Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants

Abstract

Palifermin, a recombinant human keratinocyte growth factor, is commonly given to prevent mucositis following autologous transplantation. In the allogeneic hematopoietic stem cell transplant (allo-HSCT) setting, safety and efficacy data are limited. We performed a retrospective study in 251 patients undergoing allo-HSCT, 154 of whom received peritransplant palifermin. In all patients, palifermin significantly decreased the mean number of days of total parenteral nutrition (TPN, 13 vs 16, p=0.006) and patient-controlled analgesia (PCA, 6 vs 10, p=0.023), and the length of initial hospital stay (LOS, 32 days vs 37 days, p=0.014). However, the effect of palifermin was only significant in patients who received a TBI but not busulfan-based chemotherapy conditioning regimen. In TBI recipients, palifermin decreased the mean number of days of TPN (13 vs 17, p<0.001) and PCA (7 vs 12, p=0.033), and the length of stay (32 days vs 38 days, p=0.001). Palifermin did not affect graft-versus-host disease, graft failure, or relapse. Therefore, in the largest analysis with this patient population to date, we demonstrate that palifermin is safe in allo-HSCT patients, decreases TPN and PCA use and decreases LOS following TBI-based but not chemotherapy-based allo-HSCT.

Introduction

Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment for hematologic malignancies. Mucositis, resulting from injury to epithelial cells lining the oral cavity and gastrointestinal (GI) tract, is a complication of both high dose chemotherapy and radiation-based conditioning. Although the use of methotrexate for graft-versus-host disease (GVHD) prophylaxis is thought to contribute to mucositis, the incidence of moderate or severe mucositis following a TBI-based myeloablative regimen has been reported to be 64%, even in the absence of methotrexate ¹. While the severity can vary with conditioning regimens, allo-HSCT associated mucositis can result in significant morbidity, including oral pain requiring narcotics for analgesia, anorexia requiring total parenteral nutrition (TPN), a prolonged hospital stay, and possibly life-threatening infections from translocated mucosal bacteria ^2–4.

Keratinocyte growth factor (KGF) is a 28-kDa endogenous protein in the fibroblast growth factor family that functions as a growth factor for epithelial cells ⁵. KGF has an important role in healing epithelium following injury ⁶. Palifermin (Kepivance, Swedish Orphan Biovitrium) is a recombinant human KGF that is more stable than endogenous KGF due to the removal of 23 amino acids from its N-terminus (product information). Preclinical data in mouse models have demonstrated that administration of palifermin is protective against chemotherapy and radiation-induced mucositis ^7–10. Clinically, palifermin has been demonstrated to mitigate mucositis after chemotherapy and total body irradiation (TBI)-based autologous HSCT ^{11, 12}. Based on a phase III study in autologous transplant patients that demonstrated a decreased incidence and duration of World Health Organization (WHO) grade III–IV mucositis following TBI conditioning, palifermin was approved by the FDA for the prevention of mucositis during autologous and allogeneic HSCT. There is however limited published experience with palifermin in the context of allogeneic-HSCT ^13–15.

To help determine if palifermin is safe and efficacious following allo-HSCT, we performed a retrospective analysis of our experience with palifermin administered to adult patients undergoing a myeloablative T cell-depleted (TCD) allo-HSCT for hematologic malignancies. The TCD setting was selected in order to study the effects of palifermin in the absence of methotrexate, which is routinely given for GVHD prophylaxis. While TCD has not been commonly used in the US, recent positive multicenter data supports a more widespread use ^{16, 17}. This study represents the largest published experience to date detailing palifermin use during allo-HSCT.

