Abstract
Purpose
Clinical trials evaluating palifermin have enrolled few pediatric patients precluding safety analyses in large groups of children. We compared hematopoietic cell transplant (HCT) outcomes among pediatric patients from a large database who did or did not receive palifermin as a preventive treatment for oral mucositis.
Patients and Methods
Pediatric patients and controls, matched for HCT and donor type, disease, disease status and age, were selected from the Center for International Blood and Marrow Transplant Research (CIBMTR) database and a 1:3 matched cohort analysis was performed. Stratified Cox proportional hazards models were built and propensity score adjustments were used to compare overall and disease-free survival outcomes between palifermin-treated and untreated patients.
Results
Three controls were identified for 90% of palifermin recipients. The remaining cases were matched with two (8%) or one (2%) controls, for a total of 210 palifermin-treated patients matched with 606 controls. Median follow-up was 31 months in cases and 36 months in controls. 57% of patients underwent allogeneic HCT, mostly for acute leukemia, and 43% underwent autologous HCT, mostly for solid tumors. In univariate analyses, two-year survival and disease-free survival rates after allogeneic HCT (58% vs 66%, P = .109; 49% vs 60%, P = .060) and after autologous HCT (73% vs 77%, P = .474; 60% vs 64%, P = .637) were similar between palifermin-treated patients and matched controls. In multivariate analysis, palifermin treatment did not significantly increase the risk of mortality (relative risk [RR] 1.20, 95% CI 0.87–1.66) or relapse (RR 1.12, 95% CI 0.78–1.62) compared with matched controls. No significant differences in rates of acute or chronic graft-vs-host disease (GVHD) were observed between palifermin-treated patients and matched controls.
Conclusion
Among the pediatric patients undergoing HCT, overall survival, disease-free survival, neutrophil recovery, and GVHD rates were similar between palifermin-treated patients and matched controls.
Introduction
Palifermin (a recombinant human keratinocyte growth factor [KGF], Kepivance®, Swedish Orphan Biovitrum AB [Sobi], Stockholm, Sweden) decreases the duration and severity of oral mucositis (OM) after intensive chemotherapy and radiotherapy for hematologic cancers.1,2 In studies of adults, palifermin also improved daily functioning activities such as swallowing, drinking, eating, talking, and sleeping, and decreased the use of opioids when compared with placebo.3 Additionally, when compared with standard of care, palifermin decreased the length of hospitalization, number of nutrition impact symptoms experienced, total parenteral nutrition and narcotic opioid use, but appeared to have little impact on infection rates or time to engraftment.4–7 Palifermin treatment does not appear to affect the incidence and severity of acute graft-versus-host disease (GVHD),5,8 although one small study reported that acute GVHD was less prevalent in patients who received palifermin compared with those who did not.4
Palifermin, which is an N-truncated human KGF, acts physiologically on cells that express the KGF receptor, stimulating their proliferation, differentiation, and survival.1 However, cells of the hematopoietic lineage do not express the KGF receptor, and the administration of palifermin for the prevention of OM in patients with hematologic malignancies does not appear to adversely affect other HCT outcomes.9 However, most of these outcomes, including outcomes pertinent to safety (e.g. mortality and count recovery) were largely evaluated in adult patients.2–5 There are few clinical data on the long-term effects of palifermin in children.10–12 In one study involving children undergoing autologous hematopoietic cell transplantation (HCT), palifermin was shown to be effective at preventing OM and contributed to a significant decrease in hospital stays and lower incidence of infections.10 However, longer term effects were not studied. To address this knowledge gap, we studied outcomes of children reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) database and compared key safety outcomes between those who were treated with palifermin and those who were not.
Patients and Methods
Data Source and Participants
The CIBMTR® is a research collaboration between the National Marrow Donor Program®/Be The Match® and the Medical College of Wisconsin. It comprises a voluntary working group of more than 450 transplant centers worldwide that contribute detailed data on allogeneic and autologous HCT. Participating centers are required to report all transplants consecutively; compliance is monitored by on-site audits and patients are followed longitudinally. Computerized checks for discrepancies, physicians’ review of submitted data, and on site audits of participating centers ensure data quality. Studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. All patients or their legal guardians signed informed consent.
