RD, a 59-year-old male with newly diagnosed Burkitt's lymphoma, presents with high risk of tumor lysis syndrome based on his labs. The best treatment is rasburicase to rapidly reduce his high uric acid level and prevent renal failure, along with IV fluids and allopurinol for comprehensive management. MM, a 62-year-old female with severe febrile neutropenia following chemotherapy, requires inpatient treatment with broad-spectrum IV antibiotics like meropenem and vancomycin due to her high risk status from low ANC, mucositis, and hypotension. This document provides guidelines for prevention, risk stratification, and treatment of tumor lysis syndrome

1. FEBRILE NEUTROPENIA & TUMOR
LYSIS SYNDROME
Nida Sehar Noman
MS (Pharmocolgy) & MBA (Finance)
nidasehar19@yahoo.com

2. TUMOR LYSIS SYNDROME

3. CASE NO: 01
 RD is a 59 year old male with newly diagnosed Burkitt’s
Lymphoma. Labs reveals WBC 12*109/ L , LDH = 810 IU/L ,
Potassium =5.7 mEq/L , SrCr= 2.1 mg/dl and uric acid 8.6
mg/dL .Vital signs and EKG are normal. Along with
allopurinol, which of the following is best to order first ?
a. 0.9% NS 1000ml * 1wide open
b. Rasburicase 0.2 mg /kg Iv *1
c. Sodium polystyrene Sulfonate
d. Consult for emergent renal dialysis

4. TUMOR LYSIS SYNDROME :
 Oncologic emergency
 Abrupt release of intracellular contents in high
quantity
 Prophylaxis and treatment aimed at assisting
body to rid electrolyte excess
 May be spontaneous or as a result of anti- cancer
therapy
 Characterized by: elevated K+ ,PO4 and uric acid
with resultant decrease in calcium.
Howard SC et al.N Engl J Med;2011;364:1844-54

5. TUMOR LYSIS SNDROME- RISK FACTORS
 Bulky, chemotherapy – sensitive disease.
 Lymphoproliferative malignancy
 Elevated lactate dehydrogenase (LDH)
 WBC > 25*109 / L
 Extensive bone marrow involvement
 Baseline volume depletion /dehydration
 Elevated baseline serum uric acid
 Pre-existing renal dysfunction.
Howard SC et l, N Engl J Med 2011;364:1844-54

6. ADULT MALIGNANCIES STRATIFIED BY TLS RISK
DISEASE LOW-RISK INTERMEDIATE-
RISK
HIGH- RISK
NON-HODGKIN
LYMPHOMA
Indolent NHL
DLBCL with (a) non-
bulky disease (b) LDH
<2* ULN
Burkitt lymphoma with
normal LDH
DLBCL with (a) non-
bulky disease and (b)
LDH > 2 * ULN
Burkitt lymphoma
with (a) bulky disease
(b) elevated LDH
DLBCL with (a) bulky
disease and (b) LDH >
2 * ULN
ALL ----- WBC < 100 *109/L
and LDH normal
WBC > 100 *109/L
or LDH > 2* ULN
AML WBC <25*109/L
And LDH < 2* ULN
WBC 25 - 100 *109/L WBC >100 *109/L
CLL All other patients WBC > 50*109 /L
Treated with
fludarabine plus
rituximab or
bendamustine plus
rituximab
--------

7. PRINCIPLES OF TLS PROPHYLAXIS
 All patients should be risk –stratified
 Ideally, begin TLS prophylaxis 24-48 hours before
chemotherapy
 Backbone of TLS prophylaxis:
 Stop concomitant interacting pharmacotherapy
 Saline –containing IVF to maintain urine output of
greater than equal to 100 ml /hr
 Allopurinol 300-900 mg daily in divided doses.
Cairo MS et al Br J Haematol 2010; 149:578-86

8. PRINCIPLES OF TLS PROPHYLAXIS (CONT.)
 Bicarbonate should not be added to IV
 GOAL : maximize renal excretion of electrolytes
 Uric acid nephropathy is most prevalent
nephrotoxin in TLS
 Aggressive IV fluids and allopurinol dosing is
critical to maximize renal function
 Rasburicase reserved for high–risk & pediatrics.
Cairo MS et al Br J Haematol 2010; 149:578-86

