Peripheral blood stem cell mobilization and collection from elderly patients and elderly healthy donor

Transfusion and Apheresis Science 53 (2015) 8–12

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Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i

Peripheral blood stem cell mobilization and collection from elderly patients and elderly healthy donor Sinem Civriz Bozdag *, Osman Ilhan Hematology Department, Ankara University school of Medicine, Ankara, Turkey

A B S T R A C T

The impact of age on peripheral blood stem cell mobilization has been reported with contradictory results. We aimed to revise these data about stem cell mobilization in elderly patients and healthy donors. © 2015 Elsevier Ltd. All rights reserved.

Either autologous or allogeneic stem cell transplantation (HSCT) has been widely used in the treatment of hematological malignancies. Autologous stem cell transplantation (ASCT) prolongs the survival of myeloma and lymphoma patients, whereas allogeneic stem cell transplantation (AlloSCT) is still the only curative treatment for the majority of myeloid and lymphoid neoplasms. Median age for diagnosis of the most hematological malignancies is over 60 years and age remains to be one of the independent prognostic parameters for prognosis. As the role of SCT has been established for elderly patients, even for those over 70 years, age cannot be accepted as a limiting factor for transplant eligibility [1–3]. Comorbidity scores and comprehensive geriatric assessment has been found to be predictive in HSCT outcome [4–6]. One of the major problems in a transplant eligible patient is stem cell mobilization failure. Factors affecting stem cell mobilization has been revised as previous use of alkylating agents or radiotherapy, marrow involvement and bone marrow fibrosis [7–9]. It has been a long time dilemma whether older age reduces the peripheral blood stem cell yields. 1. Bone marrow and aging Hematopoietic stem cells (HSC) are located adjacent to sinusoids throughout the bone marrow [10]. During minor

* Corresponding author. Ankara University school of Medicine, Hematology Department, Cebeci Campus, Mamak, Ankara, Turkey. Tel.: +90 3125957099. E-mail address: [email protected] (S.C. Bozdag). http://dx.doi.org/10.1016/j.transci.2015.05.007 1473-0502/© 2015 Elsevier Ltd. All rights reserved.

hematopoietic stress, a continuous release throughout the bone marrow to peripheral blood exists. Stem cell mobilization after the treatment with cytokines and/or chemotherapy results in the detachment of HSC from marrow stroma and entrance into the circulation [11]. Stromal derived factor (SDF-1) and CXCR-4 interactions play a pivotal role in the stem cell mobilization. Proteolytic enzymes like catephsin, elastase and matrix metaloproteinases facilitate mobilization by the degradation of adhesion molecules like VLA/VCAM or SDF-1/ CXCR4 [12,13]. Aging decreases bone marrow cellularity, and it has been postulated that both HSC numbers and colony forming capacity have been anticipated to decline with advancing age [14,15]. It has also been postulated that there can be a lineage bias of HSC population changes with age due to the relative loss of B cell, and the increase of myeloid cell potential [16]. In our previous study, we could not find out a correlation between age and BFUE, CFU-E, CFU-GM and CFU-GEMM in patients with different diagnosis of hematological malignancies [17]. Similar to our study, Bagnara et al. supported a well preserved capability of CD34+ cells in old people and centenarians who respond to hematopoietic cytokines and form BFU-E, CFU-GEMM, CFU-GM in a way indistinguishable from that of young subjects [18]. In addition, whether or not the decline in functional capacity of bone marrow HSC reflects the poor mobilization of these cells has been debated previously. In this review we aimed to summarize both the recent data about the stem cell mobilization and the collection from elderly patients and healthy donors.

