What evidence exists for the use of palifermin in the setting of allogeneic stem cell transplant, particularly in pediatric patients?

Comment by InpharmD Researcher

Current guidelines recommend against the use of palifermin in pediatric patients undergoing allogeneic stem cell transplantation due to concerns about modest benefits and potential adverse effects like rash and mucosal irritation. While palifermin has shown some effectiveness in reducing severe oral mucositis, the overall evidence supporting its routine use is limited, particularly in children. With a lack of compelling safety and efficacy data, the need for effective pharmacologic options to prevent severe oral mucositis in this population remains unmet.

Background

A 2021 updated clinical practice guideline provided recommendations for prevention of oral mucositis in pediatric cancer patients, including the use of palifermin during hematopoietic stem cell transplant. A total of 12 pediatric randomized controlled trials (RCTs) investigated were included for analysis, and palifermin was observed to significantly reduce severe mucositis (risk ratio [RR] 0.81; 95% confidence interval [CI] 0.69 to 0.95), but did not significantly reduce any mucositis or total parenteral nutrition administration compared to no prophylaxis. Short-term adverse events observed with palifermin include rash, erythema, and white film coating of the tongue and mouth. One patient developed second malignancy (squamous cell carcinoma of the oral epithelium) in a patient with chronic graft-versus-host disease. Based on these findings, the authors make a strong recommendation against use of palifermin in pediatric patients due to its only modest effect on reducing severe mucositis with potential for adverse effects. [1]

A 2017 Cochrane meta-analysis was conducted to assess interventions for prevention of oral mucositis during cancer treatment. However, due to low amounts of data in children and insufficient sample sizes, the authors concluded there was no compelling evidence that a specific agent would benefit children, although no severe safety concerns were noted. Isolated studies of pediatric patients receiving palifermin or allogeneic stem cell transplants did not provide substantial findings from the meta-analysis. [2]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What evidence exists for the use of palifermin in the setting of allogeneic stem cell transplant?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

The Impact Of Palifermin Use On Hematopoietic Cell Transplant Outcomes In Children
Design	Retrospective, matched cohort study N= 469
Objective	To evaluate the impact of palifermin on hematopoietic cell transplant (HCT) outcomes in pediatric patients, with a focus in allogeneic HCT patients
Study Groups	Palifermin (n= 120) Control (n= 349)
Inclusion Criteria	Pediatric patients (≤18 years) undergoing myeloablative allogeneic or autologous HCT for hematologic malignancy or solid tumor in the US, reported to Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005-2012
Exclusion Criteria	Not explicitly stated, but implied exclusion of patients not meeting the inclusion criteria or those without matched controls
Methods	Patient data were collected and stratified 1:3 into palifermin and control matched cohorts with propensity score adjustments. Outcomes were compared between palifermin-treated and untreated patients.
Duration	Median follow-up: 31 months for palifermin-treated, 36 months for controls
Outcome Measures	Primary: Overall survival, Disease-free survival Secondary: Neutrophil recovery, Acute and chronic GVHD rates
Baseline Characteristics		Palifermin (n= 120)	Control (n= 349)
	Age < 1 year 1-2 years 3-11 years 12-16 years 17-18 years	3% 12% 38% 40% 8%	2% 10% 39% 44% 5%
	Female	38%	42%
	White	69%	80%
	Karnofsky/Lansky score at transplant < 90 ≥ 90	17% 82%	17% 78%
	Disease Acute myeloid lymphoma CR1 CR2+ Not remission Acute lymphoblastic leukemia CR1 CR2+ Not remission Non-Hodgkin lymphoma Hodgkin lymphoma Solid tumor	23% 33% 48% 19% 72% 37% 58% 5% 6% 0 0	22% 35% 47% 18% 72% 38% 58% 4% 5% 0 0
Results	Endpoint	Palifermin (n= 120)	% Probability (95% confidence interval [CI])	Control (n= 349)	% Probability (95% CI)	p-Value
	Overall survival from transplant, n 100 days 2 years	120	87% (79 to 92) 58% (48 to 66)	349	89 (85 to 92) 66 (61 to 71)	0.488 0.109
	Disease-free survival, n 100 days 2 years	119	82% (73–87) 49% (40–58)	345	84 (80 to 88) 60 (54 to 65)	0.532 0.060
	Relapse, n 1 year 2 years	119	22% (15 to 30) 27% (19 to 35)	345	20 (16 to 24) 26 (21 to 31)	0.698 0.849
	Transplant-related mortality, n 1 year 2 years	119	21% (14 to 28) 24% (16 to 32)	345	13 (9 to 16) 14 (11 to 18)	0.058 0.033
	Neutrophil recovery, n 30 days 100 days	118	92% (84 to 96) 100%	343	89 (85 to 92) 97 (94 to 98)	0.382
	Acute GVHD, n 100 days 1 year	119	31 (23 to 40) 38 (29 to 47)	342	26 (22 to 31) 38 (33 to 43)	0.332 0.987
	Chronic GVHD, n 1 year 2 years	--	23 (16 to 32) 30 (22 to 39)	--	31 (26 to 37) 34 (29 to 39)	0.904 0.474
Adverse Events	No significant differences in acute or chronic GVHD rates between palifermin-treated patients and controls.
Study Author Conclusions	Palifermin does not adversely affect overall survival, disease-free survival, neutrophil recovery, or GVHD rates in pediatric HCT patients.
InpharmD Researcher Critique	Strengths: Large sample size, use of propensity scores for adjustment. Limitations: Retrospective design, lack of data on palifermin efficacy and reasons for treatment choice, limited follow-up duration.