9. TLS PROPHYLAXIS IN LOW -RISK PATIENTS
o Monitor for development of TLS & complications.
 Obtain labs every 24 hours
o No recommendation for hydration , oral route may
be employed
o No allopurinol or rasburicase.
o Clinical judgment and monitoring only
Cairo MS et al Br J Haematol 2010; 149:578-86

10. TLS PROPHYLAXIS IN
INTERMEDIATE RISK PATIENTS
o Monitor for development of TLS & complications.
Obtain labs every 8-12 hours
 0.9% NS at rate of 2.5-3 litres /m2/day
Less may be used if patient fluid overloaded or oligouric at
baseline
 Allopurinol 300-400 mg /m2/ day (adults) or 10-
20 mg /kg/day( children < 15 years ) PO or IV
 Use loop diuretics as needed to administer
aggressive IV hydration
Cairo MS et al Br J Haematol 2010; 149:578-86

11. TLS PROPHYLAXIS IN HIGH -RISK
PATIENTS
o Monitor for development of TLS & complications.
 Obtain labs every 6-8 hours
 0.9% NS at rate of 2.5-3 liters /m2/day
 Less may be used if patient fluid overloaded or oligouric at baseline
 Allopurinol 300-400 mg /m2/ day (adults) or 10- 20 mg
/kg/day( children < 15 years ) PO or IV
 Rasburicase 0.1-0.2 mg /kg or fixed dose IV daily
 May be proffered n pediatrics
 Use loop diuretics as needed to administer aggressive
IV hydration
Cairo MS et al Br J Haematol 2010; 149:578-86

12. CASE NO: 01
 RD is a 59 year old male with newly diagnosed Burkitt’s
Lymphoma. Labs reveals WBC 12*109/ L , LDH = 810 IU/L ,
Potassium =5.7 mEq/L , SrCr= 2.1 mg/dl and uric acid 8.6
mg/dL .Vital signs and EKG are normal. Along with
allopurinol, which of the following is best to order first ?
a. 0.9% NS 1000ml * 1wide open
b. Rasburicase 0.2 mg /kg Iv *1
c. Sodium polystyrene Sulfonate
d. Consult for emergent renal dialysis

13. PRINCIPLES OF TLS TREATMENT
 GOAL: maximize renal excretion of electrolytes
 Treat each metabolic derangement
 Backbone of TLS treatment
 Saline –containing IVF to maintain urine output of
greater than equal to 100 ml/ hr
 Allopurinol 300-900 mg daily in divided doses.
Will A. Tholour E. Br J Haematol 2011;154:3-13
Wetzstein GA Oncology Special Edition. 2004:7:125-8

14. FEBRILE NEUTROPENIA

15. CASE NO :02
 MM is a 62 year old female who received first cycle
of paclitaxel / carboplatin 12 days ago. She comes
to your cancer center clinic with 101 ºF fever and
BP 81/60 She has severe Mucositis.She has PICC
Line. Lab revealWBC 500/mm 3 with 10 %
granulocytes. Which of the following is best at this
time?
a. Low risk febrile neutropenia (FN) treat with
ciprofloxacin + amoxicillin/clavulanate
b. Low risk FN: treat with cephalexin
c. High risk FN: treat with cefipime
d. High risk FN: treat with meropenem and
vancomycin

16. DEFINITIONS
o Neutropenia:
 Absolute ANC < 0.5*109/L
 <1*109 /L with a predicted decreased to < 0.5 *109
/L in next 48 hours.
 FEBRILE NEUTOPENIA:
 ANC < 0.5 *109 /L & a single PO temp > 101 ºF
(38.3º C) or > 100.4 ºF(38 ºC) for at least an hour.
 Usual signs / symptoms of infection absent; fever
only reliable indicator
Freifeld AG et al Clin Infect Dis. 2011;52 e56-93.