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2. Hematopoietic stem cell mobilization in elderly 2.1. How do we mobilize hematopoietic stem cell? Today, granulocyte colony stimulating factor (GCSF) mobilized peripheral blood cells have been utilized as major source for stem cell transplantation. GCSF alone, in combination with chemotherapy or with plerixafor, has been widely accepted as major stem cell mobilization methods [19–21]. Granulocyte macrophage colony stimulating factor (GMCSF) has been preferred less often due to its less efficacy and more side effects [22]. The two recombinant GCSF preparations filgrastim and lenograstim have been used in stem cell mobilization of elderly patients and healthy donors in doses ranging from 10 to 20 mcg/kg/day [23–25]. Debate has been ongoing about which GCSF is more potent than the other? As age was accepted as transplant exclusion criteria previously, the maximum age of the patients was 65 in most of the studies. With the increase in the number of both elderly autologous and allogeneic transplant patients, the experience about GCSF will be detailed in near future. As there is no prospective randomized comparative study in elderly patients, until that time, we have to concern the results of the stem cell mobilization in younger patients as regards the choice of G-CSF. Stem cell mobilization efficacy of lenograstim and filgrastim has been found to be similar in some studies [26,27]. In contrast with these results, Ria et al. recently reported lenograstim as a more potent agent than filgrastim and pegfilgrastim when used in combination with chemotherapy [28]. It has also been shown that lower lenograstim doses like 7.5 mcg/kg can be equivalent to doses of 10 mcg/ kg filgrastim [29]. Biosimilar agents have been approved by authorities in some countries like ours, and preliminary data show similar efficacy with original molecules [30]. Although the treatment of neutropenia has been approved after chemotherapy, pegfilgrastim, a long, half-life filgrastim form, can also mobilize stem cells after a single administration of subcutaneous injection. In a study, pegfilgrastim after chemotherapy has been reported to have an advantage of achieving more CD34+ cells/kg on the first apheresis day with less injection numbers in multiple myeloma patients. Only 47% of the patients were over 65 years old in this study [31]. In addition, pegfilgrastim can be a valid option in stem cell mobilization of lymphoma patients [32]. GCSF after chemotherapy has been admitted as a more potent stem cell mobilization method according to GCSF alone and can be preferred as a first line attempt for patients in whom poor mobilization has been predicted [33–35]. This combination may not always be an option in elderly patients as a result of chemotherapy toxicity. Whether new potent agents like plerixafor can be used upfront instead of chemotherapy plus GCSF combination is a question to be answered in near future. Plerixafor, a novel chemokine receptor (CXCR4) antagonist, is approved in combination with GCSF to mobilize HSCs in patients with NHL and MM. It disrupts the interaction between SDF1/CXCR4 and has been shown to be effective and safe in combination with GCSF or GCSF plus chemotherapy. Plerixafor has been found to significantly increase the number of pa-

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tients achieving target CD34+ cells with fewer apheresis days compared to GCSF and placebo [36,37]. It has been also shown that mobilization attempt by using plerixafor plus GCSF resulted in more predictable days of collection, no weekend apheresis procedures, and no unscheduled hospital admissions [38]. Plerixafor in combination with chemotherapy has also been evaluated and found to be safe and useful in stem cell collection. Addition of plerixafor either before apheresis procedure or after chemotherapy has been reported to be efficient [39,40]. In phase III trial of elderly MM and lymphoma patients, efficacy and safety of plerixafor + GCSF versus placebo + GCSF have been compared. Target stem cell yield which was 5 × 10e6/kg could be achieved in a higher number of elderly patients in the plerixafor group according to placebo group. Also, a significantly higher proportion of elderly NHL and MM patients could proceed to transplant. Age was not a negative factor for stem cell mobilization of NHL patients both in plerixafor and placebo groups. However, in MM patients, age was associated with poor mobilization in the placebo group, but not in the plerixafor group. Thus, it can be concluded that plerixafor can overcome the negative impact of age in MM patients [41]. 2.2. How do we collect hematopoietic stem cell? In various studies, it has been shown that peripheral blood CD34+ cell/μl correlates with collected CD34+ cells/ kg in the apheresis product [42]. Peripheral blood CD34+ cell count has been performed in the fifth morning of GCSF or after the achievement of PBC count >1000/μl. More than 20 CD34+ cells per microliter remains to be the robust value for successful mobilization. Recent studies have pointed out the preemptive use of plerixafor for stem cell mobilization in patients who have peripheral blood counts between 10–20 CD34+ cells per microliter [42,43]. Consensus guidelines and recommendations have been published recently and the role of larger processing volumes during apheresis procedure for stem cell mobilization has been validated. Follow-up of coagulation and electrolyte parameters have rigorously been recommended in patients for whom large processing volumes have been performed [44–46]. Increasing the number of leukapheresis cycles in elderly patients can be translated into similar final stem cell yields with younger patients [47]. In contrast with these results, Tempescul et al. found identical number of apheresis cycle necessary to achieve the target stem cell yield between younger and older patients [23]. In guidelines, the maximum number of apheresis cycle has been restricted to 4 due to a prominent decline in success rate after 4 cycles [44]. We believe that these recommendations can also be considered for elderly patients as the data are scarce. 3. Poor mobilization risk in elderly patients Studies about the impact of age on peripheral blood stem cell yield during mobilization have been reported with contradictory results. Retrospective analysis of 840 patients with MM and NHL could not show the relation between poor mobilization and age [48]. Rossi et al. also did not define age

