Las infecciones en pacientes con leucemia mieloide aguda

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• JHENY LISETT USUGA DAVID• MANUELA BLANCO AGUDELO• MELISSA PINO SUCERQUIA• JUAN PABLO ARBOLEDA• JASON JAVIER CARVAJAL• JHON HENRRY SANABRIA

MA Montañés Gracia, V Recasens Flores

Aspirado de médula ósea. Tinción: Azur EosinaBibliografía: Hospital Clínico Universitario Lozano Blesa, Zaragoza, (2008). Frotis de médula ósea de una leucemia aguda promielocítica con t(15;17)(q22;q21). Destacan algunos promielocitos con abundantes astillas [image ] Available at: http://atlas.gechem.net/index.php?option=com_k2&view=item&id=67:leucemia-promielocitica-aguda [Accessed 4 Apr. 2016].

Infections in patients with acute myeloid leukemia

treated with low-intensity therapeutic regimens: Risk

factors and efficacy of antibiotic prophylaxis

2cancer.gov. [Internet].Colombia:Instituto Nacional de Cancerología-ESE- Empresa Social del

Estado - Ministerio de Salud y Protección Social;2000 [Ultima Actualización: 08-04-2016; citado el 10-04-2016]. Disponible en: http://www.cancer.gov.co/cancer_en_cifras

Leukemia in Colombia

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Review and definitions.

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M. L. SALA B, et al. Hematología clínica. sefh.es [Internet].2013 [citado el 10-04-2016];1(10):1031-1072. Disponible en:

http://www.sefh.es/bibliotecavirtual/fhtomo2/CAP10.pdf 42:47-51

• Leukemia: abnormal proliferation and differentiation of blood stem cells (2)

• Myeloid leukemia: myeloid´s cell neoplasia produced by an abnormal transformation and clonal proliferation of immature blood stem cells(2)

• Acute: It refers to the onset of symptoms in few months (2)

• Myeloid cells: Erythrocytes, Eosinophil, Neutrophil, Basophil, Monocyte and thrombocyte.

Manuela Blanco Agudelo.

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lymphoblastic leukemia

Myeloid leukemia

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Physio-pathology of AML

Transformation of a myeloid

hematopoietic cell

malignant cell(Blast cell)

clonal expansion suppression of the

normal hematopoiesis

*Anemia * High risk of bleeding *high risk of

infection

Bainschab, et al. Infections in patients with acute myeloid leukemia treated with low-intensity therapeutic regimens: Risk factors and efficacy of antibiotic prophylaxis. Elsevier Ltd. 2016;

42:47-51

Bainschab, et al. Infections in patients with acute myeloid leukemia treated with low-intensity therapeutic regimens: Risk factors and efficacy of antibiotic prophylaxis. Elsevier Ltd. 2016; 42:47-51

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Causes: • UV rays exposure• Genetic factors• Environmental factors• Random mutations

Classification of Acute Myeloid leukemia

• WHO (World health organization)

• FAB (French-American-British)

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French-American-British (FBA)

Lluesma Goñalons, et al. Leucemia mieloblástica aguda. Guías de Diagnóstico y Tratamiento. SAH. 2013; 117:148

• This classification uses a morphologic criteria after the evaluation of bone marrow aspirate.

• It indicates the level of cell differentiation.

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• It uses cytogenetic identification of structural and molecular abnormalities of the cells in the bone marrow aspirate

World Health Organization (WHO)

pubcan.org [Internet]. Europa: International Agency for Research on Cancer, World Health Organization; 2001 [Ultima Actualización: 23-10-2015; citado el 10-04-2016]. Disponible en: http://www.pubcan.org/page.php?pageid=87%20Tabla%201.07

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SymptomsOnset: 2 or 3 months• anemia• adinamia• asthenia• pallor• sweating• gingival hypertrophy• organomegaly


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• High-dose chemotherapy Allogeneic hematopoietic stem cell transplantation potentially curative treatments

• majority of AML patients are diagnosed advanced age significant comorbidities

• these patients were managed with best supportive care only.


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• low-dose Ara-C (LDAC) in LITR (Low-intensity therapeutic regimens) was shown to significantly improve the survival of AML patients unfit for high-dose chemotherapy

• Infections are frequent and serious complications of LITR AML therapy

• The article aimed to evaluate the incidence of and predisposing risk factors for infectious complications, as well as the value of antibiotic prophylaxis during LITR treatment of AML.