Patients and Methods

Patients

This is a retrospective study of all 251 adult patients who received a TCD allo-HSCT for the treatment of a hematologic malignancy at MSKCC between January 2004 and December 2009. One hundred fifty-four patients received palifermin during this time period. The allocation of patients is illustrated in figure 1. Palifermin therapy was initiated in January 2006 after its approval by the FDA. After that date, all but 3 patients who underwent TBI-based allo-HSCT received palifermin as a standard of care. Recipients of chemotherapy-based allo-HSCT after January 2006 received palifermin either on a phase II clinical trial evaluating palifermin in recipients of a chemotherapy-based TCD allo-HSCT (n= 19) or at the discretion of the attending physician (n = 58). The phase II protocol included patients with a diagnosis of myelodysplastic syndrome (MDS) or secondary acute myelogenous leukemia (AML). For patients not on protocol, the decision to administer palifermin was primarily driven by date of transplant as practice patterns of the service changed. For example, 64 of the 77 patients who received palifermin with chemotherapy-based transplants were transplanted between 6/16/06 and 5/8/09. Only 9 patients received palifermin off protocol outside this time period. Follow-up was until June 30, 2010. Written informed consent for treatment was obtained from all patients. Approval for this retrospective review was obtained from the Institutional Review and Privacy Board. Eligibility criteria for transplant included a diagnosis of a hematologic malignancy in a disease state appropriate for TCD transplantation; availability of a donor with a minimum of an 8/10 HLA match; absence of active infection; and lack of coexisting cardiac, pulmonary, hepatic, or renal dysfunction that would preclude administration of the myeloablative cytoreductive regimen. HLA matching was established by DNA sequence-specific oligonucleotide typing for HLA-A, -B, -Cw, -DQB1, and-DRB1 loci. Supportive care was per MSKCC guidelines as previously described ^18–20 and similar for the chemotherapy and TBI groups. Aside from the implementation of vancomycin as prophylaxis against oropharyngeal flora in 2005 and the initiation of palifermin use in 2006, supportive care did not change during our study period. For example, our standard practice has been to start TPN on day +2 or +3 and continue until patients achieve a documented caloric intake of 1000 calories per day. Eighty-eight percent of patients in the study were treated on this schedule. Only twelve patients (5%) were more than one day outside the standard start day with a range from d−4 to d+5. The only two patients who started later than d+4 did not receive palifermin.

Figure 1.

Allocation of patients

Transplantation Plan

Patients either received a TBI-based or chemotherapy-based preparative regimen ^18–20. The decision to administer a TBI-based versus chemotherapy based transplant was dependent both on protocol availability and the BMT Service’s discretion regarding the patient’s ability to tolerate TBI. Either of two TBI-based regimens were used: TBI 1375 cGy given in 11 fractions followed by 2 daily doses of thiotepa (5 mg/kg/day) and, 2 daily doses of cyclophosphamide (60 mg/kg/day, 39 patients) starting after thiotepa, or 5 daily doses of fludarabine (25 mg/m²/day, 82 patients) beginning on the first day of thiotepa ^{19, 20}. Hyperfractionation was employed to decrease the toxicity associated with the higher than standard dose of TBI ²¹. The cyclophosphamide-based preparative regimen lasts 8 days, while the fludarabine-based preparative regimen lasts 9 days. The chemotherapy-based preparative regimen consisted of Busulfan (0.8 mg/kg/dose) every 6 hours for 10 or 12 doses, Melphalan (70 mg/m²/day) for 2 doses and fludarabine (25 mg/m²/day) for 5 doses ¹⁸. Patients treated prior to 10/15/09 received 10 doses of Busulfan with the last 4 doses adjusted per first dose pharmacokinetics. After that date, the dose of Busulfan was increased to 12 doses with the last 6 doses dose adjusted per first dose pharmacokinetics. Both variations of this chemotherapy-based preparative regimen span 8 days.

T cells were removed from bone marrow grafts by sequential soybean lectin agglutination and sheep red blood cell (sRBC)-rosette depletion (9 patients) ¹⁹. T cell depletion of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) was accomplished by positive selection of CD34+ stem cells using the ISOLEX 300i Magnetic Cell Separator and subsequent sRBC-rosette depletion (231 patients) ²⁰ or the positive selection of CD34+ stem cells using the Miltenyi CliniMACS system without subsequent sRBC rosette depletion (11 patients) ¹⁶. T-cell depleted marrow or PBSC was infused within 24–48 hours after completion of the chemotherapy. Conditioning regimens included antithymocyte globulin (ATG) for 0–3 doses. Pharmacologic GVHD prophylaxis was not given because the patients received a fully ex-vivo TCD graft.

