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© Borgis - Postępy Nauk Medycznych s3/2012, s. 9-14
*Patrycja Zielińska, Anna Koclęga, Robert Liwoch, Monika Dzierżak-Mietła, Mirosław Markiewicz, Małgorzata Krawczyk-Kuliś, Sławomira Kyrcz-Krzemień
Plerixafor – wyniki mobilizacji macierzystych komórek krwiotwórczych oraz ich autotransplantacji u pacjentów z chłoniakami i szpiczakiem plazmocytowym – doświadczenia własne
Plerixafor – the results of mobilization regimen of hematopoietic stem cells and their autologous transplantation in lymphoma and myeloma patients – single center experience
Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice
Head of Department: prof. Sławomira Kyrcz-Krzemień, MD, PhD
Streszczenie
Wstęp. Mobilizacja komórek macierzystych krwi obwodowej jest obecnie preferowanym źródłem pozyskiwania komórek macierzystych w celu autoprzeszczepienia. Niestety u około 35% pacjentów nie udaje się uzyskać wystarczającej liczby komórek dla celów autotransplantacji. Plerixafor został ostatnio wprowadzony do praktyki klinicznej jako czynnik zwiększający szanse na skuteczność zabiegu mobilizacji.
Materiał i metody. Prezentowane dane są prospektywnym badaniem oceniającym skuteczność mobilizacji komórek macierzystych z zastosowaniem plerixafor u ciężko przeleczonych pacjentów z chłoniakami i szpiczakiem plazmocytowym, którzy byli hospitalizowani w Klinice Hematologii i Transplantacji Szpiku Śląskiego Uniwersytetu Medycznego w Katowicach. Grupa 21 pacjentów (mediana wieku: 52, zakres: 22-59) otrzymywało plerixafor w tutejszej Klinice w okresie ostatnich dwóch lat. Protokół mobilizacyjny obejmował iniekcje podskórne granulocytowego czynnika wzrostu (G-CSF) w dawce 10 μg/kg codziennie rano przez okres 4 dni oraz iniekcje podskórne plerixaforu w dawce 240 μg/kg, począwszy od dnia czwartego. Trzech pacjentów otrzymało plerixafor wraz ze standardowym leczeniem chemomobilizującym.
Wyniki. Aferezy komórek macierzystych zostały przeprowadzone u wszystkich pacjentów otrzymujących plerixafor. Uzyskano medianę 1,45 x 106 komórek CD34+/kg (zakres: 0,03-6,74) podczas 2 zabiegów aferezy (mediana: 2, zakres: 2-4). U dziesięciu pacjentów (47,5%) uzyskano ≥ 2 x 106 CD34+/kg. Mediana WBC wynosiła 11,35 x 108/kg (zakres: 6,92-21,94).
Wnioski. Mobilizacja komórekmacierzystych z zastosowaniem plerixafor stanowi szansę na zgromadzenie wystarczającej liczby komórek do autotransplantacji u ciężko przeleczonych pacjentów z chłoniakami i szpiczakiem plazmocytowym, u których wystąpiło niepowodzenie mobilizacji z zastosowaniem standardowej chemomobilizacji.
Summary
Introduction. Mobilized peripheral blood is currently the preferred source of stem cells for autologous transplantation. Unfortunately around 35% of patientsfail to mobilize the successful number of stem cells. Plerixafor has been recently introduced for clinical use to enhance peripheral blood stem cells mobilization to collect the satisfactory number of cells to proceed to AHCT.
Material and methods. This is a prospective study to assess the efficacy of peripheral stem cells mobilization using plerixafor regimen in heavily pretreated lymphoma and multiple myeloma patients who were hospitalized in the Department of Hematology and Bone Marrow Transplantation in Katowice. Total of 21 patients aged 52 (22-69 years) were mobilized with plerixafor in our institution over two-year period. The protocol included a daily injection of granulocyte colony stimulating factor – G-CSF (10 μg/kg) administered subcutaneously each morning for 4 consecutive days, followed by plerixafor administration (240 μg/kg s.c.) starting on the fourth day at around 10 p.m. Three patients were given chemo-mobilization regimen.
Results. Stem cell aphaeresis was performed in all patients receiving plerixafor and a median of 1.45 x 106 per kg (range: 0,03-6.74) CD34(+) cells were collected with a median of two aphaeresis (2-4). Ten patients (47.5%) collected ≥ 2 x 106 CD34+ per kg. The median number of collected WBC was 11.35 x 108 per kg (range: 6.92-21.94).