References:

Saber W, Zhang MJ, Steinert P, Chen M, Horowitz MM. The Impact of Palifermin Use on Hematopoietic Cell Transplant Outcomes in Children. Biol Blood Marrow Transplant. 2016;22(8):1460-1466. doi:10.1016/j.bbmt.2016.04.008

Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial
Design	Open-label, single-arm, multicenter phase I study N= 27
Objective	To determine a safe and tolerable dose of palifermin and to characterize the pharmacokinetic profile and efficacy in pediatric patients in different age groups
Study Groups	1-2 cohort (n= 9) 3-11 cohort (n= 9) 12-16 cohort (n= 9)
Inclusion Criteria	Patients aged 1 to 16 years with acute lymphoblastic leukemia or acute myeloid leukemia requiring myeloablative allogeneic hematopoietic stem cell transplant (HSCT), Lansky Performance Status score ≥ 60%, adequate kidney, liver, cardiac, and pulmonary functions
Exclusion Criteria	Previous treatment with keratinocyte growth factors (KGFs)
Methods	Palifermin was administered as an intravenous (IV) bolus for 3 consecutive days before and after stem cell infusion. Safety and PK parameters were monitored, and oral mucositis (OM) was assessed using World Health Organization (WHO) Oral Toxicity criteria.
Duration	Follow-up assessments at day +100; months 6, 9, and 12; and then annually until completion of study.
Outcome Measures	Primary: Safety and tolerability, pharmacokinetic profile Secondary: Efficacy in reducing oral mucositis, incidence of acute graft-versus-host disease (aGVHD)
Baseline Characteristics		1-2 cohort (n= 9)	3-11 cohort (n= 9)	12-16 cohort (n= 9)
	Age, years	1.3	6.8	14.8
	Female	22%	67%	44%
	White	33%	22%	22%
	Weight, kg	12.36	28.06	64.40
	Body surface area, m²	0.528	0.951	1.673
	Disease Acute lymphoblastic leukemia Acute myeloid leukemia	78% 22%	89% 11%	78% 22%
Results	Endpoint	1-2 cohort (n= 9)	3-11 cohort (n= 9)	12-16 cohort (n= 9)
	Incidence of aGVHD, n 0 1 2 3 4	33% 33% 0 33% 0	22% 44% 11% 22% 0	56% 22% 0 11% 11%
	Most patients developed ulcerative oral mucositis, however, the lowest incidence of severe oral mucositis occurred in the group that received the highest dose of 80 mg/kg/day of palifermin with no incidence of grade 4 oral mucositis occurring in this group. In general, the palifermin concentrations declined rapidly in the first 30 minutes after dosing. After the initial rapid decline, a slight increase in palifermin concentration occurred at 2 to 4 hours postdose for most patients, which was followed by a second, slow decline phase. By 24 hours postdose, palifermin concentrations were not quantifiable in most patients.
Adverse Events	Reported events include rash, pruritus, extremity and testicular pain, gingival hyperplasia, lip swelling, oral pharyngeal plaque, face edema No dose-limiting toxicity or treatment-related serious adverse event were reported
Study Author Conclusions	Palifermin was well tolerated with a good safety profile at all dose levels. No effect of age on PK was observed, and no drug accumulation was seen. The incidence of severe OM was lower in the 80 mg/kg/day dose group, indicating increased efficacy with higher doses.
InpharmD Researcher Critique	Strengths: Comprehensive safety and PK analysis, inclusion of multiple age cohorts. Limitations: Small sample size, lack of a control group, variability in PK parameters.

