- Email: [email protected]
Plerixafor (Mozobil) and other mobilizing agents
Transfusion and Apheresis Science xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Plerixafor (Mozobil) and other mobilizing agents Luca Pierelli, Paolo Perseghin SIdEM, Italy
Peripheral blood stem cell (PBSC) collection has become the prevalent modality for the procurement of hematopoietic stem/precursor cells for autologous and allogeneic transplantation. The basic principles of PBSC collection from peripheral blood consist in the ability of chemotherapeutic agents and/or growth factors to mobilize these cells from bone marrow and in the capacity to concentrate them by modern and efficient blood cell separators. The combination of a ‘‘good mobilization’’ with an efficient PBSC collection translates into the ability to harvest a very large amount of PBSC in a given patients or donors, as compared to bone marrow aspiration which represents the original approach for stem cell collection for clinical purposes. Albeit the efficiency of blood separators in collecting PBSC is consistently higher than 40/45% (i.e., they collect more than 40/45 PBSC out of 100 which pass into the separation chamber of the machine during each unit of time), some patients (more rarely, donors) experience a variable, sometimes defective, PBSC mobilization following proper treatments because several known and unknown factors. Known conditions for unsatisfactory mobilization include marrow involvement by the underlying disease, previous extensive chemotherapy/chemoradiotherapy, age, prevalent use of alkylating agents or marrow fibrosis. Nowadays, patient/donor PBSC mobilization is generally accomplished by the use of subcutaneous administration of un-glycosylated (filgrastim) or glycosylated (lenograstim) recombinant human granulocyte colony stimulating factor (rhGCSF). Normal donors are treated for 4 days by rhG-CSF at a dose of 10hg/kg/day prior to the 5th day that coincided with the first day of apheresis collection. Donor treatment by rhG-CSF at the indicated dose is continued daily from day 4 onward until the target PBSC dose has been collected, for a maximum of two apheresis collections. Patients may be mobilized by an identical treatment schedule as indicated for donors or, after a chemotherapy course, by administration of 5hg/kg/day rhG-CSF at a variable time distance from the last day of chemotherapy (3–8 days). In
the case of patient mobilization by chemotherapy plus rhG-CSF, patients’ peripheral blood must be monitored for CD34+ cell concentration during the early leukocyte recovery from myelosuppression. Generally, a CD34+ cell concentration of 20 103/ml in peripheral blood is judged as the minimal mobilization to start apheresis and, as predicted by available and reported prediction systems [1], it may translate in the collection of no less than 1.6 for 106/ kg after a blood volume processing of about 200 ml/kg. In the setting of autologous mobilization of PBSC, the use of recombinant human granulocyte–macrophage colony stimulating factor (rhGM-CSF) does not offer any advantage as compared to rh G-CSF which remains the standard treatment for mobilization of both patients and donors. The administration of pegylated rhG-CSF at the single dose of 6 or 12 mg following chemotherapy seems to be equivalent to rhG-CSF in mobilizing patients with lymphoproliferative disorders. Recently, the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has proposed a definition of patients with poor mobilizing capacity (PM) by an analytic hierarchy process, which has been used in setting prioritized criteria [2]. Lymphoma or myeloma patients were defined as proven PM when: (a) after adequate mobilization circulating CD34+ cell peak is <20 103/ml up to 6 days after mobilization with rhG-CSF or up to 20 days after chemotherapy and rhG-CSF or (b) they yielded <2.0 for 106 CD34 + cells per kg in 3 apheresis. Patients were defined as predicted PM if: (a) they failed a previous collection attempt; (b) they previously received extensive radiotherapy or full courses of therapy affecting PBSC mobilization; and (c) they met two of the following criteria: advanced disease (P2 lines of chemotherapy), refractory disease, extensive bone marrow involvement or cellularity <30% at the time of mobilization, age > 65 years. When these criteria had been applied in Lazio region by a data analysis carried out by the SIdEM local board, we found that 39 out of 227 patients met the criteria for proven PM (17.2%) and 11 the criteria for predicted PM (4.9%). Fig. 1 depicts values of CD34+ cell concentration in peripheral blood of our series which has been classified as normal
E-mail address: [email protected] (L. Pierelli) 1473-0502/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.02.005
Please cite this article in press as: Pierelli L, Perseghin P. Plerixafor (Mozobil) and other mobilizing agents. Transf Apheres Sci (2013), http://dx.doi.org/10.1016/j.transci.2013.02.005
2
L. Pierelli, P. Perseghin / Transfusion and Apheresis Science xxx (2013) xxx–xxx
Good Mobilizer Proven Poor Mobilizer Predicted Poor Mobilizer according to Major criteria Predicted Poor Mobilizer according to Minor criteria Fig. 1. CD34+ cells per 103/ml in 227 patients who had been classified by GITMO criteria for mobilization. Arrows indicate the ‘‘area’’ of possible Mozobil administration. (Obtained and modified with permission from Piccirillo N et al. ‘‘Poor mobilizer: a retrospective study on proven and predicted incidence according to GITMO criteria’’, Transfusion and Apheresis Science, in press.)
