenomegaly, it is important to consider ASR as a rare, but possible complication. To our knowledge, this is the only reported patient treated with SAE in the context of ASR from CMML, demonstrating that SAE can be an effective nonoperative strategy for treatment of CMML-associated ASR. This case report also highlights postoperative complications and management in this patient population, specifically a profound leukocytosis and TLS, for which close monitoring should be performed.

The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation.

Acute myeloid leukemia (AML) is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter gene SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione, and multiple tricarboxylic acid (TCA) cycle metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, which binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed patients and patients who have experienced relapse while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells.

Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia.

Venetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.

The propriety of upgrading responses to venetoclax + azacitidine in newly diagnosed patients with acute myeloid leukemia.

Widely-used response criteria, conditional upon count recovery, were developed for acute myeloid leukemia (AML) in the context of intensive chemotherapy (IC). Extending these definitions to continuously-administered venetoclax-based therapies might underestimate responses. Best practices for venetoclax-based therapies mandate interruption after an end-of-cycle 1 bone marrow biopsy shows morphologic remission with cytopenias. We analyzed 435 patients with newly-diagnosed AML and follow-up response assessments. Of the 101 who responded to venetoclax + azacitidine, overall survival for patients whose response was upgraded due to count recovery during a 14-day post-disease assessment period, from complete remission (CR) with incomplete recovery of blood counts to CR, was not different compared to patients who did not need the 14-day period for count recovery. These results were distinct from 138 IC patients. Although sample sizes for the comparison groups were small, and conclusions are exploratory and must be verified, these findings support consideration of new response criteria for venetoclax-based regimens.

The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG.

Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties and also contribute to systemic changes that influence physiologic responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via upregulating expression of endothelial lipase in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid-mediated pathways, but also promotes survival by stabilizing antiapoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event that further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge. SIGNIFICANCE: The studies presented herein demonstrate that the liver provides a microenvironment in which leukemia cells acquire unique metabolic properties. The adaptations that occur in the liver confer increased resistance to chemotherapy. Therefore, we propose that therapies designed to overcome liver-specific metabolic changes will yield improved outcomes for patients with leukemia.This article is highlighted in the In This Issue feature, p. 211.

Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells.

We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.

Perinatal exposure to octabromodiphenyl ether mixture, DE-79, alters the vasopressinergic system in adult rats.

Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants considered as neurotoxicants and endocrine disruptors with important biological effects ranging from alterations in growth, reproduction, and effects on the hypothalamus-pituitary-adrenal axis. The vasopressinergic (AVPergic) system is a known target for pentaBDEs mixture (DE-71) and the structurally similar chemicals, polychlorinated biphenyls. However, the potential adverse effects of mixtures containing octaBDE compounds, like DE-79, on the AVPergic system are still unknown. The present study aims to examine the effects of perinatal DE-79 exposure on the AVPergic system. Dams were dosed from gestational day 6 to postnatal day 21 at doses of 0 (control), 1.7 (low) or 10.2 (high) mg/kg/day, and male offspring from all doses at 3-months-old were subjected to normosmotic and hyperosmotic challenge. Male offspring where later assessed for alterations in osmoregulation (i.e. serum osmolality and systemic vasopressin release), and both vasopressin immunoreactivity (AVP-IR) and gene expression in the hypothalamic paraventricular and supraoptic nuclei. Additionally, to elucidate a possible mechanism for the effects of DE-79 on the AVPergic system, both neuronal nitric oxide synthase immunoreactivity (nNOS-IR) and mRNA expression were investigated in the same hypothalamic nuclei. The results showed that perinatal DE-79 exposure AVP-IR, mRNA expression and systemic release in adulthood under normosmotic conditions and more evidently under hyperosmotic stimulation. nNOS-IR and mRNA expression were also affected in the same nuclei. Since NO is an AVP regulator, we propose that disturbances in NO could be a mechanism underlying the AVPergic system disruption following perinatal DE-79 exposure leading to osmoregulation deficits.

Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia.

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

Venetoclax for AML: changing the treatment paradigm.

