The role of pegfilgrastim in mobilization of hematopoietic stem cells

The role of pegfilgrastim in mobilization of hematopoietic stem cells

Available online at www.sciencedirect.com Transfusion and Apheresis Science 38 (2008) 237–244 intl.elsevierhealth.com/journals/tras Review The role...

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Available online at www.sciencedirect.com

Transfusion and Apheresis Science 38 (2008) 237–244 intl.elsevierhealth.com/journals/tras

Review

The role of pegfilgrastim in mobilization of hematopoietic stem cells Frank Kroschinsky *, Kristina Ho¨lig, Gerhard Ehninger Medical Department I, Dresden University Hospital, Fetscherstrasse 74, 01307 Dresden, Germany

Abstract Granulocyte colony-stimulating factors (G-CSF) are established prerequisites for the mobilization of peripheral blood stem cells (PBSC). Pegylated filgrastim (pegfilgrastim) has a substantially increased elimination half-life due to decreased serum clearance. A single-dose of pegfilgrastim is equivalent in enhancing neutrophil recovery after chemotherapy compared to daily filgrastim administrations. Several clinical trials also investigated chemotherapy plus single-dose pegfilgrastim in the mobilization of autologous PBSC in patients with lymphoma or myeloma. The results indicated similar efficacy compared to unconjugated G-CSF in terms of blood CD34+ cell count, stem cell yields as well as engraftment of after reinfusion. However, the number of patients in these trials were limited and there were non-randomized controls only. Furthermore, the mobilization of 12 mg pegfilgrastim was not superior over the 6 mg dose, and in one trial insufficient results were observed in heavily pretreated patients. In allogeneic stem cell donors a single-dose of 12 mg pegfilgrastim has been shown to induce a sufficient increase of blood CD34+ cells with a similar kinetics as known from conventional G-CSF. Adequate numbers of PBSC for transplantation could be harvested mostly by a single apheresis. Bone pain and headaches appeared to be more severe and about 90% of donors required analgetics. Additional concerns are due to spleen enlargement and hyperleukocytosis. Promising insights were reported from preclinical studies which revealed a modulating impact on both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after transplantation of pegfilgrastim mobilized PBSC. Further trials are needed which carefully evaluate the issues of donor safety, but also the impact on graft composition and recipients’ outcome. Ó 2008 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

*

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rationale for the use of pegfilgrastim in stem cell mobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mobilization of autologous PBSC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stem cell mobilization in allogeneic donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Toxicity in healthy donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +49 351 458 8110; fax: +49 351 458 8120. E-mail address: [email protected] (F. Kroschinsky).

1473-0502/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2008.04.007

238 238 239 240 241

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5.

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Perspectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

1. Introduction The development of peripheral blood stem cell (PBSC) transplantation has been crucial to improve outcome in cancer patients. While a combination of chemotherapy and granulocyte colony-stimulating factors (G-CSF) is the commonly used regimen to mobilize autologous PBSC in patients with hematological malignancies or solid tumors, short-term treatment with G-CSF alone followed by leukapheresis represents the standard procedure to obtain CD34+ stem cells from allogeneic donors. Different forms of recombinant G-CSF are available for clinical application, including filgrastim, lenograstim (glycosylated form of G-CSF) and nartograstim (N-terminal mutated form of G-CSF). Most recently pegfilgrastim (NeulastaTM, Amgen Inc., Thousand Oaks, USA) was introduced, which is the covalent conjugate of filgrastim and monomethoxypolyethylene glycol. The pegylation of filgrastim leads to a larger molecule of approximately 39 kd with an increased elimination half-life due to decreased serum clearance [1]. Both filgrastim and pegfilgrastim exert stimulatory effects on proliferation, differentiation and cell function of hematopoietic cells by binding to specific receptors. After chemotherapy a single injection of pegfilgrastim is equivalent to daily filgrastim in enhancing neutrophil recovery [2–4]. The agent was also evaluated to reduce the myelotoxicity of dose-intensified chemotherapy regimens in patients with breast cancer or malignant lymphomas [5–7]. The role of cytokines in stem cell mobilization is not yet fully understood. Since only a small number of progenitors can be found in peripheral blood (PB) under steady-state conditions the administration of G-CSF is known to induce an increase of circulating CD34+ hematopoietic stem cells. The effect on the bone marrow pool of stem and progenitor cells seems to be more complex. Due to recent studies a lot of different cell–cell and cell–stroma interactions are involved not only in mobilization but also in stem cell homing after reinfusion. The models mainly focus on the expression of adhesion molecules [8–11] and an enhanced cleaving activity of marrow proteases [12–14]. In contrast, the expression of the G-CSF receptor on hematopoietic stem