Patients who received palifermin received the drug per the approved dosing schedule ¹². Three daily doses (60 mcg/kg/day) were given prior to transplant admission with the third dose given no fewer than twenty-four hours prior to administration of chemotherapy or radiotherapy. Starting six hours after stem cell infusion, patients received three further daily doses of palifermin (60 mcg/kg/day).

Efficacy Evaluation

Data were collected on the number of days patients required TPN and patient-controlled analgesia (PCA) with narcotics ^{12, 14}. Patients were placed on PCA by the transplant attending physician when patients complained of any mouth or throat pain that interfered with swallowing. The PCA was discontinued when the patient did not require “demand doses” in the absence of a basal rate. Our practice of administering TPN is described above. In addition, length of the initial hospital stay for transplant (LOS) from the time of admission was determined for all patients.

Transplant-related toxicity evaluation

The diagnosis of GVHD was made on clinical grounds and confirmed pathologically whenever possible. Acute GVHD (aGVHD) was graded according to CIBMTR criteria ²². Patients were evaluable for aGVHD after engraftment. Patients surviving more than 100 days were evaluable for chronic GVHD (cGVHD). Chronic GVHD was classified as limited or extensive by the criteria of Sullivan ²³. NIH Consensus Criteria were not used in this study because its retrospective nature limited the data available for cGVHD grading.

Primary graft failure was defined as the absence of neutrophil recovery (≥500/μl) by day 28 and bone marrow biopsy with ≤5% cellularity. Secondary graft failure was defined as loss of ANC to <500/μl after primary engraftment with bone marrow biopsy showing ≤5% cellularity ¹⁸.

Biostatistics

We compared the continuous outcomes PCA use, TPN use and LOS between palifermin recipients and non-recipients using the t test. Linear regression models were fitted to evaluate the effect of palifermin on each of these mucositis-related outcomes, after adjusting for age, ATG use and preparative regimen (TBI-based and chemotherapy-based). While it was not expected that ATG use would affect mucositis, it was carried over to these multivariate analyses to be consistent with the analyses for time to development of aGVHD. Competing risk analysis and multivariable competing risks regression controlling for age, ATG use and preparative regimen were used to evaluate the effect of palifermin on the time to acute and chronic GVHD. To evaluate the effect of palifermin on survival outcomes, the log-rank test was applied to overall survival (OS) and event free survival (EFS). The Cox regression model was used for these time-to-event outcomes, adjusting for age, ATG use and preparative regimen.

Results

Patient characteristics

Table 1 details the patient characteristics. The median age at transplant was 55 years (range 19–73 years). The diagnoses were varied and are detailed in the table. One hundred twenty-one patients received TBI-based conditioning (48%, Figure 1). Of these patients, seventy-seven (64%) received palifermin. Of the 130 patients who received a chemotherapy-based allo-HSCT (52%), seventy-seven (59%) received palifermin. Nine patients received bone marrow as their stem cell source and the remaining patients received peripheral blood stem cell grafts. Two hundred thirteen patients (85%) received ATG prior to their stem cell infusion and two patients received ATG post stem cell infusion. ATG was not administered to the other 36 patients, who were all recipients of matched related donors and conditioned with TBI, thiotepa and fludarabine (n=34) or TBI, thiotepa and cyclophosphamide (n=2) ²⁰.

Table 1.