The CIBMTR collects data at two levels: Transplant Essential Data (TED) level and Comprehensive Report Form (CRF) level. The TED-level data is an internationally accepted standard data set that contains a limited number of key variables for all consecutive transplant recipients. TED-level data, with some additional details of donor and graft characteristics, comprise the data submitted to the SCTOD (Stem Cell Therapeutic Outcomes Database), which is maintained by CIBMTR, and required by federal statute for all allogeneic transplants in the United States. When a transplant is registered with the CIBMTR, a subset of patients is selected for the CRF level of data collection through a weighted randomization scheme. The CRF-level captures additional patient, disease and treatment-related data. TED and CRF level data are collected pre-transplant, 100 days and six months post-transplant, annually until year 6 post-transplant and biannually thereafter until death.
Eligible patients for this study were 18 years old or younger at time of transplantation for a hematologic malignancy or solid tumor, received myeloablative allogeneic or autologous HCT in a center in the United States, and had their outcomes were reported at the CRF level to the CIBMTR from 2005 and 2012. We attempted to match all pediatric patients treated with palifermin who met the inclusion criteria to a control patient in a 1:3 palifermin to control ratio. Matching variables included transplant type (autologous vs allogeneic), donor type, and disease type and status. Patients matched for these variables were considered a possible matched control if 1) both patients’ ages were <2 years old with an age difference ≤1 years, or if 2) both patients’ ages were >2 years old with an age difference of ≤5 years. Matched controls were selected with the smallest age differences among all potential matched controls.
The pre-matching study cohort consisted of 216 patients who were given palifermin and 4,287 patients with no palifermin exposure. Matching at 1:3 was successful for 90% of pairs (n = 190 pairs); the remaining pairs were matched at 1:2 (8%; n = 16 pairs) or 1:1 (2%; n = 4 pairs), for a total of 816 patients and 210 matched pairs. Six palifermin cases could not be matched to any controls.
Endpoints
Overall survival was estimated as the interval from HCT to death from any cause. Disease-free survival was calculated as the interval from HCT to time of disease relapse or death from any cause. Relapse was defined as the onset of recurrent disease after a documented complete remission. Risk of relapse was estimated using cumulative incidence function with death in remission treated as the competing risk. Transplant-related mortality was defined as time to death from any cause while in remission, and disease relapse was considered a competing risk. Acute graft versus host disease (GVHD) was diagnosed and graded based on consensus criteria, and chronic GVHD was diagnosed based on clinical criteria.13, 14 Neutrophil recovery was defined as time to an absolute neutrophil count (ANC) > 0.5 × 109/L (first of 3 consecutive days). Neutrophil recovery and GVHD events were estimated using cumulative incidence function treating death without the event as a competing risk. Data on efficacy outcomes of palifermin (such as the incidence of OM post-HCT, narcotic use, quality-of-life during the transplant process and enteral/parenteral nutrition use), is not collected on CIBMTR data collection forms and, hence, not analyzed in the current study which focused on safety.
Analytic Methods
Stratified Cox proportional hazards models were constructed on matched pairs. Propensity scores were used to further adjust for covariates in the multivariate analysis. Covariates analyzed to derive the propensity scores were: age, sex, race, Karnofsky/Lansky performance score (KPS/LPS), disease/disease status, conditioning regimen, donor type, donor-recipient cytomegalovirus (CMV) match, donor-recipient gender match, antithymocyte globulin (ATG) use, GVHD prophylaxis, year of HCT, and transplant type. The final propensity score model included KPS/LPS, ATG use, conditioning regimen, CMV match, and donor type. The propensity score is the probability of a particular patient receiving palifermin treatment given the patient’s individual characteristics.13–16 If accurately modeled, one can adjust for many observed confounders and obtain a less-biased estimate of the effect of an exposure on an outcome by including the propensity scores in a multivariate regression model. In this study, the logistic regression model used for the propensity score was logit(πi) = α + β´Zi, where πi = P(Yi = 1) for Yi =1 if the ith patient received palifermin or Yi = 0 if they did not, and Zi represented the covariates listed. Using this model, the predicted propensity score was calculated for each patient based on his/her characteristics. Equal propensity scores indicated patients with similar probabilities of being treated with palifermin. The distributions of estimated propensity scores (Table 2) were significantly different between palifermin-treated and control patients (P < .0001) overall, and including among autologous (P = .0268) and allogeneic HCT recipients (P < .0001) separately. Within the model, adjustment with the propensity score was used while estimating the impact of palifermin use for each clinical outcome.
