1. Safety and Effectiveness of Intravenous Pentamidine for Prophylaxis of Pneumocystis jirovecii Pneumonia in Pediatric Hematology/Oncology Patients
Loriel Solodokin, PharmD.
Assistant Professor of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences University
Clinical Oncology Pharmacist, Dana Farber Cancer Institute/Massachusetts General Hospital
BIT 3rd Annual World Congress of Pediatrics
November 2, 2017

2. Conflicts of Interest
None of the study investigators have anything to disclose concerning possible conflicts of interest related to this presentation

3. Background Pneumocystis jirovecii pneumonia (PCP)
Opportunistic infection
Breakthrough infection rate sans prophylaxis
22%-45% in HIV negative children with hematological malignancies
Advent of trimethoprim-sulfamethoxazole (TMP/SMX)
Significantly ↓ PCP incidence in pediatric hematology/oncology patients
Mortality rates
Lower in non-HIV/AIDS patients vs. those with HIV/AIDS
Children: (non-HIV+, with ALL)
Crozier F. J Pediatr Oncol Nurs
Pyrgos V, et al. Paediatr Respir Rev
Hughes WT, et al. N Engl J Med

4. PCP Risk Factors In HIV negative children
High-dose, prolonged steroid therapy
Chemotherapy-induced immunosuppression
Solid organ/bone marrow transplant (BMT)
Primary immune deficiency
Malignancy diagnosis
Crozier F. J Pediatr Oncol Nurs
Pyrgos V, et al. Paediatr Respir Rev

5. PCP Prophylaxis: Guideline Recommendations
Line of Therapy
Drug
Dosing
First-line
(Gold Standard)
Trimethoprim-sulfamethoxazole (TMP/SMX)
Children: 5 mg/kg/day divided BID x 2-3 consecutive days/week
Adolescents/adults: 1 DS tab daily x 2-3 consecutive days/week
(max: 320 mg TMP/day)
Second-line
Pentamidine
IV: ≥ 2 yrs: 4 mg/kg every 4 weeks
Inh: ≥ 5 yrs: 8 mg/kg, via Respirgard II nebulizer, every 4 weeks
(max: 300 mg/dose)
Atovaquone
1-3 mo or > 24 mo: 30 mg/kg/dose
4-24 mo: 45 mg/kg/dose
≥ 13 yo: 1500 mg daily
(max: 1500 mg/day)
Dapsone
Infants and children: 2 mg/kg/dose daily OR
4 mg/kg/dose weekly
Adolescents: 100 mg/day in 1-2 divided doses (monotherapy)
(max: 100 mg/day or 200 mg/wk)
TMP/SMX breakthrough: 0-0.2%
Cons to 2nd line agents
-Dapsone-heme toxicities (aplastic anemia, dyscrasias, G6PD deficiency, derm, peripheral neuropathy, heptotoxicity)
-Atovaquone-PO absorption issues, hepatotoxicity
Prevention and treatment of cancer-related infections (Version 1). National Comprehensive Cancer Network Website. Updated August Accessed April 2015.
Altman AJ, ed. Supportive Care of Children with Cancer. Baltimore, MD.: The Johns Hopkins University Press; 2004.

6. Previous Data Kim SY, et al. DeMasi JM, et al. Clark A, et al.
Study design
Retrospective chart analysis between 1/2001 and 5/2006
Retrospective chart analysis between 1/2005 and 9/2011
Retrospective chart analysis between 1/2010 and 7/2013
Population
232 pediatric oncology pts ± allogeneic/autologous BMT
BMT patients: 46%
137 pediatric hematopoietic stem cell transplant pts
Autologous SCT: 32%
Allogeneic SCT: 68%
333 pediatric transplant patients
BMT patients: 85.2%
Intervention
Monthly IV pentamidine
4 mg/kg, as second-line prophylaxis, if TMP/SMX not tolerated
4 mg/kg, as first-line prophylaxis
IV pentamidine 4 mg/kg every 3-4 wks, as first- or second-line prophylaxis
Results
Breakthrough rates
Total: 1.3%
BMT patients: 1.9%
< 2 yo: 6.5%
< 2 yo + BMT: 9.1%
Total: 0%
< 2 yo: 0%
Total 0.3%
Adverse events
No significant intolerances
Total: 9%
Nausea/vomiting (10%)
Anaphylactic reactions (2%)
Pentamidine d/c: (9%)
IV pentamidine → inh pentamidine: (9%)
Total (BMT; 6.6%)
Tachycardia (2%)
Shortness of breath (1.4%)
Pancreatitis, QTc prolongation , ↑LFTs (0.7%)
Fever, numbness/tingling, anaphylaxis (0.35%)
Demasi: one of the anaphylactic rxns occurred d/t inc admin rate of pentamidine. Slower infusion rates did not result in any rxns
Higher breakthrough rates in younger patients may be associated with the type of immunodeficiencies seen in younger children and increased drg metabolism in that cohort of patients (elimination half life of IV pentamidine is days
Pentamidine frequency (Levy, ER, et al. PIDJ. 2016;35(2):
2009 survey: 20/25 HSCT centers in Primary Immunodeficiency Treatment Consortium use pentamidine as their preferred 2nd line agent
--10/20 administer it q4wks
--3/20 administer it q3wks
--7/20 administer it q2wks (Cowan 2009, personal communication)
Kim SY, et al. Pediatr Blood Cancer
DeMasi JM, et al. Pediatr Infect Dis J
Clark A, et al. Pediatr Transplantation

