Emergencies in hematology - PowerPoint Presentation

Slide1

Emergencies in hematology

Jakub DębskiKlinika Hematologii, Nowotworów Krwi i Transplantacji SzpikuUM, Wrocław

Slide2

Patient 1

Interview: 59-year-old patient with chronic lymphocytic leukemia diagnosed in 2009 in stadium - Rai II, Binet B was transferred from the Internal Medicine Department to the Department of Hematology for the treatment of pneumonia and significant progression of the disease. The patient who was previously untreated

hematologically, did not agree to the proposed chemotherapy during

several

visits

in

the

outpatient

clinics

- the last visit on

8.01.

2014. In March 2015, he was hospitalized

in

the

Surgery

Unit

due to

phlegmon

of

the

left

thigh

. Then

we

found

:

leukocytosis

800 G / l,

osteolytic

lesions of left

thigh

and pelvic

bones

, and in the performed on 17.03.2015 ultrasound examination of the abdominal cavity -

hepatosplenomegaly

with significantly enlarged lymph nodes, the largest with dimensions of 85 x 24 mm. The patient was advised to report urgently to the Hematology Clinic, but he did not. For about 3-4 days he

had

been

observ

ing

cough, weakness, fever up to 40

C. H

ospitalized

in

the

Internal

Medicine

Unit

between

29-30.04.

20

15

,

in

which

he

has been diagnosed with right-sided pneumonia with severe course and progression of untreated chronic lymphocytic leukemia.

Slide3

Patient 1At the reception on 30.

04.2015:very severe condition, ECOG-3/4, drowsy, in a simple logical contact, conscious, aware, he

reported a worsening of vision.In

the

physical

examination

:

c

achectic

, right-sided rattling and crackling, left-sided crackles,

RHA

,

tachypnoe

22 /min,

abdomen

arched above the chest level, soft, tender, without peritoneal symptoms,

hepatosplenomegaly

, numerous lymph node packages palpable through the abdominal wall, lymph nodes

-

cervical,

axillary

, inguinal

–

enlarged

up to 2-3 cm in diameter, organized in packets,

n

umerous

scars and skin cavities of the left lower leg

due

to

the

phlegmon

(

cured

).

Slide4

Patient 1Peripheral blood

morphology: WBC 982.77 10*3/uL [4-10] , IG% 0.3 % ,

NEUT% 1.6 % [40-75] , LYMPH% 89.4 % [25-45] ,

MONO% 9 % [2-12] ,

EO% 0 % [1-6] ,

BASO% 0 % ,

NRBC% 0 % ,

IG# 2.72 10*3/

uL

,

NEUT# 14.99 10*3/uL [1.6-7.5] , LYMPH# 878.61 10*3/uL [1-4] , MONO# 88.9 10*3/uL [0.08-1.2] , EO# 0.07 10*3/uL [0.04-0.6] , BASO# 0.2 10*3/uL [0-0.1] , NRBC# 0.41 10*3/uL , RBC 2.06 10*6/uL [4.5-5.9] , HGB 5.8 g/dL [14-18] , HCT 19.1 % [37-53] , MCV 92.7 fL [81-98] , MCH 28.2 pg [26-34] , MCHC 30.4 g/dL [31-37] , RDW-SD 63.2 fL [37-54] , RDW-CV % 18.9 % [11-16] , PLT 51 10*3/uL [130-400] , PDW 12.4 fL [9-17] , MPV 10 fL [9-13] , P-LCR 28.2 % [13-43] .

Slide5

Patient 1In laboratory

tests:In peripheral blood morphology –

Leukocytes 982.77 G / l,Hemoglobin 5.8 g / dl,

Thrombocytes

51 G / l,?

Procalcitonin

36.02

ng

/ ml,

SaO2 82-84%,

Biochemistry – Increased level of glucose, CRP, LDH, urea, uric acid, ASPAT, ALP, total and direct bilirubin, magnesium, fibrinogen, D-dimers Decreased level of potassium, total protein, albuminWhat should be the further management of the patient?