Patient Characteristics

Characteristic	Number (%)
	TBI-based			Chemo-based			All Patients
	Palifermin Y (n=77)	Palifermin N (n=44)	P-value	Palifermin Y (n=77)	Palifermin N (n= 53)	P-value
Age – yr			0.50			0.27
Median	47	46.5		59	58		55
Range	19–64	21–63		25–73	31–68		19–73
Sex			0.33			0.99
Male	51 (66%)	25 (57%)		41 (53%)	29 (55%)		146 (58%)
Female	26 (34%)	19 (43%)		36 (47%)	24 (45%)		105 (42%)
Diagnosis			0.41			0.56
AML	37 (48%)	19 (43%)		47 (61%)	33 (62%)		136 (54%)
MDS	2 (3%)	2 (5%)		25 (32%)	14 (26%)		43 (17%)
ALL	25 (32%)	11 (25%)		0 (0%)	1 (2%)		37 (15%)
NHL	11 (14%)	8 (18)		0 (0%)	0 (0%)		19 (8%)
MM	0 (0%)	0 (0%)		4 (5%)	5 (9%)		9 (4%)
CML	2 (3%)	2 (5%)		0 (0%)	0(0%)		4 (2%)
Other	0 (0%)	2 (5%)		1 (1%)	0(0%)		3 (1%)
HLA Matching			0.18			0.74
Matched related	34 (44%)	25 (57%)		23 (30%)	14 (26%)		96 (38%)
Matched unrelated	22 (29%)	11 (25%)		30 (3%)	21 (40%)		84 (33%)
Mismatched related	2 (3%)	3 (7%)		2 (39%)	0 (0%)		7 (3%)
Mismatched unrelated	19 (25%)	5 (11%)		22 (29%)	18 (34%)		64 (25%)

All patients except for two achieved a level of CD3+ cell depletion of < 1 × 10⁵/kg. The remaining two patients were given grafts with 1.5 × 10⁵ CD3+ cells/kg (PBSC graft) and 3.0 × 10⁵ CD3+ cells/kg (bone marrow).

Efficacy endpoints

The effect of palifermin on the clinical endpoints studied is summarized in Table 2. In univariate analysis, patients who received palifermin had fewer mean days on PCA (6 vs 10, p = 0.020), fewer mean days on TPN (13 vs 16, p = 0.010) and a shorter mean LOS (32 days vs 37 days, p = 0.016). After controlling for age at transplant, ATG use and preparative regimen, these differences remain significant (p= 0.023, p=0.006, and p=0.014, respectively). Analyzing patients who received TBI-based versus chemotherapy-based preparative regimens separately, the benefit of palifermin was limited to patients who received TBI (Table 3a). For these patients, palifermin decreased the number of days on PCA (7 vs 12, p = 0.023) and TPN (13 vs 17, p = 0.002), and the LOS (32 vs 38 days, p = 0.003) in univariate analysis. In the multivariate analysis, this benefit persisted (p = 0.033, p < 0.001, p = 0.001, respectively). However, for recipients of the chemotherapy-based preparative regimen (Table 3b), no benefit was observed.

Table 2.

Mucositis outcomes and palifermin use for all adult patients

	Palifermin Use		p-Value
	Yes Mean (SD)	No Mean (SD)	t Test	Palifermin effect*
Age	52 (12)	51 (12)	0.522
Days on PCA	6 (10)	10 (13)	0.020	0.023*
Days on TPN	13 (8)	16 (9)	0.010	0.006*
Length of Hospital Stay	32 (9)	37 (15)	0.016	0.014*

^*Adjusted for age, ATG use and conditioning regimen type.

Table 3a.

Mucositis outcomes and palifermin use for TBI patients (n=121)

	Palifermin Use		p-Value
	Yes Mean (SD)	No Mean (SD)	t Test	Palifermin effect*
Age	46 (10)	44 (12)	0.408
Days on PCA	7 (9)	12 (17)	0.023	0.033*
Days on TPN	13 (7)	17 (8)	0.002	<.001*
Length of Hospital Stay	32 (8)	38 (13)	0.003	0.001*

^*Adjusted for age and ATG use.

Table 3b.

Mucositis outcomes and Palifermin use for chemotherapy patients (n=130)

	Palifermin Use		p-Value
	Yes Mean (SD)	No Mean (SD)	t Test	Palifermin effect*
Age	58 (9)	56 (9)	0.406
Days on PCA	5 (12)	7 (9)	0.275	0.288*
Days on TPN	13 (8)	14 (10)	0.447	0.490*
Length of Hospital Stay	33 (10)	35 (16)	0.426	0.459*

^*Adjusted for age. All patients received ATG.