7. Study Rationale Limited published data
Hematopoietic stem cell transplant patient population
IV pentamidine as second-line agent
IV Pentamidine Practice at NYULMC
Used when TMP/SMX is not preferred
Often given first-line over TMP/SMX
Dosed every 3-4 weeks
Information gaps
IV pentamidine’s effectiveness
As first-line prophylaxis
In non-transplant population

9. Study Objective
Describe the effectiveness and safety of IV pentamidine as PCP prophylaxis, when administered every 3 to 4 weeks, in pediatric hematology/oncology patients

10. Study Design IRB approved retrospective chart review
Patients identified from electronic health record databases
All patients who received pentamidine
Data collected by review of electronic health records
Baseline demographics
TMP/SMX use and reasons for discontinuation
Pentamidine use as a first- and second-line prophylactic agent and frequency of administration
Changes in blood pressure, electrolytes, liver/renal/cardiac function
Adverse effects
Descriptive statistics
Demographics: malignancy diagnosis and receipt of chemotherapy/radiation/SCTs
Aes: such as nausea, fatigue, and infusion-site reactions

11. Study Design Inclusion criteria Definitions Patient follow-up
Patients ≤ 22 years old
Patients who received ≥ 1 dose of IV pentamidine, from 1/2009 to 7/2014, in inpatient and outpatient settings
Definitions
Possible PCP
Hypoxic respiratory distress
Radiographic evidence of PCP
On treatment for PCP
Probable PCP
Methenamine silver stain
Direct fluorescent antibody
Polymerase chain reaction
Sputum culture
Patient follow-up
6 months post last documented IV pentamidine dose OR
Death OR
Last clinic visit/hospital admission
Patient follow-up: which ever was furthest
Orgel E, Rushing T. Pediatr Infec Dis J

12. Study Endpoints Primary Outcome Secondary Outcomes
Incidence of breakthrough PCP
Secondary Outcomes
Incidence of adverse effects
Infusion-site reactions
Allergies
Nausea
Fatigue
Blood chemistry changes

13. Population Reviewed, N = 184 Included, n = 122
Not included, n = 62
Age > 22 yrs, n = 39
Inadequate documentation of IV pentamidine in medical record, n = 21
IV pentamidine for PCP treatment, n = 2
Included, n = 122
IV pentamidine first-line, n = 75
IV pentamidine second-line, n = 47

14. Patient Characteristics
Demographic Data*
All Patients (N = 122)
Age†, yr
 5.5 (3-13)
Age ≤ 2 yr
24 (20)
Sex, male
 74 (61)
Race
Caucasian
50 (41)
Other
38 (31)
Asian
13 (11)
African American
12 (10)
Hispanic
7 (6)
Unknown
2 (2)
Actual weight†, kg
 22.2 ( )
BMI†, kg/m2
 17.9 ( )
*All values expressed as n (%), unless otherwise specified
†Values expressed as median (IQR)

15. Patient Characteristics
Demographic Data*
All Patients (N = 122)
Diagnosis
Acute lymphoblastic leukemia
50 (41)
Brain tumor
38 (31)
Other hematological malignancy
12 (10)
Sarcoma
7 (6)
Acute myeloid leukemia
5 (4)
Lymphoma
4 (3)
Solid tumor
3 (2)
Chemotherapy
117 (96)
Radiation
24 (20)
Concomitant corticosteroids
94 (77)
Stem cell transplant
Autologous
Allogeneic
*All values expressed as n (%), unless otherwise specified