cells is not required for their mobilization by G-CSF, as could be shown in an animal model [15]. 2. Rationale for the use of pegfilgrastim in stem cell mobilization The ability of pegfilgrastim to mobilize CD34+ stem cells into the circulation was evaluated in animal models [16] and early human studies. In a small randomized trial 13 patients who were treated with carboplatin and paclitaxel for non-small cell lung cancer received 30, 100 or 300 lg/kg of single-dose SD/01 (which was the investigational name of pegfilgrastim) or 5 lg/kg daily filgrastim after and also before chemotherapy [17]. At all dose levels significant increases of CD34+ cells were observed and the effects of SD/01 were comparable or greater than those achieved with daily filgrastim. The administration of single-dose pegfilgrastim (30, 60, 100 or 300 lg/kg) in 32 healthy volunteers has also been shown to induce a sufficient increase of CD34+ PBPC in the peripheral blood with kinetics similar to that of conventional G-CSF [18]. The use of pegfilgrastim for PBSC mobilization seems to be promising since its specific pharmacokinetic properties could make it superior to conventional, non-pegylated G-CSF in terms of stem cell liberation. It was assumed that continuously increased G-CSF levels exert a higher biological activity than pulsatile elevations after intermittent injections of unconjugated filgrastim. Increased stem cell yields was found after administration of G-CSF twice daily compared to single-dose treatment in patients as well as in allogeneic donors [19–22]. Furthermore, an intraindividual cross-over study in four healthy volunteers showed higher minimum G-CSF serum levels after twice than after once daily application and an increased CD34+ cell count in the peripheral blood on day 4, which was indicative for a pharmacological effect [23]. The hypothesis was also supported by the observation of a sufficient and rapid increase of CD34+ cells during continuous subcutaneous infusion of a low dose of 72 lg/day G-CSF for five days in a small group of healthy volunteers [24]. Innovative strategies in stem cell mobilization are urgently needed to improve the harvest results in

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particular in patients who have failed after standard procedures. In addition, the more convenient manner of pegfilgrastim administration with a simplified once-per-mobilization dosing is attractive for donors of allogeneic PBSC. 3. Mobilization of autologous PBSC PBSC for autologous transplantation are usually harvested when hematopoiesis recovers after chemotherapy-induced myelosuppression. The daily administration of (unconjugated) G-CSF during aplasia does not only reduce the duration of neutropenia but also enhance the mobilizing effects of chemotherapy. Several studies reported higher yields of CD34+ PBSC after chemotherapy plus G-CSF than after mobilization by G-CSF alone [25–27]. Table 1 summarizes clinical trials which investigated the mobilizing efficacy of various chemotherapy regimens followed by single-dose pegfilgrastim. Due to current treatment strategies the studies included exclusively patients with malignant lym-

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phoma and/or multiple myeloma. The largest series randomized 92 patients with aggressive non-Hodgkin’s lymphoma (NHL) to receive single-doses of 6 or 12 mg pegfilgrastim or daily doses of 5 lg/kg filgrastim after ICE chemotherapy. The maximum number of circulating CD34+ cells and PBSC harvests showed no statistical differences between the treatment arms [29]. In line with this are the results from another trial, which used a historical cohort for comparison [31]. From these reports it appears that, in terms of stem cell mobilization, there is no difference whether pegfilgrastim or unconjugated filgrastim is used as adjunct to chemotherapy. Furthermore, a dose of 6 mg pegfilgrastim was shown equally potent to a dose of 12 mg with regard to CD34+ cell mobilization and yield. For daily unconjugated G-CSF the data are controversial. While in a series of 120 myeloma patients increased G-CSF doses did not lead to higher numbers of blood CD34+ cells [34], two randomized trials including patients with lymphoproliferative malignancies and solid tumors compar-

Table 1 Clinical trials investigating chemotherapy followed by single-dose pegfilgrastim for the mobilization of autologous peripheral blood stem cells Reference

Patients

Chemotherapy and cytokine treatment

Peak PB-CD34 median [1/lL]

Yield of CD34+ cells [106/kg]

Isidori 2005 [28]

n = 25 HD, NHL n = 92 NHL

IEVa (days 1–3) ? 6 mg pegfilgrastim (day 6)

141 (12.8–386)

8.7 (1.78–17.3)

ICEb (days 1–3) ? 6 mg pegfilgrastim

n.a.