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Patient 1The course of treatment:The patient was

monitored, hydrated, and an urgent leukapheresis was performed followed by the first cycle of CVP (cyclophosphamide, vinblastine

) chemotherapy in fractionated doses along with intravenous corticosteroids. RBC concentrate

was

transfused

. In addition, broad-spectrum antibiotics and supportive care were used,

achieving

in the next days of stay an improvement in the general condition of the patient, along with moderate

cytoreduction

and a

significant decrease in inflammation parameters. Due to the rebound of leukocytosis on 8.05.2015, another leukapheresis procedure was performed and the second and third CVP chemotherapy courses were implemented on 8.05.15 and 28.05.15, followed by further cytoreduction and moderate reduction of the size of the lymph nodes, liver and spleen. Because of insufficient response achieved after the 3 cycles of CVP, the therapeutic protocol was changed to FC-R (fludarabine, cyclophosphamide, rituximab), the first cycle of which was introduced with good tolerance.

Slide7

Patient 1Leukapheresis - a method

of selective mechanical purification of plasma from

morphotic elements -

leukocytes

(

granulocytes

,

monocytes

,

leukemic

blasts, CD34 + peripheral blood stem cells) using a separator.

Slide8

Hyperleukocytosis

Definition: leukocytes > 100 G / lIt leads to complications

: LS - leukostasis

syndrome

  DIC –

disseminated

intravascular

coagulation

  TLS - tumor lysis syndromeThe risk of complications depends on the biology of leukemic cells.Epidemiology: - AML - acute myeloid leukemia (10-20%) - subtypes M4, M5, microgranular variant M3 - ALL - acute lymphoblastic leukemia (10-30%) - T-cell subtypes, males, infants, 10-20 years of age (rarely leukostasis syndrome) - BL - lymphoma / Burkitt's leukemia - mainly TLS- CLL - chronic

lymphocytic leukemia – symptomatic > 400 G / l (

rarely leucostatic

syndrome)

- CML -

chronic

myeloid

leukemia -

mainly

in

the

blast

crisis

phase

Slide9

Leukostasis syndrome- symptomatic

hyperleukocytosis (clinical concept, not laboratory) - disturbances of blood flow and tissue perfusion as a result of accumulation of leukemic cells in the lumen of microcirculation vessels, often with activation of coagulation- most often affects the lungs (30%) and CNS (40%)Symptoms:

- dyspnoea, hypoxia

,

diffuse

vesicular

hemorrhage

,

acute respiratory failure (ARDS)- visual impairment, optic nerve edema, retinal hemorrhages - disturbances of consciousness, dizziness, tinnitus, drowsiness, headache, delirium, coma, focal neurological deficits, intracranial hemorrhage- myocardial ischemia / ACS- acute limb ischemia- renal vein thrombosis, exacerbation of preexisting renal failure- priapism- intestinal infarction

- fever (

due to cytokine

release or

associated

infection

)

-

progression

of respiratory

distress

sometimes

in

patients

after

the

start of

chemotherapy

, (

acute

lysis

pneumopathy

)

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In laboratory tests:pseudohypoxemia

pseudohypoglycemiapseudohyperkalemiahypocalcaemia

hyperphosphatemiahyperuricaemia

lactic

acidosis

DIC

features

-

about

40% TLS features - about 10%Leukostasis syndrome

Slide11

Leukostasis syndromeTreatment:

- urgent leukapheresis – 2 procedures with an interval of 12-24 hours

Diagnosis

Symptomatic

hyperleukocytosis

(G/l)

Asymptomatic

hyperleukocytosis

(G/l)AML 50 100ALL 150 300CML 150NoCLL 500NoAPLNoNoIndications for a leukapheresis:

Slide12

Leukostasis syndromeTreatment:

- cytoreduction: hydroxycarbamide 50-100 mg / kg, usually 2-4 g / day

, reduction in

the

value

of

leukocytosis

by 50-80%

within

24-48 hours - chemotherapy inducing remission - implemented when leukocytes < 50 G / l- adequate hydration and prophylaxis of tumor lysis syndrome- management of the coexist. intravascular coagulation syndrome- RBC concentrate transfusions - cautiously, slowly during or after the leukapheresis procedure- Platelet concentrate transfusions - maintenance of PLT level > 20-30 G / l