Table 2.
Propensity scores for palifermin-treated patients and controls who have undergone autologous or allogeneic HCT
| Palifermin | Control | ||||
|---|---|---|---|---|---|
| HCT | n | Median (Range) | n | Median (Range) | P-value |
| Autologous | 90 | 0.25 (0.16–0.33) | 257 | 0.25 (0.16–0.33) | .0268 |
| Allogeneic | 120 | 0.34 (0.01–0.87) | 349 | 0.17 (0.01–0.74) | < .0001 |
| All | 210 | 0.26 (0.01–0.87) | 606 | 0.25 (0.01–0.74) | < .0001 |
HCT: Hematopoietic cell transplantation
Propensity scores (PS) for Autologous (% of Palifermin vs Control): PS=0.16 (7% vs 13%); PS=0.25(61% vs 65%); PS=0.33(32% vs 22%).
Results
Patient disposition and demographics
Most patients were Caucasian (77%), male (60%) and had a KPS/LPS ≥90 (73%; Table 1). The median age at transplantation was 9 years for all patients, 11 years for allogeneic HCT recipients and 5 years for autologous HCT recipients.
Table 1.
Characteristics of patients (age ≤18) who underwent either autologous or allogeneic HCT, with or without palifermin registered to CIBMTR between 2005 and 2013
| Autologous HCT | Allogeneic HCT | All HCT | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Variable | Palifermin n=90 |
Control n=257 |
Total n=347 |
Palifermin n=120 |
Control n=349 |
Total n=469 |
Palifermin n=210 |
Control n=606 |
Total n=816 |
| Patient-related | |||||||||
| Patients, n | 90 | 257 | 347 | 120 | 349 | 469 | 210 | 606 | 816 |
| US study centers, n | 21 | 71 | 27 | 73 | 37 | 82 | |||
| Median follow-up of survivors, months (range) | 25 (<1–72) | 34 (<1–97) | 38 (3–75) | 36 (6–96) | 31 (1–75) | 36 (1–97) | |||
| Median age at transplantation, years (range) | 5 (1–18) | 5 (1–18) | 11 (<1–18) | 11 (<1–18) | 9 (<1–18) | 9 (<1–18) | |||
| Age in years, n (%) | |||||||||
| <1 | 1 (1) | 3 (1) | 4 (1) | 3 (3) | 7 (2) | 10 (2) | 4 (2) | 10 (2) | 14 (2) |
| 1–2 | 19 (21) | 52 (20) | 71 (20) | 14 (12) | 36 (10) | 50 (11) | 33 (16) | 88 (15) | 121 (15) |
| 3–11 | 41 (46) | 120 (47) | 161 (46) | 45 (38) | 135 (39) | 180 (38) | 86 (41) | 255 (42) | 341 (42) |
| 12–16 | 19 (21) | 54 (21) | 73 (21) | 48 (40) | 154 (44) | 202 (43) | 67 (32) | 208 (34) | 275 (34) |
| 17–18 | 10 (11) | 28 (11) | 38 (11) | 10 (8) | 17 (5) | 27 (6) | 20 (10) | 45 (7) | 65 (8) |
| Gender, n (%) | |||||||||
| Male | 47 (52) | 168 (65) | 215 (62) | 74 (62) | 202 (58) | 276 (59) | 121 (58) | 370 (61) | 491 (60) |
| Female | 43 (48) | 89 (35) | 132 (38) | 46 (38) | 147 (42) | 193 (41) | 89 (42) | 236 (39) | 325 (40) |
| Race, n (%) | |||||||||
| Caucasian | 68 (76) | 200 (78) | 268 (77) | 83 (69) | 278 (80) | 361 (77) | 151 (72) | 478 (79) | 629 (77) |
| Non-Caucasian | 21 (23) | 54 (21) | 75 (22) | 33 (28) | 64 (18) | 97 (21) | 54 (26) | 118 (19) | 172 (21) |
| Unknown-missing | 1 (1) | 3 (1) | 4 (1) | 4 (3) | 7 (2) | 11 (2) | 5 (2) | 10 (2) | 15 (2) |
| Karnofsky/Lansky score at transplant, n (%) | |||||||||