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LITR

Cytarabine (ARA-C)Decitabine Azacitidine


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2. Methods and data analysis


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• This retrospective analysis included 40 consecutive AML patients, who were treated with 215 cycles of LITR at the Medical University of Graz between December 2008 and May 2015.

• The study was approved by the institutional review board of this institution.

• AML was classified according to French–American–British (FAB) and World Health Organization (WHO) guidelines.

Methods and data analysis


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1. subcu-taneous LDAC (low dose Ara c ), 20 mg twice daily over ten days.2. Intravenous Decitabine, 20 mg per square meter body surface area over 5 days.3. subcutaneous Azacitidine, 75 mg per square meter bodysurface area over 7 days.

• Treatment cycles were scheduled every 4 weeks for all drugs until progression, relapse or intolerance occurred.


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Agentes que interactuan indirectamente con el ADN –

Antimetabolitos

The University of Arizona

guía sobre el Ciclo Celular y MitosisBibliografía: The University of Arizona, (1998). Etapas del Ciclo celular.. [image ] Available at:http://www.biologia.arizona.edu/cell/tutor/mitosis/cells2.html

Ara-C citosina arabonosido

Decitabina

Azacitidina

Análogos de purinas y pirimidinas

• Interfieren o enlentecen Sin. De ADN• Citotoxicidad C. anormales • Hipometilación del ADN.

http://www.vademecum.es/atc-l01bc






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• Ciclos de Tto. cada 4 semanas con todo los medicamentos, hasta que:

- Progreso.

- Intolerancia o Recaída.

• Azacitadina se empleó un esquema 5-2-2 ---- 2 días de descanso, el fin de semana.

- Administro 12 ciclos en 3 pacientes con una dosis reducida, los restantes 203 C. RBIT se administro en una dosis completa.

Factores evaluados para Dx AML incluyeron:

Edad conteo de células blancas (CCB)

grupo de riesgo citogenético

presencia de comorbilidades

ICC (Sistema de puntuación de comorbilidad de Charlson) http://touchcalc.com/calculators/cci_js

http://touchcalc.com/calculators/cci_js


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• Se evaluó la administración de profilaxis durante cada ciclo de RBIT.• Dx, la documentación y la definición de las infecciones fue realizado de

acuerdo a las guías publicadas e incluyeron: - fiebre de origen desconocido que requirió tratamiento anti-infeccioso - Infecciones con un origen clínicamente documentado - Infecciones con un origen microbiológico documentado.

factores valorados al inicio del Tto. con RBIT y el inicio de cada ciclo incluyeron:

-Recuento absoluto de neutrófilos (CAN) -Proteína C reactiva (PCR)

-Lactato de deshidrogenasa (LDH) -Creatinina

- Tasa de Filtración glomerular (TFG) - Dependencia de transfusión.


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• Valor: factores de riesgo de aparición de complicaciones infecciosas, evaluado en Dx de la LMA = Wilcoxon-Mann-Whitney para: edad, recuento de células blancas y ICC; Además con el test de exactitud de Fisher para grupos de riesgo cito genéticos.

• F.R. putativos valorados al inicio de la terapia con RBTI y al inicio de cada de cada ciclo. Variante de regresión logística de la ecuación de estimación generalizada (EEG)

• Compensar muchos recibieron más de un ciclo/tratamiento RBIT produciendo variables dependientes.


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• Valor de la profilaxis, se evaluó de la misma forma y se incluyó en el grupo de datos valorados en cada ciclo de RBIT.

• Debido al pequeño tamaño de la muestra no se realizó valores de corte y plaquetas calculadas, CAN, LDH, PCR, creatinina y TFG como variables continuas.

• Pruebas múltiples: controlar la razón de falsos descubrimientos (RFD) [Benjamini y Hotchberg].

• Fueron bilaterales (de dos colas) con un valor-p de <0.050 en pruebas individuales y una RFD de <0.050 en pruebas múltiples fueron consideradas estadísticamente significativas.


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3. RESULTS


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• FORTY (40) PATIENTS RECEIVED LITR

• first-line (n = 30)

• assalvage therapy after the failure of high-dose therapies (n = 10).