mobilizers, proven or predicted PM following GITMO criteria. As indicated in Fig. 1, the frequency of CD34+ cells in peripheral blood of patients failing mobilization is mostly below the value of 15/10 103/ml and thus these patients appear not eligible for apheresis. When an unsatisfactory
mobilization occurs in patients with lymphoproliferative disorders, the use of a CXCR4 agonist, namely Plerixafor (Mozobil), administered with rhG-CSF at a single dose of 0.24 mg/kg 6–12 h before CD34+ cell count and apheresis may ‘‘rescue’’ PM in 70% of cases, allowing the collection of a PBSC dose >2 106/kg in these patients [3]. Mozobil may be administered either in combination with rhG-CSF alone or with chemotherapy and rhG-CSF with the same chance of success. A very interesting approach could be the administration of Mozobil in a pre-emptive fashion, treating immediately those patients who fail to increase their ‘‘real time’’ CD34 level beyond 15/10 103/ml after 4 days with rhG-CSF alone and 14–16 days with chemotherapy plus rhG-CSF. The good standardization of conventional methods for PBSC mobilization by standard rh-GCSF treatment in both donors and patients (see Table 1 for GITMO-SIdEM recommendations for patients/donor mobilization), associated with an accurate CD34+ assay by dedicated flow cytometric approach and with a welltimed collection phase by apheresis, allow a complete success in PBSC procurement in most subjects. Some patients have clinical characteristics which determine their inability to mobilize a proper number of CD34+ cells in peripheral blood but, if this circumstance occurs in patients with lymphoproliferative disorders, the administration of Mozobil may ‘‘rescue’’ at least 70% of them. Nevertheless, the development of further drugs to induce powerful and rapid PBSC mobilization is to be hoped. Finally, a specific warning about the use of biosimilars for mobilization of patients and donors must be given due to the scarce availability of comparative studies in this setting.