References:

Morris J, Rudebeck M, Neudorf S, et al. Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial. Biol Blood Marrow Transplant. 2016;22(7):1247-1256. doi:10.1016/j.bbmt.2016.02.016

Phase I Study of the Tolerability and Pharmacokinetics of Palifermin in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Design	Phase I study N= 12 participants
Objective	To evaluate the tolerability and pharmacokinetics of palifermin at doses of 40, 60, and 90 mcg/kg/day in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT)
Study Groups	All subiects (N = 12)
Inclusion Criteria	Children aged 2-18 years with hematologic malignancy, scheduled for allogeneic HSCT with a 5/6 or 6/6 HLA allele-matched donor, adequate organ function, performance score of 100
Exclusion Criteria	Active oral ulcerations or gastrointestinal bleeding, hypersensitivity to E. coli-derived proteins, active infections within 2 weeks, previous HSCT
Methods	Palifermin was administered as a daily IV bolus for 3 consecutive days before the conditioning regimen (days −9 to −7 for matched sibling donor [MSD] HSCT and days −11 to −9 for matched unrelated donor [MUD] HSCT) and for 3 additional days on days +1 to +3. Three dose levels (40 mcg, 60 mcg, and 90 mcg/kg/day) were tested in 3 patients each, with progression to the next dose if no dose-limiting toxicity (DLT) occurred at the prior level. Dosing was based on actual body weight. Toxicity was assessed using National Cancer Institute (NCI) criteria.
Duration	Follow-up mean of 2.7 years (range 1.1-4.1 years)
Outcome Measures	Primary: Maximum tolerated dose (MTD), nonhematologic toxicities Secondary: Pharmacokinetics of palifermin
Baseline Characteristics	Characteristics	All subkects (N = 12)
	Age, years	9.2 (2-16)
	Female, n	7
	Underlying Disease, n Acute myelogenous leukemia Acute lymphoblastic leukemia	7 5
	Remission Status, n CR1 CR2 CR3	7 4 1
	Pretransplantation Weight, kg	34.2
	HSCT, n MSD MUD	3 9
	Time to neutrophil and platelet engraftment, days MSD MUD	22 27
	CD34+ cell dose, cells/kg	7 × 10⁶
	CR= complete remission, HSCT= hematopoietic stem cell transplantation; MSD= matched sibling donor; MUD= matched unrelated donor
Results	Endpoint	All subjects (N = 12)
	Survival at the time of follow-up *	10 (83%)
	* One patient relapsed at 9 months, underwent a second HSCT, and is well. One died of progressive disease, and another from adenoviral sepsis.
	Pharmacokinetic data: The area under the concentration–time curve increased proportionally with dose, with 97% of palifermin exposure occurring within the first 24 hours. Clearance increased linearly with body weight, supporting weight-based dosing. The mean clearance was 1893 mL/hour/kg and remained consistent between the first and last doses (p = 0.80). The mean elimination half-life was 4.6 hours.
Adverse Events	Palifermin at 90 mcg/kg/day was well tolerated, with no dose-limiting toxicities. All 12 patients had at least one adverse event, mostly NCI grade 1 or 2. The most common was macular rash (67%), lasting 48–72 hours in most cases. Three patients developed mucositis, and two experienced grade 2–3 abdominal pain. Other adverse effects included mild headache, numbness, dry mouth, skin issues, and transient liver enzyme elevations. No significant amylase or lipase increases were observed, and the patient receiving methotrexate had mild AST elevation without mucositis.
Study Author Conclusions	Our data show that palifermin was tolerated at a dose of 90 mcg/kg/day, and exhibits linear pharmacokinetics in children undergoing allogeneic HSCT.
InpharmD Researcher Critique	The study's limitations include a small sample size, absence of a control group, and restriction to a single center.

References:

Srinivasan A, Kasow KA, Cross S, et al. Phase I study of the tolerability and pharmacokinetics of palifermin in children undergoing allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(8):1309-1314. doi:10.1016/j.bbmt.2012.04.013