Palifermin toxicity

Side effects commonly associated with palifermin use were observed in our patient population. These toxicities were in all cases mild and resolved without any intervention once the course of palifermin was completed. Documented side effects included erythema or rash (64 patients, 42%), oral hyperplasia or discoloration (22 patients, 14%) and edema of hands and feet or eyelids (11 patients, 7%). Of the 154 patients who received palifermin, 77 patients (50%) were noted to have at least one reaction to palifermin and eighteen patients (12%) had more than one reaction.

Transplant related toxicity

Consistent with our prior experience in TCD allo-HSCT, the three-month cumulative incidence rate of grade 2–4 aGVHD was 12% (95%CI: 8%–16%) and the one-year cumulative incidence rate of cGVHD was 10% (95%CI: 6%–14%). There was no observed effect of palifermin on the development of aGVHD (Figure 2a) or cGVHD (Figure 2b). In addition, palifermin did not affect the rate of graft failure. In the entire cohort, two primary graft failures and four late graft failures were noted. Of the patients who received palifermin, 4/154 (2.6%) suffered graft failure. Two patients of the 97 who did not receive palifermin (2.1%) also had graft failure.

Figure 2.

Figure 2a. Cumulative incidence rate of aGVHD for all adults by palifermin use

Figure 2b. Cumulative incidence rate of cGVHD for all adults by palifermin use

Overall and event-free survival

With a median followup of 16.3 months (range 0.03–75.8 months), the median OS is 53 months (95%CI: 32 months – not achieved) and the median EFS is 39 months (95%CI: 25 months – not achieved). There was no significant effect of palifermin on either OS (Figure 3a) or EFS (Figure 3b). However, age at transplant was a significant prognostic factor for OS (HR 1.02, 95%CI: 1.00–1.04, p = 0.05) and EFS (HR 1.02, 95%CI: 1.00–1.04, p = 0.04), controlling for ATG use and preparative regimen.

Figure 3.

Figure 3a. Overall survival by palifermin use

Figure 3b. Event-free survival by palifermin use

Discussion

Our results represent the largest published experience with palifermin in allo-HSCT recipients to date. Recognizing the limitations of a retrospective study, including possible physician bias, we are able to demonstrate for the first time that palifermin does not increase transplant-related toxicity in the allogeneic transplant setting and is efficacious following TBI-based allo-HSCT. Previous studies evaluating palifermin with allo-HSCT were limited because they were smaller in size, were focused on GVHD prevention and/or did not use palifermin at the currently approved dosing schedule ^13–15.

In our study, 154 patients undergoing allo-HSCT received peri-transplant palifermin. Because this was a retrospective study, we were unable to accurately report the effect of palifermin on the WHO grade of mucositis. Outside of prospective studies specifically designed to assess mucositis, mucositis scoring is inconsistently recorded in the medical chart. Clinical endpoints associated with mucositis that have been described in previous studies ^{12, 14, 15} were used and we demonstrated a significant reduction in TPN use, PCA use and length of stay. Analyzing recipients of TBI-based and chemotherapy-based allo-HSCT separately, the benefit of palifermin was limited to recipients of TBI. In this group of patients, palifermin decreased the mean number of days patients received PCA and TPN by 5 days (p = 0.033) and 4 days (p < 0.001), respectively. In addition, the LOS for the transplant hospitalization in patients who received palifermin was also 6 days shorter (p = 0.001). Common side effects associated with palifermin use were observed at similar rates as previously published¹².

Our study also demonstrated that palifermin administration did not increase transplant-related toxicity during allo-HSCT. In this large patient population receiving the FDA approved dosing of palifermin, no apparent increased rate of acute and chronic GVHD or graft failures was seen. However, since all patients received ex-vivo TCD allo-grafts and ATG, it is possible that palifermin may have an effect on the development of GVHD in other settings. Furthermore, there was also no difference in OS or EFS between the 2 groups (p = 0.704 and p = 0.463, respectively).

