Las infecciones en pacientes con leucemia mieloide aguda

• 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 Eosina
Bibliografía: 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].
1

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
2

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
4
• 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.

5
lymphoblastic
leukemia
Myeloid
leukemia

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;
6

7
Causes:
• UV rays exposure
• Genetic factors
• Environmental factors
• Random mutations
Classification of Acute Myeloid leukemia
• WHO (World health organization)
• FAB (French-American-British)

Lluesma Goñalons, et al. Leucemia mieloblástica aguda. Guías
de Diagnóstico y Tratamiento. SAH. 2013; 117:148
8
• This classification uses a
morphologic criteria after
the evaluation of bone
marrow aspirate.
• It indicates the level of cell
differentiation.

9
• It uses cytogenetic
identification of structural and
molecular abnormalities of
the cells in the bone marrow
aspirate
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

Onset: 2 or 3 months
• anemia
• adinamia
• asthenia
• pallor
• sweating
• gingival hypertrophy
• organomegaly
10

11

12
• 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.

13
• 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.

Cytarabine (ARA-C)
14
Decitabine Azacitidine

15

• 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.
16

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.
17

The University of Arizona
guía sobre el Ciclo Celular y Mitosis
Bibliografía: 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.
18

• 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.
19
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

• 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.
20
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.

• 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.
21

• 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.
22

23

• 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
24

25

Pseudomonas aeruginosa
Stenotrophomonas maltophilia
Legionella
Enterobacter
Escherichia coli
ALL OF THEM STAPHYLOCOCCI
Staphylococcus aureus, n = 2
Staphylococcus 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
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

27

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 NOT
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
28

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
29

30

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 cycles
moxifloxacin 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
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
31

Absence of antibiotic prophylaxis in a given LITR cycle thereby
Correlated with the occurrence of infections within this
cycle
32

administration of antibiotic prophylaxis was significantly associated
with low neutrophil counts
Eliminated ANC as risk factor for infections
33

34

• 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.
35

• 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%.
36

• 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.
37

• 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.
38

• 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.
39

• 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.
40

• 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
41

• 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
42

43

• 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
44

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 Eosina
Bibliografía: 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].
45

Tafadycursos
Hematopoyesis.jpg
Bibliografía: tafadycursos , (2001). Hematopoyesis.. [imagen ] Disponible en : ht
tp://www.tafadycursos.com/imagenes/27/aparato-cardiovascular-hemopoyesis.jpg [Acceso 10 Apr. 2016].
46
Pharmacy Times
Decitabine for Injection
Bibliografía: Pharmacy Times , (2014). Decitabine for Injection .. [imagen ] Disponible en : ht
http://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 : ht
http://america.pink/cytarabine_1137430.html [Acceso 10 Apr. 2016].
PLM
Azacitidine
Bibliografía: PLM, (2016). Azacitidine .. [imagen ] Disponible en : ht
http://www.medicamentosplm.com/home/productos/vidaza_suspension_inyectable/13/101/51665/201 [Acceso 10
Apr. 2016].

47

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