Table 1 GITMO-SIdEM recommendations for patients/donor mobilization (shown as a part of ‘‘Best practice for peripheral blood progenitor cell mobilization and collection in adults and children: results of a Società Italiana Di Emaferesi e Manipolazione Cellulare (SIDEM) and Gruppo Italiano Trapianto Midollo Osseo (GITMO) consensus process’’, Pierelli L et al., Transfusion 2011 October 7). PBPC mobilization in autologous SCT Which is the best schedule of myeloid growth factors in PBPC mobilization with chemotherapy? RECOMMENDATIONS. The mobilization yield of a regimen including chemotherapy plus myeloid growth factors is higher than myeloid growth factors alone. Filgrastim and lenograstim are the standard myeloid growth factors for PBPC mobilization in adult and pediatric patients. The daily dose of filgrastim and lenograstim should be at least 5hg/kg/body weight by two or one subcutaneous administrations. The latest filgrastim or lenograstim dose should be administered at least 2–3 h before CD34 count in peripheral blood and 3–4 h before starting a planned apheresis. Pegylated filgrastim can be administered at a total dose of 6–12 mg for PBPC mobilization in adult patients with lymphoproliferative disorders. Pegylated filgrastim is licensed only for the treatment of chemotherapy-driven neutropenia. Those adult patients who attempt mobilization after prior failures should receive standard mobilization therapy with filgrastim or lenograstim associated with plerixafor because of an increase of peripheral CD34+ cell count to more than 5 106 cells/l. Plerixafor should be administered at the daily dose of 0.24 mg per kg/body weight 6–12 h before CD34 count and apheresis. Plerixafor cannot be recommended in patients with acute myeloid leukemia. Clinical studies including plerixafor in children are awaited for. Which is the best schedule of myeloid growth factors in PBPC mobilization without chemotherapy? RECOMMENDATIONS. Filgrastim and lenograstim are the standard myeloid growth factors for PBPC mobilization in adult and pediatric patients. The daily dose of filgrastim and lenograstim should be 10hg/kg/body weight by two or one subcutaneous administrations. The latest filgrastim or lenograstim dose should be administered at least 2–3 h before CD34 count in peripheral blood and 3–4 h before starting a planned apheresis procedure. Those adult patients who attempt mobilization after prior failures should receive standard mobilization therapy with filgrastim or lenograstim associated, since the fourth therapy day, with plerixafor at the daily dose of 0.24 mg/kg body weight administered 6–12 h before CD34 count and apheresis. Plerixafor cannot be recommended in patients with acute myeloid leukemia. Clinical studies including plerixafor in children are awaited. PBPC mobilization in allogeneic SCT Which is the best schedule of myeloid growth factors in PBPC mobilization? RECOMMENDATIONS. Filgrastim and lenograstim are the growth factors of choice for mobilizing PBPCs in healthy donors. The recommended dose is 10hg/ kg/body weight daily, preferably by a split administration, until the target dose has been collected, for a maximum of 5 days, provided that white blood cell (WBC) count does not exceed 60 109/l. A dedicated policy should be applied to donors under the age of 18 years and in the haploidentical setting. Poor mobilizer sibling donors should be proposed additional procedures, such as a prolonged stimulation and collection not longer than 7 days, or marrow stem cell collection. No evidence definitely supports safety and efficacy of G-CSF biosimilars for PBPC mobilization in the allogeneic SCT setting (adults and children).
Please cite this article in press as: Pierelli L, Perseghin P. Plerixafor (Mozobil) and other mobilizing agents. Transf Apheres Sci (2013), http://dx.doi.org/10.1016/j.transci.2013.02.005
L. Pierelli, P. Perseghin / Transfusion and Apheresis Science xxx (2013) xxx–xxx
References [1] Pierelli L, Maresca M, Piccirillo N, Pupella S, Gozzer M, Foddai ML, et al. Accurate prediction of autologous stem cell apheresis yields using a double variable-dependent method assures systematic efficiency control of continuous flow collection procedures. Vox Sang 2006;91:126–34. PubMed PMID: 16907873. [2] Olivieri A, Marchetti M, Lemoli R, Tarella C, Iacone A, Lanza F, et al. Proposed definition of ‘poor mobilizer’ in lymphoma and multiple
3
myeloma: an analytic hierarchy process by ad hoc working group Gruppo italianoTrapianto di Midollo Osseo. Bone Marrow Transplant 2011(May 30). [3] Attolico I, Pavone V, Ostuni A, Rossini B, Musso M, Crescimanno A, et al. Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collection in predicted poor mobilizer patients with multiple myeloma or lymphoma. Biol Blood Marrow Transplant 2012;18:241–9.