| <90 | 29 (32) | 57 (22) | 86 (25) | 20 (17) | 58 (17) | 78 (17) | 49 (23) | 115 (19) | 164 (20) |
| ≥90 | 55 (61) | 168 (65) | 223 (64) | 98 (82) | 272 (78) | 370 (79) | 153 (73) | 440 (73) | 593 (73) |
| Unknown/Not reported | 6 (7) | 32 (12) | 38 (11) | 2 (2) | 19 (5) | 21 (4) | 8 (4) | 51 (8) | 59 (7) |
| Disease-related | |||||||||
| Disease, n (%) | |||||||||
| AML | N/A | N/A | N/A | 27 (23) | 78 (22) | 105 (22) | 27 (13) | 78 (13) | 105 (13) |
| CR1 | 9 (33) | 27 (35) | 36 (34) | 9 (33) | 27 (35) | 36 (34) | |||
| CR2+ | 13 (48) | 37 (47) | 50 (48) | 13 (48) | 37 (47) | 50 (48) | |||
| Not in remission | 5 (19) | 14 (18) | 19 (18) | 5 (19) | 14 (18) | 19 (18) | |||
| ALL | N/A | N/A | N/A | 86 (72) | 252 (72) | 338 (72) | 86 (41) | 252 (42) | 338 (41) |
| CR1 | 32 (37) | 96 (38) | 128 (38) | 32 (37) | 96 (38) | 128 (38) | |||
| CR2+ | 50 (58) | 146 (58) | 196 (58) | 50 (58) | 146 (58) | 196 (58) | |||
| Not in remission | 4 (5) | 10 (4) | 14 (4) | 4 (5) | 10 (4) | 14 (4) | |||
| Non-Hodgkin lymphoma | 6 (7) | 16 (6) | 22 (6) | 7 (6) | 19 (5) | 26 (6) | 13 (6) | 35 (6) | 48 (6) |
| Chemosensitive | 6 (100) | 16 (100) | 22 (100) | 7 (100) | 19 (100) | 26 (100) | 13 (100) | 35 (100) | 48 (100) |
| Hodgkin lymphoma | 15 (17) | 42 (16) | 57 (16) | 0 | 0 | 0 | 15 (7) | 42 (7) | 57 (7) |
| Chemosensitive | 15 (100) | 42 (100) | 57 (100) | 15 (100) | 42 (100) | 57 (100) | |||
| Solid tumor | 69 (77) | 199 (77) | 268 (77) | 0 | 0 | 0 | 69 (33) | 199 (33) | 268 (33) |
| Central nervous system tumors | 6 (9) | 18 (9) | 24 (9) | 6 (9) | 18 (9) | 24 (9) | |||
| Neuroblastoma | 43 (62) | 123 (62) | 166 (62) | 43 (62) | 123 (62) | 166 (62) | |||
| Medulloblastoma | 6 (9) | 18 (9) | 24 (9) | 6 (9) | 18 (9) | 24 (9) | |||
| Others | 14 (20) | 40 (20) | 54 (20) | 14 (20) | 40 (20) | 54 (20) | |||
| Transplant-related, n (%) | |||||||||
| Donor type | N/A | N/A | N/A | ||||||
| HLA Identical Sibling | 33 (28) | 97 (28) | 130 (28) | 33 (16) | 97 (16) | 130 (16) | |||
| HLA Match other related | 3 (3) | 9 (3) | 12 (3) | 3 (1) | 9 (1) | 12 (1) | |||
| HLA Mismatch other related | 2 (2) | 6 (2) | 8 (2) | 2 (1) | 6 (1) | 8 (1) | |||
| HLA Match Unrelated | 24 (20) | 72 (21) | 96 (20) | 24 (11) | 72 (12) | 96 (12) | |||
| HLA Mismatch Unrelated | 29 (24) | 79 (23) | 108 (23) | 29 (14) | 79 (13) | 108 (13) | |||
| Cord blood | 29 (24) | 86 (25) | 115 (25) | 29 (14) | 86 (14) | 115 (14) | |||
| Donor/Recipient CMV status | N/A | N/A | N/A | ||||||
| +/+ | 28 (23) | 69 (20) | 97 (21) | 28 (13) | 69 (11) | 97 (12) | |||
| +/− | 15 (13) | 31 (9) | 46 (10) | 15 (7) | 31 (5) | 46 (6) | |||
| −/+ | 34 (28) | 124 (36) | 158 (34) | 34 (16) | 124 (20) | 158 (19) | |||
| −/− | 41 (34) | 97 (28) | 138 (29) | 41 (20) | 97 (16) | 138 (17) | |||
| Not tested/Missing | 2 (2) | 28 (8) | 30 (6) | 2 (1) | 28 (5) | 30 (4) | |||
| Donor/recipient gender match | N/A | N/A | N/A | ||||||