• Overall response (OR), defined asachieving at least hematologic improvement , was seen in 13/25 (52%) of eligible patients

• median survival from the start of LITR therapy was 8.95 months

• Complete remission was observed in five patients


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3.2 Prevalence and severity of infections

Pseudomonas aeruginosaStenotrophomonas maltophilia

LegionellaEnterobacter

Escherichia coli

ALL OF THEM STAPHYLOCOCCI Staphylococcus aureus, n = 2Staphylococcus hominis, n = 1

Staphylococcus haemoyticus, n = 1 Staphylococcus intermedius, n = 1; Staphylococcus epidermidis, n = 1,

Coagulase-negative staphylococci n = 1

two of them caused by viruses of the Herpes group

one by Influenza



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3.3 factors predicting infections

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categories of parameters: 1. putative risk factors assessedat the start of each LITR cycle.2. at the start of LITR therapy.3. at diagnosis of AML.

putative risk factors at the start of each LITR cycle (n = 215)increased LDH (p = 0.027)transfusion dependency (p = 0.008)

occurrence of infection in the corresponding LITR cycle

putative risk factors correlated with infection in univariate analysis

correlated with infection in multivariate models.

CRP: p = 0.003 YES NOT

ANC: p = 0.028 YES NOTBainschab, et al. Infections in patients with acute myeloid leukemia treated with low-intensity therapeutic regimens: Risk factors and efficacy of

antibiotic prophylaxis. Elsevier Ltd. 2016; 42:47-51

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In patients receiving LITR as first line therapy Platelets, creatinine and GFR = statistical significance

in conclusión the factors predicting infections are: LDH Transfusion dependence.

Antonia, Bainschab et al. Infections in patients with acute myeloid leukemia treated with low-intensity therapeutic regimens: Risk factors and efficacy of antibiotic prophylaxis. Enfermedades Infecciosas y Microbiología Clínica 2016; 42:47-51


42:47-51


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3.4 Efficacy of antibiotic prophylaxis

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aimed at analyzing:Whether antibiotic prophylaxis during a specific LITR cycle = risk for infections

with in the corresponding therapeutic cycle. 79 of 215 LITR cycles were performed under antibiotic prophylaxis.

levofloxacin 500 mg qd in 62 cyclesmoxifloxacin 400 mg qd in 10 cycles amoxicillin/clavulanic acid 1 g bd in 5 cycles and both ciprofloxacin 500 mg bd and cefixime 400 mg qd in 1 cycle

fluoroquinolones



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Absence of antibiotic prophylaxis in a given LITR cycle thereby

Correlated with the occurrence of infections within this cycle


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administration of antibiotic prophylaxis was significantly associated with low neutrophil counts

Eliminated ANC as risk factor for infections


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4. Discussion


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Discussion• The establishment of LITR has significantly improved the

survival of AMI patients who are either at an advanced age or who are suffering from co-morbidities.

• However, occurrence of infections might complicate the administration of LITR, thereby jeopardizing the survival benefit gained by these drugs.


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• In a recent study by Lee and coworkers, decitabine treatment of myelodysplastic syndrome (MDS) patients was complicated by infections in approximately 12% of administered cycles.

• Azacitidine has been studied by several groups in high-risk MDS and AML. As shown for decitabine, the frequency of azacitidine cycles with occurrence of infections ranged from approximately 8 to 17%.


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• By analyzing 2015 LITR cycles in 40 AML patients, they were able to identify infectious complications as a serious problem.

• More than 70% of patients exhibited at least one infection, with more than 20% of them succumbing to this complication.

• Also, when looking at single LITR cycles, infection occurred in 25% of them.


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• AML is characterized by a more aggressive disease course resulting in decreased LITR response rates and consequently a lower number of total LITR cycles administered per patient.

• Activity of the underlying disease in earlier LITR cycles has been suggested as a major risk factor for infections previously.


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• Recently, the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology published guidelines on the primary antibacterial prophylaxis in hematological malignancies and solid cancers.

• A high-risk group, especially prone to infections has been defined and comprises patients with an expected duration of neutropenia of > 7 days and/or with the occurrence of additional risk factors.

• Administration of immunosuppressive therapies, stage of the underlying disease, advanced age as well as the presence of various co-morbidities.


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• A recommendation for antibiotic prophylaxis, primarily by fluoroquinolones, has been given for these patients (graded as A-I). LITR approaches in AML often produce duration of neutropenia > 7 days and very frequently, absolute or functional neutropenia is already caused by the disease itself.