12 mg pegfilgrastim 5 lg/kg daily filgrastim Variousc ? 6 mg pegfilgrastim

81 (10–565)

Median harvest/LPH: 1.2 (0.0–11.4) 1.4 (0.0–9.5) 1.6 (0.0–10.4) 9.8 (1.5–88.1)

Russellg 2005 [29]

Kroschinsky 2006 [30] Bruns 2006 [31]

Nosari 2006 [32] Fruehauf 2007 [33]

n = 30 MM, NHL n = 45 MM

n = 28 HD, NHL n = 26 MM

Endoxan 2 g/m2 (days 1 + 2) ? 6 mg pegfilgrastim (day 4) 12 mg pegfilgrastim (day 4) 8 lg/kg daily filgrastim (day 4+) (historic cohort) DHAPd or IPADe ? 6 mg pegfilgrastim

131 (39–1084) 75 85 (7–1055) 75(5–760) 171.2 (21.2– 544.5)

CADf (days 1–4) ? 12 mg pegfilgrastim (day 5) 3 pts required additional unconjugated GCSF

72.6 (7.2–842)

10.2 (4.2–72.4) 7.4 (2.3–38.0) 8.6 (5.0–87.0) 17.3 (2.5–28.9) single LPH in 25/27 pts 1 pt failed 9.7 (4.9–40.5)

PB – peripheral blood; HD – Hodgkin’s disease; NHL – non-Hodgkin’s lymphoma; MM – multiple myeloma; LPH – leukapheresis; n.a. – not available. a IEV = ifosfamide 2500 mg/m2 (days 1–3), epirubicin 100 mg/m2 (day 1), etoposide 150 mg/m2 (days 1–3). b ICE = ifosfamide 5 g/m2 (day 2), carboplatin AUC5 (day 2), etoposide 100 mg/m2 (days 1–3). c Various combinations including VAD, CAD, DexaBEAM, DHAP and other platin-containing regimen. d DHAP = cisplatin 100 mg/m2 (day 1), cytarabine 2 g/m2 (day 2), dexamethasone 20 mg (days 1–4). e IPAD = idarubicin 12 mg/m2 (day 1), cisplatin 50 mg/m2 (days 1 + 2), cytarabine 2 g/m2 (day 2), dexamethasone 20 mg (days 1–4). f CAD = endoxan 1 g/m2 (day 1), doxorubicin 15 mg/m2 (days 1–4), dexamethasone 40 mg (days 1–4). g Indicates randomized trials.

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ing 5 versus 10 lg/kg/day and 8 versus 16 lg/kg/ day, respectively, demonstrated improved stem cell yields after higher G-CSF doses [35,36]. The mobilization of autologous PBSC with GCSF alone is a commonly used alternative in patients in whom chemotoxicity should be avoided. The efficiency of 12 mg pegfilgrastim in steady-state mobilization was investigated in a recent series with 19 myeloma patients [37]. Only patients after thalidomide, dexamethasone or bortezomib were eligible for the trial, whereas patients who had received chemo or radiotherapy were not included. The leukapheresis was started when blood CD34+ cells exceeded 15 lL. A median of 8.4  106 (range 4.1– 15.8) CD34+ cells/kg was harvested. The median number of required leukapheresis was 2 (range 1– 5). A comparison to eight patients who were also screened for the study but were ineligible and therefore received daily 10 lg/kg filgrastim showed nearly identical results for all endpoints in the two cohorts. However, the number of patients in the reported phase II studies is limited and the only randomized trial has not yet been published as a full paper. Therefore, further evaluation of efficacy, dose and schedule is needed before single-dose pegfilgrastim is used routinely in the context of autologous stem cell mobilization. Careful observation should also be directed on the efficacy in poor mobilizers. In our own series 10 out of 40 patients (25%) who had received 6 mg pegfilgrastim after chemotherapy for lymphoma or myeloma had to be treated with additional doses of unconjugated filgrastim due to inadequate mobilization [30]. The PBSC yields in these patients, all of them were heavily pretreated with chemo and/or radiotherapy, was significantly lower than those in patients with adequate mobilization after single-dose pegfilgrastim. In contrast, there is a recent report on a successful rescue mobilization after VAD and 12 mg pegfilgrastim in a myeloma patient not responsive to two previous attempts with high or standard dose chemotherapy followed by filgrastim [38]. The engraftment of pegfilgrastim mobilized autografts in all studies showed similar kinetics to those which is commonly observed after reinfusion of PBSC which were collected after unconjugated GCSF. 4. Stem cell mobilization in allogeneic donors Allogeneic PBSC are collected from HLA-compatible healthy donors after treatment with daily

