RESUMEN
CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.
Asunto(s)
Leucemia Neutrofílica Crónica , Mutación , Receptores del Factor Estimulante de Colonias , Humanos , Receptores del Factor Estimulante de Colonias/genética , Masculino , Persona de Mediana Edad , Femenino , Anciano , Leucemia Neutrofílica Crónica/genética , Leucemia Neutrofílica Crónica/patología , Estudios Retrospectivos , Adulto , Adulto Joven , Anciano de 80 o más Años , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Análisis Mutacional de ADN , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Predisposición Genética a la Enfermedad , Biomarcadores de Tumor/genética , FenotipoRESUMEN
We report a series of patients with CSF3R-mutant (CSF3Rmut) atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL) or other hematologic malignancies. We included 25 patients: 5 aCML and 4 CNL CSF3Rmut patients; 1 aCML, 2 CNL, and 2 myelodysplastic/myeloproliferative neoplasm, not otherwise specified patients without CSF3R mutation; and 11 CSF3Rmut patients with other diseases [8 acute myeloid leukemia (AML), 1 chronic myelomonocytic leukemia (CMML), 1 myelodysplastic syndrome (MDS), and 1 acute lymphoblastic leukemia (ALL)]. Patients with aCML or CNL were tested by Sanger sequencing and pyrosequencing to identify CSF3R T618I. Twenty-two patients underwent gene panel analysis. CSF3R mutations, mostly T618I (8/9), were found at high frequencies in both aCML and CNL patients [5/6 aCML and 4/6 CNL]. Two aCML patients in early adulthood with CSF3R T618I and biallelic or homozygous CEBPA mutations without other mutations presented with increased blasts and exhibited remission for >6 years after transplantation. The other 7 CSF3Rmut aCML or CNL patients were elderly adults who all had ASXL1 mutations and frequently presented with SEBP1 and SRSF2 mutations. Five AML patients had CSF3R exon 14 or 15 point mutations, and 6 other patients (3 AML, 1 CMML, 1 MDS, and 1 ALL) had truncating mutations, demonstrating differences in leukocyte counts and mutation status. In conclusion, CSF3R mutations were found at a higher frequency in aCML patients than in previous studies, which might reflect ethnic differences. Additional studies are needed to confirm these findings and the relationship between CSF3R and CEBPA mutations.
Asunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa , Mutación , Receptores del Factor Estimulante de Colonias , Humanos , Receptores del Factor Estimulante de Colonias/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Anciano de 80 o más Años , Leucemia Neutrofílica Crónica/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologíaRESUMEN
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) chacaterized by persistent peripheral blood monocytosis, hypercellular bone marrow and dysplasia at least in one myeloid lineage. CMML shares much of its molecular landscape with other myeloid neoplasms, while differs from others such as chronic neutrophilic leukemia (CNL), given the high frequency of CSF3R mutations in the latter. In this article, we report a case of CSF3R-mutated CMML and dissect this rare entity by reviewing the medical literature, with the intent to understand how this rare mutation shapes CMML's clinical and morphological phenotype. CSF3R-mutated CMML emerges as a rare entity meeting the ICC/WHO diagnostic criteria for CMML and simultaneously showing clinical-pathological and molecular traits of CNL and atypical chronic myeloid leukemia, rising an important and difficult diagnostic and therapeutical issue.
Asunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa , Leucemia Mielomonocítica Crónica , Leucemia Neutrofílica Crónica , Trastornos Mieloproliferativos , Humanos , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Leucemia Neutrofílica Crónica/diagnóstico , Leucemia Neutrofílica Crónica/genética , Mutación , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Pronóstico , Receptores del Factor Estimulante de Colonias/genéticaRESUMEN
Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.
Asunto(s)
Productos Biológicos , Isocromosomas , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa , Adulto , Médula Ósea/patología , Humanos , Isocromosomas/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Mutación , Estudios RetrospectivosRESUMEN
Myeloid/lymphoid neoplasm with t(8;22)(p11.2;q11.2)/BCR-FGFR1 is an extremely rare diagnosis, with few reported cases to date. In contrast to other FGFR1-partner rearrangements that are associated with chronic eosinophilic leukemia, acute myeloid leukemia, and/or lymphoblastic lymphoma, patients with BCR-FGFR1 have a myeloproliferative disorder that closely resembles chronic myeloid leukemia (CML). The current report describes a rare case of a 61 year old man with an atypical CML phenotype associated with t(8;22)(p11.2;q11.2)/BCR-FGFR1. A literature review is presented to enhance the awareness of this rare diagnostic entity.