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• Los pacientes mas afectados• edad avanzada + comorbilidades• Detección e inicio tardío de la LMA infecciones

• A pesar que no hay un uso disciplinado de la terapia LITR• FLUOROQUINOLONAS• HIPOMETILANTES….Decitabina -Azacitidina• LITR primera línea


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• Además hay evidencia favorable. SMD-Decitabina• Se observo neutropenia- pero no se asocio como factor de

riesgo? univariado• LA APARICION DE LDH Y LA DEPENDENCIA DE TRANSFUSION

son predictores de infección antes de cada ciclo.• Profilaxis antibiótica se asocio a un menor índice de

infecciones


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Referencias• Bainschab, et al. Infections in patients with acute myeloid leukemia treated with low-

intensity therapeutic regimens: Risk factors and efficacy of antibiotic prophylaxis. Elsevier Ltd. 2016; 42:47-51

• Marco Antonio González A., et al. Manual de la terapéutica 2014-2015. 16ª ed. Medellín-Colombia: CIB;2014.

• Lluesma Goñalons, et al. Leucemia mieloblástica aguda. Guías de Diagnóstico y Tratamiento. SAH. 2013; 117:148

• cancer.gov. [Internet]. Colombia: Instituto Nacional de Cancerología-ESE- Empresa Social del Estado - Ministerio de Salud y Protección Social;2000 [Ultima Actualización: 08-04-2016; citado el 10-04-2016]. Disponible en: http://www.cancer.gov.co/cancer_en_cifras

• M. L. SALA B, et al. Hematología clínica. sefh.es [Internet].2013 [citado el 10-04-2016];1(10):1031-1072. Disponible en: http://www.sefh.es/bibliotecavirtual/fhtomo2/CAP10.pdf

• pubcan.org [Internet]. Europa: International Agency for Research on Cancer, World Health Organization; 2001 [Ultima Actualización: 23-10-2015; citado el 10-04-2016]. Disponible en: http://www.pubcan.org/page.php?pageid=87%20Tabla%201.07

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Otras Referencias

PDG SALUD

La leucemia mieloide aguda.Bibliografía: PDG SALUD, (2013). La leucemia mieloide aguda.. [imagen 1] Disponible en : http://pdg.estalos.com/la-leucemia-mieloide-aguda# [Acceso 4 Apr. 2016].

PDG SALUD

La leucemia mieloide aguda.Bibliografía: PDG SALUD, (2013). La médula ósea, células madre y la producción de células sanguíneas... [imagen 2 ] Disponible en: http://pdg.estalos.com/la-leucemia-mieloide-aguda# [Acceso 4 Apr. 2016].

MA Montañés Gracia, V Recasens Flores

Aspirado de médula ósea. Tinción: Azur EosinaBibliografía: Hospital Clínico Universitario Lozano Blesa, Zaragoza, (2008). Frotis de médula ósea de una leucemia aguda promielocítica con t(15;17)(q22;q21). Destacan algunos promielocitos con abundantes astillas [imagen ] Disponible en : http://atlas.gechem.net/index.php?option=com_k2&view=item&id=67:leucemia-promielocitica-aguda [Acceso 4 Apr. 2016].

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Otras Referencias Tafadycursos

Hematopoyesis.jpgBibliografía: tafadycursos , (2001). Hematopoyesis.. [imagen ] Disponible en : http://www.tafadycursos.com/imagenes/27/aparato-cardiovascular-hemopoyesis.jpg [Acceso 10 Apr. 2016].

Pharmacy Times

Decitabine for InjectionBibliografía: Pharmacy Times , (2014). Decitabine for Injection .. [imagen ] Disponible en : hthttp://www.pharmacytimes.com/publications/issue/2014/october2014/generic-product-news-1014 [Acceso 10 Apr. 2016].

America Pink

Cytarabine Bibliografía: America Pink, (2012). Cytarabine: Medical uses.. [imagen ] Disponible en : hthttp://america.pink/cytarabine_1137430.html [Acceso 10 Apr. 2016].

PLM

AzacitidineBibliografía: PLM, (2016). Azacitidine .. [imagen ] Disponible en : hthttp://www.medicamentosplm.com/home/productos/vidaza_suspension_inyectable/13/101/51665/201 [Acceso 10 Apr. 2016].


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THANK YOUGRACIAS

Las infecciones en pacientes con leucemia mieloide aguda

Health & Medicine

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