| Male-Male | 38 (32) | 112 (32) | 150 (32) | 38 (18) | 112 (18) | 150 (18) | |||
| Male-Female | 22 (18) | 67 (19) | 89 (19) | 22 (10) | 67 (11) | 89 (11) | |||
| Female-Male | 35 (29) | 88 (25) | 123 (26) | 35 (17) | 88 (15) | 123 (15) | |||
| Female-Female | 23 (19) | 77 (22) | 100 (21) | 23 (11) | 77 (13) | 100 (12) | |||
| Missing | 2 (2) | 5 (1) | 7 (1) | 2 (1) | 5 (1) | 7 (1) | |||
| Allogeneic graft type | N/A | N/A | N/A | ||||||
| Bone marrow | 62 (52) | 199 (57) | 261 (56) | 62 (30) | 199 (33) | 261 (32) | |||
| Peripheral blood | 29 (24) | 64 (18) | 93 (20) | 29 (14) | 64 (11) | 93 (11) | |||
| Cord blood | 29 (24) | 86 (25) | 115 (25) | 29 (14) | 86 (14) | 115 (14) | |||
| TBI | |||||||||
| Yes | 2 (2) | 0 | 2 (1) | 105 (88) | 298 (85) | 403 (86) | 107 (51) | 298 (49) | 405 (50) |
| No | 88 (98) | 257 (100) | 345 (99) | 15 (13) | 51 (15) | 66 (14) | 103 (49) | 308 (51) | 411 (50) |
| Conditioning regimen | |||||||||
| TBI + others | 2 (2) | 0 | 2 (1) | 105 (88) | 298 (85) | 403 (86) | 107 (51) | 298 (49) | 405 (50) |
| Busulfan ± others | 11 (12) | 27 (11) | 38 (11) | 12 (10) | 50 (14) | 62 (13) | 23 (11) | 77 (13) | 100 (12) |
| Thiotepa ± others | 25 (28) | 63 (25) | 88 (25) | 3 (3) | 1 (<1) | 4 (1) | 28 (13) | 64 (11) | 92 (11) |
| BEAM + BEAM-like | 40 (44) | 153 (60) | 193 (56) | 40 (20) | 153 (25) | 193 (24) | |||
| CBV + CBV-like | 9 (10) | 13 (5) | 22 (6) | 9 (4) | 13 (2) | 22 (3) | |||
| ICE-like | 1 (1) | 0 | 1 (<1) | 1 (<1) | 0 | 1 (<1) | |||
| Others | 2 (2) | 1 (<1) | 3 (1) | 2 (1) | 1 (<1) | 3 (<1) | |||
| ATG | N/A | N/A | N/A | ||||||
| Yes | 64 (53) | 85 (24) | 149 (32) | 64 (30) | 85 (14) | 149 (18) | |||
| No | 56 (47) | 264 (76) | 320 (68) | 146 (70) | 521 (86) | 667 (82) | |||
| GVHD prophylaxis | N/A | N/A | N/A | ||||||
| CsA + FK506 ± others | 1 (<1) | 9 (3) | 10 (2) | 1 (<1) | 9 (1) | 10 (1) | |||
| CsA ± others | 68 (57) | 192 (55) | 260 (55) | 68 (32) | 192 (32) | 260 (32) | |||
| FK506 + Methotrexate ± others | 23 (19) | 106 (30) | 129 (28) | 23 (11) | 106 (17) | 129 (16) | |||
| FK506 ± others | 20 (17) | 27 (8) | 47 (10) | 20 (10) | 27 (4) | 47 (6) | |||
| Other | 8 (7) | 15 (4) | 23 (5) | 8 (4) | 15 (2) | 23 (3) | |||
| Year of transplant | |||||||||
| 2005–2009 | 38 (42) | 138 (54) | 176 (51) | 67(56) | 194 (56) | 261 (56) | 105 (50) | 332 (55) | 437 (54) |
| 2010–2012 | 52(58) | 119 (46) | 171(49) | 53(44) | 155 (44) | 208 (44) | 105 (50) | 274 (45) | 379 (46) |
ALL: Acute lymphocytic leukemia; AML: Acute myeloid leukemia; ATG: Anti-thymocyte globulin; BEAM: BiCNU, Etoposide, cytosine Arabinoside, Melphalan; CBV: Cyclophosphamide, BCNU, VP-16; CMV: Cytomegalovirus; CR: Complete remission; CsA: Cyclosporin A; GVHD: Graft-versus-host disease; HCT: Hematopoietic cell transplantation; HLA: Human leukocyte antigen; ICE: Ifosfamide, Carboplatin, Etoposide; N/A: Not applicable; TBI: Total body irradiation.