17. FEBRILE NEUTROPENIAAND WBC
COLONY -STIMULATING FACTOR
 PRIMARY PROPHYLAXIS
 Expect greater than equal to 20% incidence of FN.
 SECONDARY PROPHYLAXIS
 Experienced prior neutropenic complications and dose reduction
may compromise survival.
o Do not use WBC CSF for the treatment of
established FN
Smith T J et al J Clin Oncol. 2006;24:3187-205
Freifeld AG et al Clin Infect Dis 2011:52e56-93

18. PREVENTION OF FEBRILE NEUTROPENIA
 NCCN & IDSA GUIDELINES :
 Consider fluoroquinolones in high risk
 Expected ANC < 1*10 9 /L > 7 days
 Levofloxacin & ciprofloxacin have most data & are
considered roughly equivalent
 Role of anti bacterial prophylaxis controversial
No data showing improvement in over all survival or reduction
in incidence / severity of FN
Freifeld AG et al Clin Infect Dis 2011:52e56-93
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

19. PREVENTION OF FEBRILE NEUTROPENIA
 Antibacterial prophylaxis not recommended for
low risk patients.
 < 7 days neutropenia
 2009 ASCO guidelines : amifostine may reduce
grade 3 and 4 neutropenia associated with
chemotherapy:
 However dose reduction or use of CSF are alternatives
Freifeld AG et al Clin Infect Dis 2011:52e56-93
Hensley ML et al J Clin Oncol 2009;27:127-45

20. TREATMENT OF HIGH RISK FN
 MASCC SCORE < 21
 Patient with any of the following condition
 Hospitalized at onset of fevers
 Clinically unstable (hypotension)
 Significant co-morbidities ( pneumonia )
 Prolonged , severe neutropenia
 ANC less than equal to 0.1*10 9 /L for > 7 days
 Abnormal liver or renal function
 Grade 3 or 4 mucositis or enteritis
 Uncontrolled cancer
Freifeld AG et al Clin Infect Dis 2011:52e56-93
Freifeld AG et al Clin Infect Dis 2011:52e56-93
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

21. MASCC SCORING INDEX
CHARACTERISTICS SCORE
Absent to mild symptoms
Moderate symptoms
Severe
5
3
0
No hypotension (SBP > 90 mm Hg) 5
No COPD (presently or past medical
history)
4
Solid tumor or lymphoma w/o fungal
infection
4
No dehydration 3
Outptaient status ( at onset of fever) 3
Age < 60 years 2
Score greater than equal to 21 (out of 26 possible ) = low risk
Klastersky J et al Supportive Care Cancer 2013;21:1487-95

22. EMPIRIC TREATMENT FOR LOW RISK –FN
 Preferred therapy : ciprofloxacin +
amoxicillin/clavulanate
 If penicillin allergic: ciprofloacin + clindamycin
 Attempt to maintain outpatient status
 Avoid oral antibacterials in patients who received
fluoroquinolones prophylaxis
Flowers CR et al J Clin Oncol.2013;31:794-810

23. EMPIRIC TREATMENT OF HIGH RISK –FN
 Requires IV Antibiotics & inpatient status
 Cefepime
 Ceftazidime
 Note: resistance increasing to ceftazidime
 Antipseudomonal carbapenem ( imipenem –cilastatin , or
meropenem)
 Piperacillin /tazobactum
 Note: doses for FN indications different than non-FN
indications
Freifeld AG et al Clin Infect Dis 2011:52e56-93
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

24. TREATMENT PRINCIPLES FOR FN-
COMBINATION THERAPY
 Six indications to add gram positive agent
1. Sepsis syndrome / hemodynamic instability
2. Skin or skin structure infections (SSSI)
3. Central catheter- related infection
4. Colonization with MRSA , penicillin resistant s.pneumonia
or vancomycin- resistant enterococci spp.
5. Gram positive organism cultured
6. Severe mucositis
Freifeld AG et al Clin Infect Dis 2011:52e56-93
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