doses of 10–20 lg/kg of unconjugated G-CSF. Leukapheresis are started commonly on day 5. The experiences with pegfilgrastim in this setting are very limited. Recently we presented an update of our study evaluating feasibility, efficacy and toxicity of single-dose pegfilgrastim in allogeneic stem cell mobilization [39,40]. Thirty-five allogeneic PBSC donors (15 related, 20 unrelated, 23 male, 12 female, median age 40 years) were included in this trial. The donors received a single subcutaneous injection of 12 mg pegfilgrastim if body weight was between 60 and 100 kg (resulting in a median dose of 161 lg/kg). This was due to the observation that in healthy volunteers the administration of 100 or 300 lg/kg pegfilgrastim has been shown to induce a sufficient increase of CD34+ cells in the peripheral blood with a similar kinetics as known from conventional G-CSF [18]. PBSC were collected starting on day 5 by large-volume leukapheresis (4 blood volume). The results were compared with a historical cohort of 64 donors (2 related, 62 unrelated, 44 male, 20 female, median age 31 years), who had received unconjugated filgrastim (NeupogenTM, Amgen Inc., Thousand Oaks, USA) at a dose of 10 lg/kg on 5 consecutive days. In all donors sufficient numbers of CD34+ cells for allografting could be collected. Peripheral blood CD34+ count on day 5 (Fig. 1) was significantly higher after pegfilgrastim compared to filgrastim (72/lL versus 53/lL, p = 0.03). Whereas an apheresis on day 6 had to be performed only in 6 donors (17%) after pegfilgrastim, a second procedure was needed in the majority of donors who had received daily filgrastim administrations. The harvest results of both cohorts are presented in detail in Table 2. Although CD34+ yields on day 5 were significantly higher after pegfilgrastim than after filgrastim the total numbers of collected stem cells were not different. The worse yields on day 6 in the pegfilgrastim cohort correspond to the observation that blood CD34+ cells were higher on day 4 than on day 6, which is in contrast to the kinetics of CD34+ mobilization with conventional G-CSF [41,42]. Very similar results were also reported from another phase I/II study [43]. In this trial 37 donors were treated with single-doses of 6 mg or 12 mg pegfilgrastim or daily doses of 10 lg/kg non-pegylated filgrastim. The administration of 6 mg pegfilgrastim in five donors resulted in suboptimal mobilization of CD34+ PBSC. All donors in this cohort required two aphereses to achieve a sufficient stem cell yield

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Table 3 Cytokine related side effects in allogeneic stem cell donors after a single-dose of 12 mg pegfilgrastim (PEGFIL) or daily dose of 10 lg/kg unconjugated filgrastim (FIL)

Fig. 1. Kinetics of blood CD34+ cells after12 mg pegfilgrastim in 35 allogeneic stemcell donors (j) and comparison of median blood CD34+ cell count on day 5 after single-dose pegfilgrastim (12 mg) and daily doses of filgrastim (10 lg/kg, days 1–5 ) (p = 0.03).

for transplantation. After escalation of pegfilgrastim dose to 12 mg in 12 out of 13 donors sufficient numbers of stem cells could be harvested in a single apheresis (8.9 ± 1.4  106 CD34+ cells/kg recipient weight). The peak of blood CD34+ cell count after 12 mg pegfilgrastim was significantly higher than after 10 lg/kg of daily unconjugated G-CSF (99.0 ± 11.0 lL versus 69.3 ± 8.5 lL, p < 0.025). 4.1. Toxicity in healthy donors Bone pain, headache and transient elevations of liver enzymes and lactate dehydrogenase were the main side effects of pegfilgrastim in allogeneic stem

Symptom

Grade

PEGFIL (n = 35)

FIL (n = 64)

Bone pain

Total Mild Moderate Severe

30 5 11 14

57 18 25 14

Headache

Total Mild Moderate Severe

18 (52%) 3 (9%) 7 (20%) 8 (23%)

Reaction at site of injection

Total Mild Moderate

12 (34%) 8 (23%) 4 (11%)

n.a. n.a. n.a.