The median follow-up time of survivors was 31 months for patients treated with palifermin and 36 months for controls. Forty-three percent of patients underwent autologous HCT, mostly for solid tumors. Patients who underwent autologous HCT were mostly treated with BCNU, etoposide, cytosine arabinoside, and melphalan (BEAM) or similar BEAM-like or Thiotepa-based regimens. Forty patients treated with palifermin received BEAM/BEAM-like conditioning followed by autologous HCT for neuroblastoma (NB) (n=30), Hodgkin disease (HD) (n=8), and other solid tumors (n=2). Twenty five patients received thiotepa-based regimens for NB (n=9), medulloblastoma (n=6), other CNS tumors (n=5), other solid tumors (n=4), and NHL (n=1). Nine patients received CBV+CBV like regimens for NHL (n=5), HD (n=2), NB (n=1), and other solid tumor (n=1). Eleven patients received Bu/Mel for HD (n= 4), other solid tumors (n=4), and NB (n=3). Five patients received other types of conditioning regimens for solid tumors (n=3), HD (n=1), and CNS tumor (n=1).
Fifty-seven percent of patients underwent allogeneic HCT, mostly for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Among patients receiving allogeneic HCT, 56% received a bone marrow graft, 20% a peripheral blood graft, and 25% a cord blood graft (Table 1). Most received total body irradiation in their preparative regimen and received cyclosporine A (CsA) with other drugs for GVHD prophylaxis.
Outcomes
Overall survival
Univariate analyses of overall survival rates (Table 3) for patients in the autologous HCT group showed no significant differences between palifermin-treated and control patients at 100 days (95% [95% CI 88%–98%] vs 96% [95% CI 93%–98%], P = .677) and at 2 years (73% [95% CI 61%–82%] vs 77% [95% CI 71%–83%], P = .474). Similarly, among allogeneic HCT recipients, there were no significant differences between palifermin-treated and controls in overall survival rates at 100 days (87% [95% CI 79%–92%] vs 89% [95% CI 85%–92%], P = .488) and at 2 years (58% [95% CI 48%–66%] vs 66% [95% CI 61%–71%], P = .109). Multivariate analyses showed no significant differences in overall survival probabilities between palifermin-treated and control patients (Table 4, Figure 1A).
Table 3.
Univariate outcomes for the HCT population
| Autologous HCT | Allogeneic HCT | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Palifermin | Control | Palifermin | Control | |||||||
| Outcomes | n | % Prob (95% CI) |
n | % Prob (95% CI) |
P-value | n | % Prob (95% CI) |
n | % Prob (95% CI) |
P-value |
| Overall survival from transplant | 90 | 257 | 120 | 349 | ||||||
| 100 days | 95 (88–98) | 96 (93–98) | .677 | 87 (79–92) | 89 (85–92) | .488 | ||||
| 2 years | 73 (61–82) | 77 (71–83) | .474 | 58 (48–66) | 66 (61–71) | .109 | ||||
| Disease-free survival* | 73 | 250 | 119 | 345 | ||||||
| 100 days | 96 (88–99) | 93 (89–95) | .290 | 82 (73–87) | 84 (80–88) | .532 | ||||
| 2 years | 60 (47–72) | 64 (57–70) | .637 | 49 (40–58) | 60 (54–65) | .060 | ||||
| Relapse* | 73 | 250 | 119 | 345 | ||||||
| 1 year | 29 (19–41) | 20 (16–26) | .143 | 22 (15–30) | 20 (16–24) | .698 | ||||
| 2 years | 40 (27–52) | 33 (26–39) | .343 | 27 (19–35) | 26 (21–31) | .849 | ||||
| Transplant-related mortality* | 73 | 250 | 119 | 345 | ||||||
| 1 year | 0 | 3 (1–5) | .947 | 21 (14–28) | 13 (9–16) | .058 | ||||
| 2 years | 0 | 3 (2–6) | .881 | 24 (16–32) | 14 (11–18) | .033 | ||||
| Neutrophil recovery* | 89 | 250 | 118 | 343 | ||||||
| 30 days | 100 | 95 (91–97) | 92 (84–96) | 89 (85–92) | .382 | |||||
| 100 days | 100 | 98 (95–99) | 100 | 97 (94–98) | ||||||
| Acute GVHD* | 119 | 342 | ||||||||
| 100 days | 31 (23–40) | 26 (22–31) | .332 | |||||||
| 1 year | 38 (29–47) | 38 (33–43) | .987 | |||||||
| Chronic GVHD* | ||||||||||
| 1 year | 23 (16–32) | 31 (26–37) | .094 | |||||||
| 2 years | 30 (22–39) | 34 (29–39) | .474 | |||||||
Death as a competing risk
GVHD: Graft-versus-host disease; HCT: Hematopoietic cell transplantation.