Please cite this article in press as: Pierelli L, Perseghin P. Plerixafor (Mozobil) and other mobilizing agents. Transf Apheres Sci (2013), http://dx.doi.org/10.1016/j.transci.2013.02.005
Contents lists available at SciVerse ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Plerixafor (Mozobil) and other mobilizing agents Luca Pierelli, Paolo Perseghin SIdEM, Italy
Peripheral blood stem cell (PBSC) collection has become the prevalent modality for the procurement of hematopoietic stem/precursor cells for autologous and allogeneic transplantation. The basic principles of PBSC collection from peripheral blood consist in the ability of chemotherapeutic agents and/or growth factors to mobilize these cells from bone marrow and in the capacity to concentrate them by modern and efficient blood cell separators. The combination of a ‘‘good mobilization’’ with an efficient PBSC collection translates into the ability to harvest a very large amount of PBSC in a given patients or donors, as compared to bone marrow aspiration which represents the original approach for stem cell collection for clinical purposes. Albeit the efficiency of blood separators in collecting PBSC is consistently higher than 40/45% (i.e., they collect more than 40/45 PBSC out of 100 which pass into the separation chamber of the machine during each unit of time), some patients (more rarely, donors) experience a variable, sometimes defective, PBSC mobilization following proper treatments because several known and unknown factors. Known conditions for unsatisfactory mobilization include marrow involvement by the underlying disease, previous extensive chemotherapy/chemoradiotherapy, age, prevalent use of alkylating agents or marrow fibrosis. Nowadays, patient/donor PBSC mobilization is generally accomplished by the use of subcutaneous administration of un-glycosylated (filgrastim) or glycosylated (lenograstim) recombinant human granulocyte colony stimulating factor (rhGCSF). Normal donors are treated for 4 days by rhG-CSF at a dose of 10hg/kg/day prior to the 5th day that coincided with the first day of apheresis collection. Donor treatment by rhG-CSF at the indicated dose is continued daily from day 4 onward until the target PBSC dose has been collected, for a maximum of two apheresis collections. Patients may be mobilized by an identical treatment schedule as indicated for donors or, after a chemotherapy course, by administration of 5hg/kg/day rhG-CSF at a variable time distance from the last day of chemotherapy (3–8 days). In
the case of patient mobilization by chemotherapy plus rhG-CSF, patients’ peripheral blood must be monitored for CD34+ cell concentration during the early leukocyte recovery from myelosuppression. Generally, a CD34+ cell concentration of 20 103/ml in peripheral blood is judged as the minimal mobilization to start apheresis and, as predicted by available and reported prediction systems [1], it may translate in the collection of no less than 1.6 for 106/ kg after a blood volume processing of about 200 ml/kg. In the setting of autologous mobilization of PBSC, the use of recombinant human granulocyte–macrophage colony stimulating factor (rhGM-CSF) does not offer any advantage as compared to rh G-CSF which remains the standard treatment for mobilization of both patients and donors. The administration of pegylated rhG-CSF at the single dose of 6 or 12 mg following chemotherapy seems to be equivalent to rhG-CSF in mobilizing patients with lymphoproliferative disorders. Recently, the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has proposed a definition of patients with poor mobilizing capacity (PM) by an analytic hierarchy process, which has been used in setting prioritized criteria [2]. Lymphoma or myeloma patients were defined as proven PM when: (a) after adequate mobilization circulating CD34+ cell peak is <20 103/ml up to 6 days after mobilization with rhG-CSF or up to 20 days after chemotherapy and rhG-CSF or (b) they yielded <2.0 for 106 CD34 + cells per kg in 3 apheresis. Patients were defined as predicted PM if: (a) they failed a previous collection attempt; (b) they previously received extensive radiotherapy or full courses of therapy affecting PBSC mobilization; and (c) they met two of the following criteria: advanced disease (P2 lines of chemotherapy), refractory disease, extensive bone marrow involvement or cellularity <30% at the time of mobilization, age > 65 years. When these criteria had been applied in Lazio region by a data analysis carried out by the SIdEM local board, we found that 39 out of 227 patients met the criteria for proven PM (17.2%) and 11 the criteria for predicted PM (4.9%). Fig. 1 depicts values of CD34+ cell concentration in peripheral blood of our series which has been classified as normal
E-mail address: [email protected] (L. Pierelli) 1473-0502/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.02.005
Please cite this article in press as: Pierelli L, Perseghin P. Plerixafor (Mozobil) and other mobilizing agents. Transf Apheres Sci (2013), http://dx.doi.org/10.1016/j.transci.2013.02.005
2
L. Pierelli, P. Perseghin / Transfusion and Apheresis Science xxx (2013) xxx–xxx
Good Mobilizer Proven Poor Mobilizer Predicted Poor Mobilizer according to Major criteria Predicted Poor Mobilizer according to Minor criteria Fig. 1. CD34+ cells per 103/ml in 227 patients who had been classified by GITMO criteria for mobilization. Arrows indicate the ‘‘area’’ of possible Mozobil administration. (Obtained and modified with permission from Piccirillo N et al. ‘‘Poor mobilizer: a retrospective study on proven and predicted incidence according to GITMO criteria’’, Transfusion and Apheresis Science, in press.)