Asunto(s)
Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 8/genética , Reordenamiento Génico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Proteínas Proto-Oncogénicas c-bcr/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Translocación Genética , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.
Asunto(s)
Proteínas de Unión al ADN/genética , Inflamación/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Evolución Clonal , Humanos , Inflamasomas/genética , Inflamación/patología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patologíaRESUMEN
BACKGROUND: The identification of pathologically altered neutrophil granulocyte migration patterns bears strong potential for surveillance and prognostic scoring of diseases. We recently identified a strong correlation between impaired neutrophil motility and the disease stage of myelodysplastic syndrome (MDS). Here, we apply this assay to study quantitively increased neutrophils of a patient suffering from a rare leukemia subtype, atypical chronic myeloid leukemia (aCML). METHODS: A 69-year-old male was analyzed in this study. Besides routine analyses, we purified the patient's neutrophils from peripheral whole blood and studied their migration behavior using time-lapse video microscopy in a standardized assay. These live cell migration analyses also allowed for the quantification of cell morphology. Furthermore, the cells were stained for the markers CD15, CD16, fMLPR, CXCR1 and CXCR2. RESULTS: Despite cytoreductive therapy with hydroxyurea, the patient's WBC and ANC were poorly controlled and severe dysgranulopoiesis with hypogranularity was observed. Neutrophils displayed strongly impaired migration when compared to healthy controls and migrating cells exhibited a more flattened-out morphology than control neutrophils. Because of a detected CSF3R (p.T618I) mutation and constitutional symptoms treatment with ruxolitinib was initiated. Within 1 week of ruxolitinib treatment, the cell shape normalized and remained indistinguishable from healthy control neutrophils. However, neutrophil migration did not improve over the course of ruxolitinib therapy but was strikingly altered shortly before a sinusitis with fever and bleeding from a gastric ulcer. Molecular work-up revealed that under ruxolitinib treatment, the CSF3R clone was depleted, yet the expansion of a NRAS mutated subclone was promoted. CONCLUSION: These results demonstrate the usefulness of neutrophil migration analyses to uncover corresponding alterations of neutrophil migration in rare myeloid neoplasms. Furthermore, in addition to monitoring migration the determination of morphological features of live neutrophils might represent a useful tool to monitor the effectiveness of therapeutic approaches.
Asunto(s)
Biomarcadores de Tumor/genética , Movimiento Celular , Granulocitos/patología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Neutrófilos/patología , Pirazoles/efectos adversos , Anciano , Estudios de Casos y Controles , Femenino , Granulocitos/efectos de los fármacos , Granulocitos/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Estudios Longitudinales , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Nitrilos , Pronóstico , PirimidinasRESUMEN
Atypical chronic myeloid leukemia is an esoteric myeloid malignancy with features of both myeloproliferative and myelodysplastic syndromes. This disease is characterized primarily by morphologic-based criteria, and has clinical and molecular features overlapping with other myeloid malignancies. No one molecular abnormality is specific, and multiple mutations are often present in various combinations, due to the malignant multi-step clonal evolution of myeloid malignancies. In this review, we will address what we know about atypical chronic myeloid leukemia; evaluate how the molecular landscape in myeloid malignancies overlaps, and discuss what we can learn by incorporating individualized precision genomic strategies.
Asunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Síndromes Mielodisplásicos/genética , Genómica , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/metabolismo , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patologíaRESUMEN
Patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) are often asymptomatic and thus can remain undiagnosed until they become symptomatic due to progression to the accelerated phase (AP) or transformation to acute leukemia (leukemic transformation; LT). We herein report the case of a previously healthy 38-year-old man who had hyperleukocytosis with dysplastic myeloid precursor cells and severe disseminated intravascular coagulation. Hematopoietic recovery with features of atypical chronic myeloid leukemia (aCML) after induction chemotherapy was a diagnostic clue. Although rare, this case highlights the limitation of the diagnostic approach for aCML with AP or LT at the initial presentation.