- antibiotic

therapy

- glucocorticoids

Slide13

Leukostasis syndromeContraindications to

leukapheresis:- acute promyelocytic leukemia

- cardiorespiratory insufficiency

-

severe

cardiac

diseases

-

severe coagulation disorders

Slide14

Disseminated intravascular coagulation (DIC)

- 10-15% pts with generalized tumors

, 15% with leukemia -

generalized

activation

of

coagulation

with

fibrinolysis disorders + coagulopathy with consumption- in the clinical presentation: bleeding (60%) and thrombotic complications - 3 types of DIC accompanying tumors: procoagulant, hyperfibrinolytic, subclinical- diagnosis - serial analysis of platelet counts, PT and aPTT coagulation times, fibrin degradation markers: fibrin monomers, FDP, D-dimers, fibrinogen concentration

Slide15

Disseminated intravascular coagulation (DIC)

Management: - treatment of the underlying

disease- transfusions

of

blood

products:

RBC

concentrate

-

when

there is a significant loss of bloodFFP 10-15 ml / kg - active bleeding and elongation > 1.5-fold aPTT or PTFFP 15 ml / kg every 12-24 h or cryoprecipitate 1 unit / 10 kg every 24 h - active bleeding and fibrinogen < 1.0 g / l Platelet concentrate 1-2 U / kg - PLT < 20 G / l or PLT < 50 G / l + hemorrhagic diathesis - heparin (controversial) - should be considered in cases with predominant thrombotic symptoms - fibrinolysis

inhibitors - tranexamic

acid 10-15 mg / kg in

DIC with enhanced

fibrinolysis

-

in

acute

promyelocytic

leukemia - DIC

with

hyperfibrinolysis

,

life-threatening

hemorrhagic

complications

in

about

5% (65%

intracranial

bleeding

/ 32%

pulmonary

bleeding

) –

required

application

of ATRA (

all-trans

retinoic

acid

)

or

ATO (

arsenic

trioxide

)

Slide16

Tumor lysis syndrome (TLS)- life-threatening

metabolic syndrome resulting from

the rapid breakdown

of

cancer

cells

- high

proliferative

activity and high chemosensitivity of the tumor- spontaneous form - Burkitt's lymphoma, acute leukemia with high hyperleukocytosis - induced form - acute leukemia (ALL > 100 G / l, AML > 50 G / l), Burkitt's lymphoma, lymphoblastic lymphoma - renal failure increases the risk of TLS - metabolic disorders - hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcaemia, metabolic acidosis - symptoms - acute

renal failure,

arrhythmias /

sudden cardiac

death

,

hypotension

,

heart

failure

,

convulsions

,

neuromuscular

hyperactivity

Slide17

Tumor lysis syndrome (TLS)Management:

1. prophylaxis - hydration 3 l / m2 / 24 h 0.9% NaCl +

allopurinol 600-900 mg / 24 h + eventually leukapheresis

2.

treatment

-

diuresis

forced

by a

loop diuretic > 3 l / 24 h, hourly 100 ml / h + allopurinol 500 mg / m2 / day - in the case of severe hyperuricaemia - rasburicase (recombinant xanthine oxidase) 0.2 mg / kg / day i.v. - hemodialysis in the development of acute renal failure - correction of electrolyte disturbances

Slide18

Hypercalcemia- increased total

calcium concentrations > 2.6 mmol / l (10.5 mg / dl) or ionized

calcium > 1.25 mmol / l (5 mg / dl)

-

in

the

case

of protein

disorders (hypoproteinaemia, hypoalbuminaemia): calculation corrected calcium concentration (mg / dl) = [measured calcium concentration (mg / dl) - albumin concentration (g / dl)] + 4 - in hyperproteinemia - possible spurious hypercalcemia The most common causes are: - increased osteolysis in plasma cell myeloma- lymphomas and leukemia - paraneoplastic syndrome or severe osteolysis (PTH-independent