25. CASE NO :02
 MM is a 62 year old female who received first cycle
of paclitaxel / carboplatin 12 days ago. She comes
to your cancer center clinic with 101 ºF fever and
BP 81/60 She has severe Mucositis.She has PICC
Line. Lab revealWBC 500/mm 3 with 10 %
granulocytes. Which of the following is best at this
time?
a. Low risk febrile neutropenia (FN) treat with
ciprofloxacin + amoxicillin/clavulanate
b. Low risk FN: treat with cephalexin
c. High risk FN: treat with cefipime
d. High risk FN: treat with meropenem and
vancomycin

26. WHEN TO MODIFY EMPIRIC TREATMENT
CLINICAL SCENARIO ACTION TO TAKE
Antimirobial resistance ( actual or
suspected )
Add aminoglycosides,colistin,
fluoroquinolones and/or
vancomycin
Pneumonia Add vancomycin or linezolid , Add
aminoglycsides , switch to
carbapenems .
Cellulitis Add vancomycin or linezolid
Abdominal symptoms switch to carbapenems or
piperacillin/ tazobactum , add
metronidazole or oral vancomycin (
if suspect c.difficile)

27. WHEN TO MODIFY EMPIRIC
TREATMENT
CLINICAL SCENARIO ACTIONS TO TAKE
MRSA (BLOOD ) Add Vancomycin , Linezolid Or
Daptomycin
MRSA (Pneumonia) Add Vancomycin or Linezolid , add
aminoglycosides.
Extended spectrum beta-
lactamase ( ESBL )gram negative
bacteria
Switch to anti –pseudomonal
carbapenems
Klebsiella pneumonia
carbapenamase (KPC) positive
gram negative bacteria
Add colistin or tigecycline

28. TREATMENT PRINCIPLES FOR FN
(CONT.)
 Once daily and standard dosing of aminglycosides
are acceptable
 Avoid synergy dosing
 Consider linezolid or daptomycin for MRSA with
vancomycin MIC greater than equal to 2ug/ml
 Avoid daptomycin altogether for pneumonia
Freifeld AG et al Clin Infect Dis 2011:52e56-93
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

29. TREAT FN IN CLINICALLY UNSTABLE
PATIENT
 INDICATIONS : Sepsis syndrome , mental status
changes, tachypnea,etc
 EMPIRIC THERAPY WITH:
 Carbapenem or piperacillin /tazobactam plus
 Aminoglycoside plus
 Gram positive agent (vancomycin if pneumonia)
+/-
 Fluconazole or echinocandin
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

30. TREATMENT DURATION – ORGANISM
CULTURED
 Continue therapy until ANC > 0.5*10 9 /L
 Uncomplicated bacteremia = 10-14 D
 Uncomplicated GI or skin & skin structure
infection = 7-14 d
 Complicated bacteremia , pneumonia & upper
respiratory infections =10-21 D
 Typhlitis = treat until all evidence of infection
resolved & neutropenia resolved.
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

31. RECALCITRANT FN DESPITE BROAD
SPECTRUM ANTI BACTERIALS
 Consider drug induced fever
 Add empiric antifungal:
 After 4-7 days of broad spectrum antibacterials
And
 Anticipated neutropenia duration > 7 d
And
 No fever source identified
Patel RA.Gallagher JC Pharmacothera.2010;30:57-59
Freifeld AG et al Clin Infect Dis 2011:52e56-93
NCCN Clinical Practice guidelines-prevention & treatment of Cancer Related Infections ver1-2016

32. TREATMENT OF CENTRAL VENOUS
CATHETER INFECTION
 Remove catheter if culture positive for
 S.aureus
 P.aeroginosa
 Fungi
 Mycobacteria
 Retain catheter if coagulase-negative
staphylococcus infection
 Treat with systemic +/- antibiotic lock
Freifeld AG et al Clin Infect Dis 2011:52e56-93
Mermel LA et al Clin infect Dis. 2009.49:1-45

33. FOLLOW – UP OF FN PATIENT
 If vancomycin added empirically and no evidence
of gram positive infection, discontinue after 2-3
days
 For low risk FN patients receiving IV
antibacterial, may changed to oral if GI absorption
adequate
 No IV to PO switch recommendation for high risk –FN
Freifeld AG et al Clin Infect Dis 2011:52e56-93

34. THANK YOU