Asunto(s)
Coagulación Intravascular Diseminada/complicaciones , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/complicaciones , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Adulto , Antineoplásicos/uso terapéutico , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Leucocitosis/complicaciones , MasculinoAsunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Mastocitosis Sistémica/patología , Neoplasias Primarias Múltiples/patología , Anciano de 80 o más Años , Médula Ósea/patología , Granulocitos/patología , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/sangre , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Masculino , Mastocitos/patología , Mastocitosis Sistémica/sangre , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/genética , Mutación Missense , Proteínas de Neoplasias/genética , Neutrófilos/patología , Mutación Puntual , Proteínas Proto-Oncogénicas c-kit/genética , Factor de Empalme U2AF/genéticaAsunto(s)
Inflamación/sangre , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/sangre , Complejo de Antígeno L1 de Leucocito/sangre , Biomarcadores/sangre , Humanos , Inflamación/diagnóstico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Trastornos Mieloproliferativos/sangre , Neoplasias/sangreAsunto(s)
Decitabina/administración & dosificación , Leucemia Linfocítica Crónica de Células B , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa , Neoplasias Primarias Secundarias , Anciano de 80 o más Años , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/metabolismo , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Masculino , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/patologíaRESUMEN
Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare BCR-ABL1 fusion gene-negative myeloid neoplasms with a predominance of neutrophils. Since no standard therapeutic strategy currently exists for these diseases, we retrospectively evaluated the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aCML and CNL. Data from 14 aCML and 5 CNL patients as their diagnoses were collected using a nationwide survey. Allo-HSCT was performed between 2003 and 2014. Preconditioning regimens included myeloablative (n = 15), reduced-intensity (n = 3), and non-myeloablative (n = 1) regimens. Transplanted stem cells were obtained from HLA-matched related donors (n = 5) and alternative donors (n = 14). Neutrophil engraftment was successfully achieved in 17 patients. One-year overall survival rates (OS) were 54.4% (95% confidence interval [CI], 24.8 to 76.7%) and 40.0% (95% CI, 5.2 to 75.3%) in patients with aCML and CNL, respectively. Among aCML patients, 1-year OS were 76.2% (95% CI, 33.2 to 93.5%) and 20.0% (95% CI, 0.8 to 58.2%) in patients with <5% myeloblasts (n = 9) and ≥5% myeloblasts (n = 5) in peripheral blood before allo-HSCT, respectively. These results suggest that allo-HSCT achieves long-term survival in patients with aCML and CNL. Better pre-transplant management is required to improve the outcomes of aCML patients with ≥5% blasts in peripheral blood.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/terapia , Leucemia Neutrofílica Crónica/terapia , Adolescente , Adulto , Anciano , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Japón , Estimación de Kaplan-Meier , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/mortalidad , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Leucemia Neutrofílica Crónica/mortalidad , Leucemia Neutrofílica Crónica/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenAsunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/terapia , Infiltración Leucémica/terapia , Nervio Óptico/efectos de los fármacos , Nervio Óptico/efectos de la radiación , Radioterapia , Terapia Combinada , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/radioterapia , Infiltración Leucémica/tratamiento farmacológico , Infiltración Leucémica/patología , Infiltración Leucémica/radioterapia , Masculino , Persona de Mediana Edad , Nervio Óptico/patología , Agudeza Visual/fisiologíaRESUMEN
OBJECTIVE: Philadelphia-negative myeloproliferative neoplasms (MPNs) commonly share hyperactive JAK-STAT signaling affecting hematopoietic stem cells (HSC) and their progeny. The JAK1/2 inhibitor Ruxolitinib has remarkable clinical efficacy, including spleen reduction, improvement of constitutional symptoms, and bone marrow (BM) fibrosis reversal. Whether this is due to inhibition of JAK2-mutated HSC only, or whether Ruxolitinib also affects BM stroma is not known. METHODS: This study investigated potential effects of Ruxolitinib on BM mesenchymal stromal cells (MSC), which are not only major regulators of hematopoiesis but also contribute to fibrosis, from 10 healthy donors and 7 JAK2V617F -positive MPN patients. RESULTS: Ruxolitinib moderately inhibited the growth of healthy donor MSC (HD-MSC) and MSC from JAK2V617F+ MPN patients (P-MSC) in short- and long-term assays. The clonogenic potential of HD-MSC was not affected by Ruxolitinib. JAK-STAT signaling, however, was markedly inhibited in both HD-MSC and P-MSC, the latter of which showed higher expression of fibrosis-associated and hematopoiesis-maintenance genes. Moreover, Ruxolitinib reduced MSC secretion of MCP-1 and IL-6. CONCLUSION: Ruxolitinib affected JAK2 signaling in MSC at clinically relevant doses, which is likely to contribute to the normalization of the inflammatory milieu in MPNs. Thus, combined HSC and stroma-directed interventions have the potential to improve constitutional symptoms and reduce stromal proliferation in MPNs.