There have been limited data supporting the use of palifermin during allogeneic transplantation^13–15. Blazar et al ¹³ reported a phase I/II dose-escalation, randomized, placebo controlled study that evaluated the effect of palifermin on the prevention of aGVHD, based on preclinical studies that suggested palifermin may prevent aGVHD ^{24, 25}. Sixty-nine patients received palifermin, while 31 patients received placebo. No difference in the rate of aGVHD, time to engraftment, relapse or survival was noted between the 2 groups, which is consistent with our data. A subgroup analysis revealed a significant decreased incidence and mean severity of mucositis in patients conditioned with Cyclophosphamide and TBI but not Busulfan and Cyclophosphamide. This study included 4 different dosing schedules with 8 patients receiving less, and 51 patients receiving more palifermin than the current approved dose. Ten patients in the study received palifermin at the current FDA approved dosing.

Langner et al ¹⁴ also reported a limited series on palifermin in the allo-HSCT setting. They treated 30 patients with palifermin who were undergoing allo-HSCT for leukemia and compared them to a matched historical control group. There was a decreased incidence in grade II–IV mucositis for patients who received palifermin compared to control (60% vs 80%, p=0.04). There was also a decrease in the mean duration of mucositis for patients receiving palifermin (6 vs 12 days, p =0.003), a decrease in the median total dose of opioids administered (150 mg vs 378 mg, p = 0.04) and duration of TPN use (15 days vs 26 days, p = 0.002). No effect of palifermin on hematological recovery, the development of aGVHD, or OS was noted in this small study. Similarly, Nasilowska-Adamska et al ¹⁵ treated 53 patients transplanted for hematologic malignancies with palifermin and compared them with a matched historical control group. The benefit for mucositis prevention was confirmed and there was no difference between the groups with regard to development of any aGVHD. Further allogeneic transplant-specific analyses were limited because only 24 patients who received palifermin underwent allo-HSCT, while the remainder of the patients received an autologous transplant.

Our findings demonstrate a significant benefit for allo-HSCT recipients that can potentially impact their quality of life as well as the complications and cost of the transplant and hospitalization. The reduced requirement for TPN, for example, may have important implications towards decreasing infections and hepatic complications in this compromised patient population. It is possible the impact of palifermin on TPN use would have been more significant had we initiated TPN strictly based on caloric need rather than routine as patients with decreased oral mucositis may not have met the requirements for TPN. The decrease in the initial transplant hospitalization by almost one week may be expected to decrease patients’ risk for developing hospital-acquired infections and may speed recovery. Importantly, the benefits of palifermin were observed exclusively in recipients of a TBI-based conditioning regimen. Palifermin did not affect our clinical endpoints in the cohort of patients receiving a busulfan-based chemotherapy preparative regimen. These findings are consistent with those of Blazar et al ¹³, whose study employed both a different TBI-based and busulfan-based conditioning regimen and whose study utilized methotrexate as part of their GVHD prophylaxis supporting a broad applicability to our findings. The possibility that palifermin could decrease mucositis following a different or more intense chemotherapy-based conditioning regimen, however, cannot be excluded. Further validation would be required to definitively assess if palifermin will continue to be efficacious following administration of methotrexate. Although unlikely, it is possible the initiation of vancomycin prophylaxis against oral flora at around the same time as the initiation of palifermin may confound our results as an oral infection could potentially exacerbate mucositis. Another potential confounder of our results may be that the two cohorts of patients who received a TBI-based allo-HSCT could have different clinical outcomes. Furthermore, other dosing schedules, which have been published in non-transplant settings ^{26, 27}, may merit further exploration in the transplant setting.

In summary, we demonstrate in this large retrospective study that palifermin is efficacious during allo-HSCT and does not increase transplant related toxicity in this setting. Our study represents the largest cohort of patients treated at the indicated dose and therefore is a significant contribution to guide current clinical practice with this drug in the allo HSCT setting. Because palifermin use is confounded with date of HSCT and other clinical factors in this retrospective study, a prospective randomized study is needed to validate these results. We are currently planning a large, multicenter prospective study evaluating the safety and efficacy of palifermin in a TBI-based myeloablative TCD allo-HSCT patient population to confirm our findings.