Conclusions. Stem cell mobilization with plerixafor and G-CSF provides solution for majority of patients requiring autologous hematopoietic stem cell transplantation and failing mobilization with G-CSF in combination with chemotherapy.
Introduction
Hematopoietic stem cell (HSC) transplantation is a crucial treatment option for hematological malignancies. The use of peripheral blood stem cells not only for autologous but also for allogeneic transplantation is constantly increasing over the recent years. Current mobilization regimens that include cytokine (granulocyte colony stimulating factor, G-CSF) alone or in combination with chemotherapy frequently result in inadequate numbers of hematopoietic progenitor cell (HPC). The problem is of importance especially in heavily pretreated patients. Unfortunately around up to 35% patients fail to mobilize the successful number of stem cells.
Plerixafor is a CXCR4 antagonist approved for mobilization of peripheral blood stem cells in non-Hodgkin’s lymphoma and multiple myeloma patients (1, 2). The chemokine receptor CXCR4 and ligand SDF-1 are integrally involved in homing and mobilization of HPCs (1, 2). Disruption of the SDF-1/CXCR4 axis by the CXCR4 antagonist, plerixafor, was demonstrated in clinical trials to improve mobilization when it was included in the mobilization regimen (3,4). Chemotaxis of CXCR4 toward SDF-1α plays an important role in the trafficking and homing of HPCs to the bone marrow compartment (1, 2). Plerixafor reversibly blocks the ability of HPCs to bind to the bone marrow matrix. When used with granulocyte colony-stimulating factor (G-CSF), plerixafor helps increase the number of these progenitor cells in the peripheral blood. Plerixafor (AMD3100, Mozobil, Genzyme) has been recently approved by the US Food and Drug Administration (FDA; December 2008) and the European Medicines Evaluation Agency (EMEA; July 2009) to enhance mobilization of hematopoietic stem cells in combination with G-CSF in patients with lymphoma and multiple myeloma (MM).
Plerixafor was originally developed as a potential anti-HIV agent because it antagonizes the chemokine receptor 4 (CXCR4), which serves as a coreceptor for the entry of T-lymphotropic HIV strains into host T-lymphocyte cells (5). During pharmacokinetic studies of the drug, leukocytosis was observed. Hendrix et al. (5) reported that the plasma concentration of plerixafor declined gradually after a single
intravenous dose, while the white blood cell count gradually increased, reaching a maximum count of ?3 times its baseline at 6 h. This leukocytosis appeared to result from CD34+ cell mobilization. Further work demonstrated that the administration of plerixafor resulted in a consistent increase in the number of CD34+ cells in the peripheral blood, suggesting that it could be used as a potential CD34+-cell-mobilizing agent in the setting of autologous transplantation (5).
It was proved that plerixafor synergistically augments the mobilization effect of G-CSF on CD34+cells (6). Hematopoietic differentiation of transplanted CD34+cells was similar after plerixafor or G-CSF mobilization methods. Studies on patients with NHL or MM indicated that mobilization of CD34+/CD38– cells, a more primitive subset of CD34+ cells, was eightfold higher with the addition of plerixafor to a G-CSF regimen when compared to G-CSF alone (6).
Patients and methods
Study design and study group
This is a single center prospective study evaluating the outcome of mobilization regimen and autologous stem cell transplantation in myeloma and lymphoma patients mobilized using plerixafor based regimen. Total of 21 patients aged 52 (22-69 years) were mobilized with plerixafor in our institution over two-year period. 6/21(28,5%) patients received plerixafor as a rescue mobilization in the Compassionate Use Program (CUP). All patients signed the informed consent form before administration of plerixafor. The remaining 15 patients were given plerixafor in a commercial way. All of the patients failed to mobilize the satisfactory number of stem cells after standard mobilizing regimen or who failed to proceed to apheresis due to low peripheral blood CD34+ cell counts (“poor mobilizers”). We assessed the outcome of autologous transplantation (ASCT) in this group of patients.