mobilizers, proven or predicted PM following GITMO criteria. As indicated in Fig. 1, the frequency of CD34+ cells in peripheral blood of patients failing mobilization is mostly below the value of 15/10 103/ml and thus these patients appear not eligible for apheresis. When an unsatisfactory
mobilization occurs in patients with lymphoproliferative disorders, the use of a CXCR4 agonist, namely Plerixafor (Mozobil), administered with rhG-CSF at a single dose of 0.24 mg/kg 6–12 h before CD34+ cell count and apheresis may ‘‘rescue’’ PM in 70% of cases, allowing the collection of a PBSC dose >2 106/kg in these patients [3]. Mozobil may be administered either in combination with rhG-CSF alone or with chemotherapy and rhG-CSF with the same chance of success. A very interesting approach could be the administration of Mozobil in a pre-emptive fashion, treating immediately those patients who fail to increase their ‘‘real time’’ CD34 level beyond 15/10 103/ml after 4 days with rhG-CSF alone and 14–16 days with chemotherapy plus rhG-CSF. The good standardization of conventional methods for PBSC mobilization by standard rh-GCSF treatment in both donors and patients (see Table 1 for GITMO-SIdEM recommendations for patients/donor mobilization), associated with an accurate CD34+ assay by dedicated flow cytometric approach and with a welltimed collection phase by apheresis, allow a complete success in PBSC procurement in most subjects. Some patients have clinical characteristics which determine their inability to mobilize a proper number of CD34+ cells in peripheral blood but, if this circumstance occurs in patients with lymphoproliferative disorders, the administration of Mozobil may ‘‘rescue’’ at least 70% of them. Nevertheless, the development of further drugs to induce powerful and rapid PBSC mobilization is to be hoped. Finally, a specific warning about the use of biosimilars for mobilization of patients and donors must be given due to the scarce availability of comparative studies in this setting.