Venetoclax is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore activation of apoptosis in malignancies, the survival of which depends on dysregulation of this pathway. Preclinical data, using various model systems including cell lines and patient samples, suggested targeting BCL-2 could be a successful therapeutic strategy in patients with acute myeloid leukemia (AML). As predicted by this work, the use of venetoclax in the clinical setting has resulted in promising outcomes for patients with this disease. Although venetoclax showed limited activity as a single agent in the relapsed disease setting, recent studies have shown that when combined with a backbone therapy of a hypomethylating agent or low-dose cytarabine, high response rates with encouraging remission durations for older patients with newly diagnosed AML who were not candidates for intensive induction chemotherapy were observed. Furthermore, venetoclax-based therapies allowed for rapid responses and were able to effectively target the leukemia stem cell population. Here we review the preclinical data that supported the development of venetoclax in AML, as well as the results of the promising clinical trials.

First Case of Acquired Hemophilia B in a Patient with HIV Infection: Case Report and Literature Review.

Acquired hemophilia B is a rare bleeding disorder in which circulating specific antibodies inhibit the coagulation factors. Usually, it is associated with autoimmune diseases, malignancy and some infections such as hepatitis B (HBV) and C (HCV) viruses. The association with the human immunodeficiency virus (HIV) is rare. We present the first case of hemophilia B acquired in a patient with HIV. A 36-year-old woman with a history of HIV infection stage 3 acquired immunodeficiency syndrome (AIDS) (CDC 2014) and glomerulopathy secondary to HIV. She consulted for subacute non-dysenteric diarrhea. During her hospitalization, bacteremia by methicillin-sensitive Staphylococcus aureus (S.aureus) was documented, requiring hemodialysis catheter replacement with profuse bleeding during the procedure. The coagulation tests showed prolonged activated partial thromboplastin time (aPTT), normal prothrombin time (PT), mixing test with Rosner index: 8.8%, negative lupus anticoagulant, and specific tests for normal factor VIII and XI. The activity of factor IX was <50% and the inhibitor was increased, which confirms the diagnosis of hemophilia B. Acquired hemophilia B in a patient with HIV infection is not a frequent association; it should be suspected in the context of bleeding with prolonged aPTT.

Targeting the IDH2 Pathway in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. A large percentage of patients succumb to this disease in spite of aggressive treatments with chemotherapy. Recent advances with mutational analysis led to the discovery of isocitrate dehydrogenase (IDH) mutations in AML. IDH2 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate; its mutated version leads to the accumulation of the oncometabolite (R)-2 hydroxyglutarate, which disrupts several cell processes and leads to a blockage in differentiation. Targeting IDH2 is compelling, as it is an early and stable mutation in AML. Enasidenib, a specific small-molecule inhibitor of IDH2, recently gained FDA approval for the treatment of patients with relapsed/refractory IDH2-mutated AML. In this review, we will focus on the indications and efficacy of enasidenib in the treatment of patients with IDH2-mutated AML. Clin Cancer Res; 24(20); 4931-6. ©2018 AACR.

Nuclear Factor, Erythroid 2-Like 2 Regulates Expression of Type 3 Inositol 1,4,5-Trisphosphate Receptor and Calcium Signaling in Cholangiocytes.