16. Patient Characteristics
PCP Prophylaxis*
All Patients (N = 122)
Pentamidine
First-line
75 (61)
Second-line
47 (39)
Frequency, wks
Every 4 wks
68 (56)
Every 3 wks
28 (23)
Once
25 (20)
Duration†, mos
3 (1-6)
Total doses†
3 ( )
Third-line agents‡
Atovaquone
2 (2)
Dapsone
*All values expressed as n (%), unless otherwise specified
†Values expressed as median (IQR)
‡Administered after TMP/SMX and IV pentamidine

17. Patient Characteristics
PCP Prophylaxis Before Pentamidine*
All Patients (N = 122)
SMX/TMP
71 (58)
First-line
51 (72)
Duration prior to pentamidine†, mos
4.5 (2-11)
Reason for discontinuation, n = 51
Myelosuppression
28 (55)
Drug interaction
11 (22)
Unknown
9 (18)
Non-compliance
4 (8)
GI symptoms
Rash
2 (4)
Allergy
1 (2)
Inability to take PO medications
*All values expressed as n (%), unless otherwise specified
†Values expressed as median (IQR)

18. Primary Outcome: Breakthrough PCP Rates
No breakthrough PCP identified during entirety of IV pentamidine treatment course, up to 6 months post discontinuation, death, or last available record

19. Pentamidine Toxicity Profile
Adverse events (AE)*,†
All Patients (N = 122)
Total number of patients with AE
19 (16)
Patients with > 1 AE
4 (21)
Discontinuation due to AEs
3 (16)
Allergic reaction
5 (26)
Nausea
Facial/nose/labial/tongue tingling
Hypotension‡
Perioral numbness
2 (11)
Extravasation
1 (5)
Fatigue
Blood chemistry changes
*All values expressed as n (%), unless otherwise specified
† AEs assessed within 3 days of IV pentamidine administration, while changes in electrolytes and other serum levels were assessed with 7 days of IV pentamidine administration
‡n=35

20. Discussion Breakthrough PCP rates throughout follow-up period:
0% for both first (n = 63)- and second (n = 37)-line pentamidine regimens
0% for non-SCT pts (n = 84)
0% for ≤ 2 yo subset (n = 21)
Compared to published literature, similar adverse event profile
Newly recognized: facial tingling
No clinically significant changes in laboratory values noted within 7 days post-pentamidine administration
Kim et al. : <2yo n = 31 (13%), non-SCT n = 125 (54%)
Demase et al: <2yo n = 12 (9%), non-SCT n = 0
Clark et al: n=333 (0.3%)

21. Study Limitations Single-center study Retrospective chart analysis
No power analysis
Retrospective chart analysis
Data not available for all patients
Inconsistent intrapatient administration intervals
No PO TMP/SMX comparator
Use of TMP/SMX before/after IV pentamidine may have confounded incidence of breakthrough PCP
Not all patients who developed pneumonia were worked up for PCP
Lack of clinical PCP may be an underrepresentation
Presented data may only be extrapolated to pediatric population

22. Conclusion
IV pentamidine is a safe, tolerable, and effective agent for PCP prophylaxis in pediatric hematology/oncology patients
No breakthrough PCP was noted throughout the entire course of pentamidine, through 6 months post discontinuation
IV pentamidine is a reasonable therapeutic alternative when TMP/SMX is not preferred for PCP prophylaxis

23. Acknowledgements Liana Klejmont, PharmD, BCPS
Clinical Manager, Pediatric Hematology/Oncology
Marco R. Scipione, PharmD, BCPS, AQ-ID
Pharmacotherapist, Infectious Diseases
Yanina Dubrovskaya, PharmD, BCPS, AQ-ID
Clinical Manager, Infectious Diseases
Jennifer Lighter, MD
Pediatric Hospital Epidemiologist
John Papadopoulos, BS, PharmD, FCCM, BCNSP
Critical Care Pharmacist
Director, Pharmacy Residency Program
Pharmacotherapist, Critical Care

25. Safety and Effectiveness of Intravenous Pentamidine for Prophylaxis of Pneumocystis jirovecii Pneumonia in Pediatric Hematology/Oncology Patients
Loriel Solodokin, PharmD.
Assistant Professor of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences University
Clinical Oncology Pharmacist, Dana Farber Cancer Institute/Massachusetts General Hospital
BIT 3rd Annual World Congress of Pediatrics
November 2, 2017