Table 4.
Relative risks of HCT outcomes based on multivariate analyses
| Variable | Palifermin vs Control RR (95% CI) |
P-value |
|---|---|---|
| Overall mortality | 1.20 (0.87–1.66) | .274 |
| Relapse | 1.12 (0.78–1.62) | .536 |
| Treatment failure (death or relapse) | 1.14 (0.85–1.54) | .391 |
| Transplant-related mortality | 1.21 (0.72–2.03) | .482 |
| Neutrophil recovery | 1.20 (0.98–1.48) | .077 |
| Acute GVHD II–IV | 1.19 (0.79–1.81) | .406 |
| Chronic GVHD | 0.66 (0.39–1.10) | .113 |
GVHD: Graft-versus-host disease; HCT: Hematopoietic cell transplantation; RR: Relative risk.
RR>1 indicates higher probability of event occurrence.
Figure 1.
Probability curves based on multivariate analyses for pediatric palifermin-treated or control patients who have undergone HCT for hematological malignancies or solid tumors for (A) overall survival, and (B) disease-free survival (DFS).
Disease-free survival
Similar to overall survival rates, disease-free survival rates after autologous HCT were similar between palifermin-treated and control patients at 100 days (96% [95% CI 88%–99%] vs 93% [95% CI 89%–95%], P = .290) and at 2 years (60% [95% CI 47%–72%] vs 64% [95% CI 57%–70%], P = .637) as well as after allogeneic HCT at 100 days (82% [95% CI 73%–87%] vs 84% [95% CI 80%–88%], P = .532) and at 2 years (49% [95% CI 40%–58%] vs 60% [95% CI 54%–65%], P = .060). Multivariate analysis showed no significant differences in disease-free survival rates between palifermin-treated and control patients (Table 4, Figure 1B).
Relapse and transplant-related mortality
There were no significant differences after autologous HCT between palifermin-treated and control groups in relapse rates at 1 (29% [95% CI 19%–41%] vs 20% [95% CI 16%–26%], P=0.143) and 2 years (40% [95% CI 27%–52%] vs 33% [95% CI 26%–39%, P=0.343]) or in transplant-related mortality rates at 1 (0% vs 3% [95% CI 1%–5%], P=0.94) and 2 years (0% vs 3% [95% CI 2%–6%], P=0.88) (Table 3). Similarly, there were no significant differences after allogeneic HCT in relapse rates at 1 (22% [95% CI 15%–30%] vs 20% [95% CI 16%–24%], P=0.698) and 2 years (27% [95% CI 19%–35%] vs 26% [95% CI 21%–31%], P=0.849) or in transplant-related mortality rates at 1 year (21% [95% CI 14%–28%] vs 13% [95% CI 9%–16%], P=0.058) between the palifermin-treated and control groups, respectively. The 2-year transplant-related mortality rate was significantly higher for allogeneic HCT patients treated with palifermin compared with those who were not (24% [95% CI 16%–32%] vs 14% [95% CI 11%–18%]; P = 0.033) (Table 3).