Others

Total Sleeplessness Tiredness Sweats Hypotension

18 (52%) 8 (23%) 8 (23%) 3 (9%) 1 (3%)

n.a. n.a. n.a. n.a. n.a.

(86%) (14%) (32%) (40%)

(89%) (28%) (39%) (22%)

26 (41%) 18 (28%) 4 (6%) 4 (6%)

n.a. – not available. All donors were asked to describe the symptoms of growth factor treatment especially the severity of bone pain and headache using a standardized questionnaire [40].

cell donors. While the incidence of bone pain and headache was similar in both cohorts, there were a significantly higher number of donors after pegfilgrastim who characterized the symptoms as severe (Table 3). Almost 90% of donors required pain medications [39]. The specific pharmacokinetic properties of pegfilgrastim induce concerns of a prolonged or excessive leukocytosis if administered to healthy donors. Peak WBC counts in our series were in median 7-fold (range from 4- to 14-fold) higher than baseline values and occurred in 52% of the donors on day 4. An absolute peak leukocyte count of 82  109/L was observed in one donor (pegfilgrastim dose

Table 2 Harvest results in 35 allogeneic pegfilgrastima (PEGFIL) for mobilization and comparison to a historical group of 64 donors who were treated with daily doses of 10 lg/kg unconjugated filgrastim (FIL) [40] Parameterb 8

CD34 + LPH-1 [10 ] CD34 + LPH-2 [108] CD34 + total [108] CD34 + LPH-1/kg donor weight [106/kg] CD34 + LPH-2/kg donor weight [106/kg] CD34 + total/kg donor weight [106/kg] CD34 + total/kg recipient weight [106/kg]

PEGFIL (n = 35)

FIL (n = 64)

p-Value

5.80 1.66 6.64 7.85 2.28 8.23 9.30

3.72 2.10 5.75 4.71 2.62 7.62 6.90

p < 0.0001 p = 0.166 p = 0.525 p < 0.0001 p = 0.207 p = 0.342 p = 0.048

(1.10–19.06) (0.80–2.40) (1.72–19.06) (1.37–29.32) (1.00–3.69) (2.37–29.32) (3.22–39.71)

(0.54–17.13) (0.59–7.00) (1.36–21.05) (0.57–21.41) (0.80–8.75) (1.89–24.48) (1.87–36.80)

All leukaphereses (LPH) were performed as large-volume procedures (4  blood volume) on day 5 [40]. a Pegfilgrastim dose was adjusted in donors with a body weight of <60 kg (9 mg) and >100 kg (15 mg). b Results are presented as median and ranges.

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167 lg/kg). In addition to hyperviscosity excessive WBC elevations might also be associated with splenic enlargement and the potential risk of rupture. To date four case of splenic rupture were reported. All of them occured in cancer patients, who had received a single-dose of 6 mg pegfilgrastim to enhance neutrophil recovery after chemotherapy [44–47]. Further careful evaluation of safety issues is necessary before pegfilgrastim becomes a reliable alternative to unconjugated G-CSF in healthy donors. 5. Perspectives Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allograft recipients. Therefore, the results from preclinical studies appear promising which observed in animal allograft models that donor pretreatment with pegylated G-CSF significantly reduced GVHD compared to standard G-CSF application [48]. The effect was interpreted to be due to an increased production of IL-10 by regulatory T-cells. Previous investigations have also demonstrated protective effects of IL-10 released by monocytes from GCSF mobilized peripheral blood mononuclear cells [49]. While a 4- to 8-fold increase of monocyte count was reported in allogeneic stem cell donors after unconjugated G-CSF [50,51], we found more than 20-fold higher numbers of blood monocytes compared to baseline in pegfilgrastim treated donors [39]. However, the percentages of monocytes in the stem cell products were not different than reported from harvests collected after unconjugated G-CSF [52]. The separation of GVHD from graft-versus-leukemia (GVL) effect is one of the most important challenges in hematopoietic cell transplantation to improve outcome in cancer patients. Standard GCSF is known to modulate donor T-cell functions and to promote TH2 differentiation. Pegfilgrastim has been shown to cause expansion and activation of different donor T-cells subpopulations, which augment CD8+ T-cell mediated cytotoxicity and GVL effects [53]. An enhanced occupancy and stimulation of G-CSF receptors due to increased cytokine levels after pegfilgrastim is discussed as one of the mechanisms involved at the cellular level [54], with the consequence of augmentation of signaling that influence T-cell expansion and functions. Prospective clinical trials are needed to evaluate if these findings translate into the human system.

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