) or production of 1,25(OH)2D3

-

bone tissue

neoplasms

,

bone

metastases

-

primary

hyperparathyroidism

-

overdose

of

vitamin

D3

-

persistent

immobilization

-

thiazide

diuretics

,

theophylline

-

hyperthyroidism

-

adynamic

bone

disease

in

dialysis

patients

Slide19

HypercalcemiaMild hypercalcemia < 3.0

mmol / l (12 mg / dl) - asymptomaticModerate and severe hypercalcemia

3.0 - 3.75 mmol / l (12-15 mg / dl) and rapidly

increasing

-

hypercalcemic

syndrome

:

1.

kidney problems - polyuria, hypercalciuria (nephrolithiasis, nephrocalcinosis)2. gastrointestinal symptoms - lack of appetite, nausea, vomiting, constipation, gastric / duodenal ulcer, pancreatitis, cholelithiasis3. cardiovascular symptoms - arterial hypertension, tachycardia, arrhythmia, hypersensitivity to digitalis glycosides4. neuromuscular symptoms - muscle weakness, weak tendon reflexes, transient facial

muscle paralysis

5. CNS symptoms

- headache, depression

,

orientation

disorders

,

drowsiness

,

coma

6.

dehydration

In a

very

severe

hypercalcemia

> 3.75

mmol

/ l (15 mg / dl) -

hypercalcemic

crisis

:

disturbances

of

consciousness

,

nausea

,

vomiting

,

abdominal

pain

,

arrhythmias

,

dehydration

,

death

.

ECG - prolongation of the PQ interval, QT shortening, wide T wave,sometimes the Osborn wave

Slide20

HypercalcemiaManagement:- abundant

hydration - 3-5 liters / day (~ 3 l / m2 / day) 0.9%

NaCl- forced

diuresis

with

furosemide

20-40 mg iv,

diuresis: 150-200 ml / h - reducing the calcium release from bones - calcitonin 100 UI 2-4 times a day iv or bisphosphonates (eg. pamidronate 60-90 mg / 2 h iv or zoledronate 4 mg / 15 min iv) or denosumab- inhibition of calcium absorption from the gastrointestinal tract - glucocorticosteroids (eg. hydrocortisone 100 mg iv every 6 h)- in severe cases – hemodialysisIn

chronic tumor hypercalcemia

in addition

:- mitramycin

25

ug

/ kg for 4-6 h

i.v

.

or

-

gallium

nitrate

100-200 mg / m2 for 24

hours

for 4-5

days

Slide21

Superior vena cava syndrome (SVCS)

- syndrome of symptoms caused by impeding blood flow from the superior vena cava to the right atrium of the heart- 2-4% of patients with lung cancer and 2-4% with lymphoma

The most frequent causes:- narrowing of the superior vena cava

1.

external pressure + tumor infiltration of the vein wall

-

lung cancer (60-80%), lymphoma (10-15%), metastasis of breast cancer,

mediastinal

germ cell tumors, thymomas 2. non-neoplastic causes - aortic aneurysm, chronic mediastinitis- superior vena cava thrombosis - a catheter or secondary mediastinal tumor- right atrial tumor (rare)

Slide22

Superior vena cava syndrome (SVCS)

Symptoms:- swelling, erythema or bruising of the face

- conjunctival hyperemia

- swelling of the upper limbs

- symptoms associated with increased intracranial pressure: headache and dizziness, visual disturbances, convulsions

- permanent

distention

of the jugular veins and positive Pemberton

’s

sign - dyspnea- hoarseness- difficulty in swallowing- stridorThe chest CT scan is the test of choice to diagnose SVCS.Chest X-ray is normal in 5-15% of cases.