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as one of the independent parameters for PBSC mobilization [49]. In contrast, Italian group defined age as one of the predictive factors for poor or failed mobilization [50]. Recently, The Gruppo Italiano di Midollo Osseo has proposed age >65 years as one of the criteria for predicting poor mobilization. The other ‘predicted’ poor mobilizers were patients who failed a previous collection attempt received an extensive radiotherapy or full courses of therapy affecting HSC mobilization patients with an advanced disease (≥2 lines of chemotherapy), a refractory disease, an extensive bone marrow involvement or cellularity <30% at the time of mobilization [51]. Moris et al. stated that the number of months of chemotherapy given and platelet counts at the time of mobilization are statistically significant variables to predict elderly poor mobilizers [52]. In most of the studies, CD34+ cells/kg collected has been reported to be significantly lower in patients over 60 years old according to younger counterparts [53]. Slightly lower yet insignificant differences were also reported by Kumar and colleagues [54]. Subgroup analysis according to diagnosis has revealed that it seems to be hard to collect stem cells from lymphoma patients probably due to aggressive treatment before mobilization. Tempescul et al. reported lower CD 34+ cells collected per patient and per apheresis cycle both in elderly lymphoma and myeloma patients [23]. Interestingly, however, in a study, age was not found to have an influence on stem cell mobilization in acute myeloblastic leukemia (AML) patients [55]. Recommended minimum CD34+ cells for neutrophil and platelet engraftment in elderly patients are also 2 × 10e6/ kg, which is similar in younger patients. The optimum CD34+ cell levels are defined to be >5 × 10e6/kg for a single transplant. Due to the disease course, in most of the transplantation centers, multiple myeloma patients have been mobilized for double transplantation. In a recently published report, Gertz has summarized their mobilization practice in which all patients <70 years old routinely undergo mobilization for double transplantations [56]. In elderly patients, neutrophil and platelet engraftment can be safely ensured with adequate stem cell infusion, which shows the qualitative sufficiency besides the quantitativity of these cells. Despite the difficulties in the mobilization of elderly NHL, MM patients, transplant outcomes in terms of treatment related mortality and event free survival correlate with younger matched cohorts [54,57]. 4. Poor mobilization risk in elderly healthy donors Not only in a SCT but also Allo SCT transplant eligibility has increased with the current conditioning regimens and better supportive care. This brings the question about the impact of donor age both on stem cell mobilization and transplant outcomes. Although there are studies reporting age as a negative predictive factor for stem cell mobilization [58,59], there are also studies that have not proved this negative impact [60,61]. Rinaldi et al. found the peak value of peripheral blood 34+ cells lower in patients older than 60 years old [62]. Ings et al. found that CD34+ cells collected from donors aging 55 years or more were significantly fewer than younger ones [58]. Mottlo et al. reported that in

order to collect similar total CD34+ cells with younger patients, larger volumes have to be processed during apheresis [25]. In contradiction with these results, Favre et al. did not show any impact of donor age on stem cell yield [61]. Not only the age of HLA siblings but also the age of unrelated donors increases with the AlloSCT. Current NMDP policy for unrelated donors has been admitted for 60 years for healthy unrelated donors. In a study, older donors were associated with slightly lower nucleated cell doses [63]. Engraftment success of stem cells mobilized from healthy donors has also been investigated. In the study of Mottlo et al., the transplant outcomes were favorable, no differences in the terms of neutrophil and platelet engraftment, overall survival and non relapse mortality were observed. Richa et al. also reported no influence of donor age on hematopoietic recovery after HSCT [64]. Plerixafor has not been approved in stem cell mobilization of healthy donors, but there are case reports published about plerixafor rescue in poor mobilized donors. One of these reports presented an elderly patient who had allogeneic stem cell transplantation from her 68-year-old sibling who could not be mobilized with GCSF alone [65,66]. In conclusion, today with introduction of new stem cell mobilization agents and with performing larger volumes during apheresis, similar stem cell mobilization can be safely achieved in elderly patients and healthy donors.

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