Table 1 GITMO-SIdEM recommendations for patients/donor mobilization (shown as a part of ‘‘Best practice for peripheral blood progenitor cell mobilization and collection in adults and children: results of a Società Italiana Di Emaferesi e Manipolazione Cellulare (SIDEM) and Gruppo Italiano Trapianto Midollo Osseo (GITMO) consensus process’’, Pierelli L et al., Transfusion 2011 October 7). PBPC mobilization in autologous SCT Which is the best schedule of myeloid growth factors in PBPC mobilization with chemotherapy? RECOMMENDATIONS. The mobilization yield of a regimen including chemotherapy plus myeloid growth factors is higher than myeloid growth factors alone. Filgrastim and lenograstim are the standard myeloid growth factors for PBPC mobilization in adult and pediatric patients. The daily dose of filgrastim and lenograstim should be at least 5hg/kg/body weight by two or one subcutaneous administrations. The latest filgrastim or lenograstim dose should be administered at least 2–3 h before CD34 count in peripheral blood and 3–4 h before starting a planned apheresis. Pegylated filgrastim can be administered at a total dose of 6–12 mg for PBPC mobilization in adult patients with lymphoproliferative disorders. Pegylated filgrastim is licensed only for the treatment of chemotherapy-driven neutropenia. Those adult patients who attempt mobilization after prior failures should receive standard mobilization therapy with filgrastim or lenograstim associated with plerixafor because of an increase of peripheral CD34+ cell count to more than 5 106 cells/l. Plerixafor should be administered at the daily dose of 0.24 mg per kg/body weight 6–12 h before CD34 count and apheresis. Plerixafor cannot be recommended in patients with acute myeloid leukemia. Clinical studies including plerixafor in children are awaited for. Which is the best schedule of myeloid growth factors in PBPC mobilization without chemotherapy? RECOMMENDATIONS. Filgrastim and lenograstim are the standard myeloid growth factors for PBPC mobilization in adult and pediatric patients. The daily dose of filgrastim and lenograstim should be 10hg/kg/body weight by two or one subcutaneous administrations. The latest filgrastim or lenograstim dose should be administered at least 2–3 h before CD34 count in peripheral blood and 3–4 h before starting a planned apheresis procedure. Those adult patients who attempt mobilization after prior failures should receive standard mobilization therapy with filgrastim or lenograstim associated, since the fourth therapy day, with plerixafor at the daily dose of 0.24 mg/kg body weight administered 6–12 h before CD34 count and apheresis. Plerixafor cannot be recommended in patients with acute myeloid leukemia. Clinical studies including plerixafor in children are awaited. PBPC mobilization in allogeneic SCT Which is the best schedule of myeloid growth factors in PBPC mobilization? RECOMMENDATIONS. Filgrastim and lenograstim are the growth factors of choice for mobilizing PBPCs in healthy donors. The recommended dose is 10hg/ kg/body weight daily, preferably by a split administration, until the target dose has been collected, for a maximum of 5 days, provided that white blood cell (WBC) count does not exceed 60 109/l. A dedicated policy should be applied to donors under the age of 18 years and in the haploidentical setting. Poor mobilizer sibling donors should be proposed additional procedures, such as a prolonged stimulation and collection not longer than 7 days, or marrow stem cell collection. No evidence definitely supports safety and efficacy of G-CSF biosimilars for PBPC mobilization in the allogeneic SCT setting (adults and children).
Please cite this article in press as: Pierelli L, Perseghin P. Plerixafor (Mozobil) and other mobilizing agents. Transf Apheres Sci (2013), http://dx.doi.org/10.1016/j.transci.2013.02.005
L. Pierelli, P. Perseghin / Transfusion and Apheresis Science xxx (2013) xxx–xxx
References [1] Pierelli L, Maresca M, Piccirillo N, Pupella S, Gozzer M, Foddai ML, et al. Accurate prediction of autologous stem cell apheresis yields using a double variable-dependent method assures systematic efficiency control of continuous flow collection procedures. Vox Sang 2006;91:126–34. PubMed PMID: 16907873. [2] Olivieri A, Marchetti M, Lemoli R, Tarella C, Iacone A, Lanza F, et al. Proposed definition of ‘poor mobilizer’ in lymphoma and multiple
3
myeloma: an analytic hierarchy process by ad hoc working group Gruppo italianoTrapianto di Midollo Osseo. Bone Marrow Transplant 2011(May 30). [3] Attolico I, Pavone V, Ostuni A, Rossini B, Musso M, Crescimanno A, et al. Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collection in predicted poor mobilizer patients with multiple myeloma or lymphoma. Biol Blood Marrow Transplant 2012;18:241–9.
Please cite this article in press as: Pierelli L, Perseghin P. Plerixafor (Mozobil) and other mobilizing agents. Transf Apheres Sci (2013), http://dx.doi.org/10.1016/j.transci.2013.02.005