Slide23

Superior vena cava syndrome (SVCS)

Symptomatic treatment:- dexamethasone 16-32 mg / d i.v

. for 7 days, then dose reduction- control of dyspnea

- morphine,

midazolam

, oxygen therapy

- loop diuretic

(eg.

furosemide

)

- low molecular weight heparin - prophylactic or curativeCausative treatment:- urgent irradiation of the mediastinum - in the majority of cancers, the treatment of choice - chemotherapy - for chemosensitive cancers: lymphomas, lung cancer, germ cell tumors - introduction of the stent into the superior vena cava (removal of symptoms in > 75% of patients within 48 -72 h after surgery)- in the case of thrombosis - also consider thrombolysis

Slide24

Differentiation syndrome in acute

promyelocytic leukemia- life-threatening complication of the induction of acute myeloid leukemia M3 (promyelocytic)

after application of ATRA or ATO- occurs in

up

to

25% of patients within 7-12

days

of starting treatment

-

pathomechanism

is not known, probably cytokine-related- symptoms: fever, increasing dyspnea, peripheral edema, skin rash, lung infiltration, fluid in the pleural cavity and pericardium, hypotension, renal insufficiency- risk increased by leukocytosis > 50 G / l - treatment: dexamethasone 2 x 10 mg iv until the symptoms disappear, sometimes dialysis is necessary and respiratory therapy- in patients with severe organ-related complications - temporary withdrawal of ATRA or ATO- mortality is around 1%

Slide25

Neutropenic fever n

eutropenia is the most common complication of anticancer treatment, it results from the myelotoxic action of chemo-radiotherapy or bone marrow infiltration by tumor cells- neutropenic fever - 10-50% of patients with solid tumors,

> 80% with hematological malignancies

Definition of

neutropenic

fever

(

febrile

neutropenia): 1. oral temperature ≥ 38.3 C in single measurement or ≥ 38 C persistent for 1 hour 2. neutrophil count < 500 / ul or predicted decrease to < 500 / ul in 48 hoursPatients with NF rarely have local infection or they are weakly expressed. Most often, bacterial infections (Gram +> Gram-), less often fungal and viral.Blood-borne infection - 13-60% of patients, mortality 12-42%. The most serious forms of infection are: pneumonia, neutropenic enteritis, septic shock.

Slide26

Neutropenic feverManagement:

- broad-spectrum, wide-spectrum empiric antibiotic therapy, in patients at high risk of complications and death: carbapenem or piperacillin with tazobactam or

ceftazidime or cefepime iv

- addition of antifungal medication

(

eg

.

fluconazole

iv

) - microbiological tests - identification of the pathogen responsible for infection is successful in 20-30% of patients- use of granulocyte growth factors G-CSF or GM-CSF, if the patient did not receive them as a primary or secondary prophylaxisRegular assessment of the patient's condition, effectiveness of antibiotic therapy, development of complications every 24-48 hours is mandatory.In case of improvement or identification of an infectious agent - de-escalation of antibiotic therapy.

Slide27

Prophylaxis in afebrile patients with neutropenia1) a

sanitary regime, hand and cough hygiene

, sometimes patient

isolation

2)

prophylactic

use

of

fluoroquinolone (ciprofloxacin, levofloxacin) - only in high-risk patients 3) prophylactic use of antifungal drugs (azoles, echinocandins) and antivirals (aciclovir) - only in patients undergoing allo-HCT and inducing remission chemotherapy in acute myeloid leukemia4) prophylactic use of cotrimoxazole in patients with risk factors

for Pneumocystis jiroveci

infection

- purine analogs

,

corticotherapy

> 1

month

5)

prophylaxis

with

G-CSF

(

filgrastim

,

lenograstim

)

or

GM-CSF

(

molgramostim

,

regramostim

,

sargramostim

):

-

primary

-

recommended

already

during

the

first

cycle

of

chemotherapy

,

when

the risk of developing febrile neutropenia > 20%, to consider also in the case of intensive

chemotherapy

-

secondary

-

recommended

in

patients

with

complications

associated

with

neutropenia

that

occurred

after

the

first

chemotherapy

cycle

, and

reducing

the

doses

of

cytotoxic

drugs

or

delaying

their

administration

may

affect

overall

survival

6)

avoidance

of

prolonged

environmental

contact

a high

concentration

of

fungal

mold

spores

(

constructions

, old and

neglected

buildings

)