BACKGROUND & AIMS: Most cholestatic disorders are caused by defects in cholangiocytes. The type 3 isoform of the inositol 1,4,5-trisphosphate receptor (ITPR3) is the most abundant intracellular calcium release channel in cholangiocytes. ITPR3 is required for bicarbonate secretion by bile ducts, and its expression is reduced in intrahepatic bile ducts of patients with cholestatic disorders. We investigated whether the nuclear factor, erythroid 2-like 2 (NFE2L2 or NRF2), which is sensitive to oxidative stress, regulates expression of ITPR3. METHODS: The activity of the ITPR3 promoter was measured in normal human cholangiocyte (NHC) cells and primary mouse cholangiocytes. Levels of ITPR3 protein and messenger RNA were examined by immunoblot and polymerase chain reaction analyses, respectively. ITPR3 activity was determined by measuring calcium signaling in normal human cholangiocyte cells and secretion in isolated bile duct units. Levels of NRF2 were measured in liver tissues from rats with cholestasis (induced by administration of α-napthylisothiocyanate) and from patients with biliary diseases. RESULTS: We identified a musculo-aponeurotic fibrosarcoma recognition element in the promoter of ITPR3 that bound NRF2 directly in NHC cells and mouse cholangiocytes. Increasing binding of NRF2 at this site resulted in chromatin remodeling that reduced promoter activity. Mutant forms of the musculo-aponeurotic fibrosarcoma recognition element did not bind NRF2. Activation of NRF2 with quercetin or by oxidative stress reduced expression of ITPR3 and calcium signaling in NHC cells; quercetin also reduced secretion by bile duct units isolated from rats. Knockdown of NRF2 with small interfering RNAs restored expression and function of ITPR3 in NHC cells incubated with quercetin. Bile ducts from rats with cholestasis and patients with cholangiopathic disorders expressed higher levels of NRF2 and lower levels of ITPR3 than ducts from control rats or patients with other liver disorders. CONCLUSIONS: The transcription factor NRF2 binds to the promoter of ITPR3 to inhibit its expression in cholangiocytes, leading to reduced calcium signaling and bile duct secretion. This could be a mechanism by which oxidative stress inhibits these processes and contributes to cholangiopathies.

[Experiences of bullying in medical residents]. / Experiencias de maltrato y hostigamiento en médicos residentes.

BACKGROUND: Harassment and abuse are forms of persistent intimidating behavior against a person and in medical practice those are accepted and justified at all levels of education and are considered specific to the hospital culture. OBJECTIVE: To identify the frequency of harassment and some factors related to its existence on residents of medical specialties in Mexico City. METHOD: A linear study was carried out in which a total of 260 interns pertaining to the following medical specialties: surgery, internal medicine, gynecology and obstetrics, and pediatrics participated. The study took place in three general hospitals in Mexico City. Two evaluations with Leymann Inventory of Psychological-Terrorization (LIPT-60) with 6 months between assessments were performed. RESULTS: Comparison between the first and second evaluations did not show differences in any of the harassment measurements obtained. Of all residents, 265 (98.5%) claimed to have experienced some type of harassing behavior against them at least once during the previous 6 months, with a 1.4 (±0.5) average intensity, showing no difference between men and women. Women received a higher grade than men on the communication block scale. Harassing behaviors that obtained the highest average values were evident intimidation and occupational discredit. Among all harassment measurements, the specialty of gynecology and obstetrics showed the highest grade. The hospital influenced the reported harassment. CONCLUSIONS: The most common harassing behaviors were occupational discredit, verbal threats, shouting, and mockery. The high frequency of harassment that medical residents experience during their hospital training deserves our attention.

Antecedentes: el hostigamiento y el maltrato son conductas intimidantes persistentes que se ejercen contra una persona; en la práctica médica, son aceptadas y justificadas en todos los niveles de la formación y propias de la cultura hospitalaria. Objetivo: conocer la frecuencia del acoso y algunos factores relacionados en médicos residentes de la Ciudad de México. Material y métodos: estudio longitudinal en el que participaron 260 residentes de las especialidades médicas de cirugía, medicina interna, ginecología y obstetricia y pediatría de tres hospitales generales de la Ciudad de México. Se realizaron dos evaluaciones con seis meses de diferencia utilizando el Leymann Inventory of Psychological-Terrorization (LIPT-60). Resultados: la comparación entre la primera y la segunda aplicación no mostró cambios en ninguna de las medidas de acoso. Del total de residentes, 256 (98.5%) manifestaron haber sufrido por lo menos una conducta de acoso durante los últimos seis meses, con una intensidad promedio de 1.4 (DE ± 0.5), sin diferencias entre hombres y mujeres. Las mujeres calificaron más alto en la escala de bloqueo de la comunicación que los hombres. Las conductas de acoso con promedios más altos fueron la intimidación manifiesta y el desprestigio laboral. La especialidad de ginecología y obstetricia tuvo los puntajes más elevados en todas las medidas de acoso. El hospital influyó sobre los reportes de esta conducta. Conclusiones: las formas de acoso con los puntajes mayores fueron: el demérito del trabajo, amenazas verbales, gritos o ridiculización. La alta frecuencia de acoso dentro de la formación de los médicos residentes amerita atención.