Multivariate analyses showed no significant differences in risks for relapse (RR 1.12, 95% CI 0.78–1.62), treatment failure (RR 1.14, 95% CI 0.84–1.53), transplant-related mortality (RR 1.20, 95% CI 0.71–2.00), and overall mortality (RR 1.20, 95% CI 0.87–1.66) between the palifermin-treated and control groups (Table 4).
Neutrophil recovery
There were no significant differences in the 30- and 100-days neutrophil recovery rates between the palifermin-treated and control patients in both allogeneic and autologous HCT groups (Table 3). Multivariate analyses showed no significant differences in rates for neutrophil recovery between those who received palifermin and those who did not (RR 1.20, 95% CI 0.98–1.48) (Table 4).
Acute and chronic GVHD
In the allogeneic HCT group, the 100-day and 1-year acute GVHD grade II–IV rates and the 1- and 2-year chronic GVHD rates were not significantly different between those who received palifermin and those who did not (Table 3). Similarly, multivariate analyses (Table 4) showed no significant difference in risk between the palifermin-treated and control groups for grades II to IV acute GVHD (RR 1.19, 95% CI 0.79–1.80) or for chronic GVHD (RR 0.66, 95% CI 0.39–1.10).
Discussion
As in adults, palifermin is an effective treatment to prevent OM. This retrospective matched cohort analysis of other HCT outcomes in children receiving HCT for hematologic malignancy or solid tumors shows no difference in overall or disease-free survival between palifermin-treated patients and matched controls. Furthermore, there were no significant differences in neutrophil recovery, acute GVHD, chronic GVHD, or relapse rates. Although the risk of transplant-related mortality after allogeneic HCT was slightly higher in the palifermin-treated patients in univariate analysis, this difference disappeared after propensity score adjustment in multivariate analysis. To our knowledge, this is the first study comparing the effects of palifermin on longer term outcomes in a pediatric population. It indicates that palifermin has no adverse effect on disease outcomes in children being treated for the prevention of OM while undergoing HCT.
Our results are consistent with a long-term follow-up (of up to 15 years) study reporting comparable long-term safety outcomes (overall survival and progression-free survival times, and incidence of secondary malignancies) between palifermin- and placebo-treated adults undergoing autologous HCT for hematological malignancies.9 Similarly, in a randomized, double-blind trial of adults undergoing allogenic HCT; palifermin treatment had no significant effect on time to engraftment, aGVHD, or survival.8
In our study, we chose to use propensity scores as an approach to further adjust for covariates in the multivariate model. The propensity score is the likelihood that the patient receives the treatment based on their observed characteristics. In this study, the score was calculated by performing a logistic regression model in which palifermin was the dependent variable and other patient characteristics were included as independent variables. The propensity score was then used as an additional covariate in the multivariate analysis. One observational study has shown that multivariate analyses adjusted for propensity scores yielded results that were consistent with those of a published meta-analysis of randomized clinical trials.17 The results of that study suggest that the use of propensity scores in observational studies may yield relevant comparative effectiveness results, which can be especially useful when randomized clinical trials are not feasible or when the goal is to understand the real-world impact of a treatment.17
One of the limitations of this study is that the study was retrospective in nature and was not designed as a randomized controlled trial. However, real world data are also valuable and give insight into the type and outcome of treatments being given to patients. Another limitation of the study is the lack of information on the reasons why palifermin was chosen as a treatment and its overall efficacy. Data on incidence of OM, narcotic use, quality-of-life, enteral/parenteral nutrition are not routinely collected by the CIBMTR. The focus of this study was on long-term safety outcome. The median follow-up time for survivors in this study was 2.5–3 years; additional follow up is needed and is planned.
In conclusion, among pediatric patients who underwent HCT for hematologic malignancies or solid tumors, overall survival, disease-free survival, neutrophil recovery, or GVHD rates were similar between patients who were treated with palifermin and matched controls, at least out to 2.5 years posttransplant.
Acknowledgments
This analysis was sponsored by Sobi, Inc. The authors also acknowledge the medical writing assistance of Dominique Verlaan, PhD (Precise Publications, LLC), which was supported by Sobi, Inc.
CIBMTR Support List
The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Be the Match Foundation; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; *Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Mesoblast; *Millennium: The Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. – Japan; Oxford Immunotec; Perkin Elmer, Inc.; Pharmacyclics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; *Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Telomere Diagnostics, Inc.; TerumoBCT; Therakos, Inc.; University of Minnesota; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
*Corporate Members
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