Asunto(s)
Antineoplásicos/farmacología , Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/efectos de los fármacos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Anciano , Anciano de 80 o más Años , Médula Ósea/enzimología , Médula Ósea/inmunología , Médula Ósea/patología , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Femenino , Fibrosis , Células Madre Hematopoyéticas/enzimología , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/patología , Humanos , Interleucina-6/genética , Interleucina-6/inmunología , Janus Quinasa 1/genética , Janus Quinasa 1/inmunología , Janus Quinasa 2/genética , Janus Quinasa 2/inmunología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/enzimología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/inmunología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Masculino , Persona de Mediana Edad , Mutación , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/inmunología , Trastornos Mieloproliferativos/patología , Nitrilos , Cultivo Primario de Células , Pirimidinas , Transducción de SeñalRESUMEN
BACKGROUND: The physical symptom burden of patients with myeloproliferative neoplasms (MPNs) may last for extended periods during their disease trajectories and lead to psychologic distress, anxiety, or depression or all of these. OBJECTIVE: This study evaluated the relationship between physical symptom burden captured by the Physical Problem List (PPL) on the Distress Thermometer and Problem List and psychologic outcomes (distress, anxiety, and depression) in the MPN setting. METHODS: Patients (N = 117) with MPNs completed questionnaires containing the Distress Thermometer and Problem List and the Hospital Anxiety and Depression Scale in a dedicated MPN clinic within an academic medical center. They reported symptoms from any of 22 physical problems on the PPL. Items endorsed by more than 10% of participants were assessed for their associations with distress (Distress Thermometer and Problem List), anxiety (Hospital Anxiety and Depression Scale-Anxiety), and depression (Hospital Anxiety and Depression Scale-Depression). The total number of endorsed PPL items per participant was also evaluated. RESULTS: Nine of 22 PPL items (fatigue, sleep, pain, dry skin/pruritus, memory/concentration, feeling swollen, breathing, and sexual) were reported by >10% of participants. In univariate analyses, all PPL items but one were associated with distress and depression, and all but 2 were associated with anxiety. In multivariate analyses, the total number of PPL items was associated with depression only (p < 0.001) when controlling for covariates. CONCLUSION: Physical symptom burden in MPN patients was clearly associated with psychologic symptoms. Depression was uniquely associated with overall physical symptom burden. As such, the endorsement of multiple PPL items on the Distress Thermometer and Problem List should prompt an evaluation for psychologic symptoms to improve MPN patients' overall morbidity and quality of life.
Asunto(s)
Ansiedad/etiología , Depresión/etiología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/psicología , Estrés Psicológico/etiología , Ansiedad/psicología , Depresión/psicología , Femenino , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Estrés Psicológico/psicología , Encuestas y CuestionariosRESUMEN
The aim of our study was to review the clinicopathologic features and management of atypical chronic myeloid leukemia (aCML). Relevant manuscripts published in English were searched using PubMed. aCML is diagnosed as per WHO 2016 classification in the presence of leukocytosis ≥13 × 109/l with circulating neutrophil precursors ≥10%, monocytes less than 10%, minimal basophils, hypercellular bone marrow with granulocytic proliferation and dysplasia, bone marrow blast less than 20% and absence of BCR/ABL fusion gene. Common cytogenetic features and mutations include trisomy 8, and mutations in SETBP1 and ETNK1. Median survival is 1-2 years. Hematopoietic stem cell transplant may be the only curative option. Ruxolitinib and dasatinib are emerging therapeutic options. Thus, aCML is a rare entity with poor survival. Novel therapies are needed.
Asunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/epidemiología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Terapia Molecular Dirigida , Células Neoplásicas Circulantes/patología , Proteínas Portadoras/genética , Dasatinib/uso terapéutico , Manejo de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/terapia , Mutación , Nitrilos , Proteínas Nucleares/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pirazoles/uso terapéutico , PirimidinasRESUMEN
One of the pathogenic causes of cutaneous inflammatory pseudotumors is chronic localized fibrosing leukocytoclastic vasculitis (CLFLCV), a vasculitic reaction pattern seen in granuloma faciale (GF), a localized vasculitis, and erythema elevatum diutinum (EED), a generalized vasculitis. Patients with myelodysplastic syndromes (MDSs) are at risk for a diverse spectrum of cutaneous neutrophilic dermatoses such as EED. Herein, we report a 74-year-old man who presented with a large ulcerative, fungating tumor affecting the right flexor ankle caused by CLFLCV. During his workup and management, MDS and Philadelphia chromosome-negative chronic myeloid leukemia was diagnosed. Surgical excision of the inflammatory mass promptly triggered tumor recurrence, whereas antineutrophil therapy (dapsone coupled with hydroxyurea, and prednisone) lead to tumor regression. Histopathologic examination revealed an eosinophilic-rich small-vessel neutrophilic vasculitis associated with storiform and angiocentric fibrosis (GF-like). In the regions of fibrosis, dilated lymphatic and vascular spaces were numerous, some of which were congested with small CD3-positive lymphocytes (intralymphatic and intravascular lymphocytosis). These findings indicate coexisting localized lymphedema. By direct immunofluorescence, IgM and C4d vessel deposits were detected. The pathogenesis of the fibrotic nodules and plaques of CLFLCV is suspected to be due to recurring bouts of immune-complex vasculitis, creating a cycle of vessel damage followed by reparative granulation tissue. Poor lymphatic drainage may be the underlying factor initiating and maintaining recurrent, localized episodes of immune-complex vasculitis and progressive fibrosis. Although his tumor histopathology resembled GF-eosinophilic rich CLFLCV-the clinical context points to a solitary and paraneoplastic case of EED.
Asunto(s)
Granuloma de Células Plasmáticas/patología , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Linfedema/patología , Linfocitosis/patología , Síndromes Paraneoplásicos/patología , Vasculitis Leucocitoclástica Cutánea/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Dapsona/uso terapéutico , Resultado Fatal , Granuloma de Células Plasmáticas/inmunología , Granuloma de Células Plasmáticas/terapia , Humanos , Hidroxiurea/uso terapéutico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/inmunología , Linfedema/inmunología , Linfedema/terapia , Linfocitosis/inmunología , Linfocitosis/terapia , Masculino , Síndromes Paraneoplásicos/inmunología , Síndromes Paraneoplásicos/terapia , Pentoxifilina/uso terapéutico , Prednisona/uso terapéutico , Inducción de Remisión , Resultado del Tratamiento , Vasculitis Leucocitoclástica Cutánea/inmunología , Vasculitis Leucocitoclástica Cutánea/terapiaRESUMEN
BACKGROUND: The introduction of novel prognostic factors such as minimal residual disease (MRD) and genomic profiling has led to the reevaluation of the role of cytogenetics and other conventional factors in risk stratification for acute lymphoblastic leukemia (ALL). METHODS: This study assessed the impact of baseline cytogenetics on the outcomes of 428 adult patients with Philadelphia chromosome-negative ALL who were receiving frontline chemotherapy. Three hundred thirty patients (77%) were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone-based regimens, and 98 (23%) were treated with the augmented Berlin-Frankfurt-Munster regimen. RESULTS: The median age was 40 years (range, 13-86 years). One hundred eighty-six patients (43%) had diploid cytogenetics, 32 (7%) had complex cytogenetics (defined as ≥ 5 chromosomal abnormalities), 27 (6%) had low hypodiploidy/near-triploidy (Ho-Tr), 24 (6%) had high hyperdiploidy, and 24 (6%) had a mixed-lineage leukemia (MLL) rearrangement. Patients with an MLL rearrangement, Ho-Tr, or a complex karyotype had significantly worse relapse-free survival (RFS) and overall survival (OS) than the diploid group. According to a multivariate analysis including all the baseline characteristics and MRD status, Ho-Tr and a complex karyotype were independent predictive factors for worse RFS and OS. Furthermore, survival among all cytogenetic groups was similar, regardless of the treatment received. CONCLUSIONS: A complex karyotype and Ho-Tr are adverse prognostic factors for adults with ALL independently of the MRD status. These findings suggest that pretreatment cytogenetics remain a valuable prognostic tool in this population. Cancer 2017;123:459-467. © 2016 American Cancer Society.