Protocol of plerixafor administration
The protocol included a daily injection of G-CSF (10 μg/kg) administered subcutaneously each morning for 4 consecutive days, followed by plerixafor administration (240 μg/kg s.c.) starting on the fourth day at around 10 p.m. The following morning the patients underwent apheresis procedure (blood volumes as per site preference). Administration of G-CSF and plerixafor injection were repeated the following day. Three patients were given chemo-mobilization regimen (plerixafor and G-CSF plus chemotherapy – high-dose of cyclophosphamide in all three cases). These patients were predicted to be poor mobilizers on the basis of low CD34+ cell numbers in the peripheral blood at optimal time points following chemotherapy and G-CSF. Two of them collected the satisfactory number of CD34+ cells.
Data collection
The following parameters were recorded: age, sex, body weight, diagnosis, stage of the disease, the number of prior chemotherapy lines, prior radiotherapy, previous mobilization regimens, number of apheresis days, CD34+ yield, WBC yield, the volume of frozen apheresis product. During the transplant and post-transplant period the following data were collected: the count of CD34+ in the graft, time to granulocyte and platelet engraftment and progression free survival (PFS). Engraftment was assessed using conventional EBMT criteria considering the transplant day as day 0. Neutrophil engraftment was defined as the first of three consecutive days on which the neutrophil count reached ≥ 0.5 x 109/L. Platelet engraftment was defined as the first of three consecutive days on which the platelet count reached ≥ 20 x 109/L without platelet transfusion for at least 48 h.
Statistical analysis
The PFS was estimated by the Kaplan-Meier method. All statistical analysis was performed using Statistica10 software.
Results
Patient characteristics
The prospective analysis included 21 patients (“poor mobilizers”), 6 multiple myeloma patients, including one patients with POEMS, and 14 lymphoma patients including diffuse large B-cell (3 pts), follicular (2 pts), nodal marginal zone lymphoma (1 pt), Waldenstroem’s disease (1 pt), malignant lymphocytic lymphoma (4 pts) and Hodgkin’s lymphoma (3 pts), also 1 pt with Kostmann syndrome. The disease status at the time of mobilization was defined as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD) according to commonly accepted criteria (7, 8). The table 1 summarizes the patient characteristics.
Table 1. The characteristics of patients included in the study.
 Multiple myeloma
(n=6)
Lymphoma
(n=14)
Age, median (range), years59 (52-69)42.5 (22-67)
Sex
  Male
  Female
3
3
9
6
Disease status
  CR
  PR
  SD
  PD
1
4
1
0
8
3
1
2
Prior chemotherapy (regimens), median23
Prior radiotherapy04
Body weight, median (range), kg75 (49-107)79 (51-122)
All the patients had been treated previously for their primary disease. Four lymphoma patients (19%) underwent radiotherapy before. Two patients (9.5%) in the lymphoma group and one patient (4, 7) in the multiple myeloma group had a history of autologous stem cell transplantation. All the patients received chemotherapy before the attempt at mobilization. Patients had received a median of three lines of chemotherapy (range: 1-8) before plerixafor based mobilization regimen. A chemotherapy regimen was defined as one or more courses of chemotherapy of a certain type, including conditioning regimen and chemotherapy used for previous stem cell mobilization. The number of chemotherapy courses was recorded accordingly. Within the MM group, these lines included lenalidomide in two patients (9.5%) and a previous ASCT in two (9.5%). Among the lymphoma patients, six had been treated with combination chemotherapy containing fludarabine or cladribine (28%), one patient had a history of previous ASCT.
Overall, there were 19 failed previous mobilization attempts in this series. All of these attempts combined chemotherapy and G-CSF. A total of 15 patients (71%) had one, and four (19%) had 2 failed mobilization attempts before plerixafor administration. No patient had a history of bone marrow harvest. As a result of these previous attempts, 11 patients (5 – MM and 6 – lymphoma) had collected variable numbers of PBSCs, for a median of 0.6 x 106 per kg CD34+ cells (0.16-0.94). Two patients entered the plerixafor group without a previous mobilization attempt.

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otrzymano: 2012-06-20
zaakceptowano do druku: 2012-07-18

Adres do korespondencji:
*Patrycja Zielińska
Department of Hematology and Bone Marrow Transplantation Silesian Medical University
ul. Dąbrowskiego 25, 40-032 Katowice
tel.: +48 (32) 259-12-81, fax : (32) 255-49-85
e-mail: klinhem@sum.edu.pl

Postępy Nauk Medycznych s3/2012
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