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Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors
G Model
ARTICLE IN PRESS
TRASCI-2271; No. of Pages 4
Transfusion and Apheresis Science xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors Serkan Ocakci ∗ , Selda Kahraman, Seckin Cagirgan Department of Hematology, Medicalpark Izmir Hospital, Izmir, Turkey
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Donor Age Allogeneic
a b s t r a c t It took several years to succeed safe hematopoietic stem cell transplantations. HLA-matched unrelated donors have become the most common donor source for allogeneic hematopoietic stem cell transplants worldwide. The sibling donor may have more comorbidity and decreased regenerative potential of stem and immune cells. The purpose of this retrospective study was to examine whether aging had any negative effect on aging donor or patient. 27 patients who received a hematopoietic stem cell transplantation (HSCT) from February 2013 to May 2016 and their donors were analyzed. We showed that transplantation from older relative donor was feasible. Adverse event rate was low. Donors tolerated the procedure very well. Good CD34+ cell harvest was possible. © 2017 Elsevier Ltd. All rights reserved.
Contents 1. 2.
3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction In 1957, Thomas ED published the first Bone Marrow Transplantation (BMT) for acute leukemia patients. None of the patients survived [1]. In 1968, three patients suffering from a congenital immune deficiency were successfully transplanted with hematopoietic HLA-matched sibling donor stem cells [2]. In 1979, Hansen and colleagues performed the first successful unrelated donor marrow transplant for an acute leukemia patient [3]. HLA-matched unrelated donors have become the most common donor source for allogeneic hematopoietic cell transplants [4]. The National Marrow Donor Program (NMDP) was established in 1986 to recruit and conduct HLA typing of unrelated donors. Current
NMDP obligation for donor age is 18-60 years. The National Donor Program in Turkey is named as "Türkök” and requires that donors must be between the ages of 18 and 50 years. Turkey is a developing country with limited sources. Recruited unrelated donor count is below NDMP. Unlike United States, patients usually have more than one sibling and the percentage of finding a matched sibling donor is higher. For older-age patients a sibling donor is usually of an age similar to that of the patient. Therefore, the sibling donor may have more comorbidity and decreased regenerative potential of stem and immune cells. The purpose of this retrospective study was to examine whether aging had any negative effect on aging donor or patient. 2. Patients and methods
∗ Corresponding author at: Yeni Girne Blv. 1825 Sokak No: 12 Karsiyaka, Izmir, Turkey. E-mail address: [email protected] (S. Ocakci).
27 patients who received hematopoietic stem cell transplantation (HSCT) from February 2013 to May 2016 and their donors were
https://doi.org/10.1016/j.transci.2017.11.014 1473-0502/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ocakci S, et al. Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors. Transfus Apheresis Sci (2017), https://doi.org/10.1016/j.transci.2017.11.014
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S. Ocakci et al. / Transfusion and Apheresis Science xxx (2017) xxx–xxx
2 Table 1 Patient and donor characteristics. Parameters Relation
Patient sex Donor sex Comorbidity
Type of Disease
Mother Brother Cousin Male Female Male Female BPH DM,HT DM, HT, OA Epilepsy Hypothyroidism HT HT, nephrectomy HT, hypothyroidism HT, CAD Osteoporosis None ALCL AML DLBCL CML LL MCL MDS-EB MM Myelofibrosis
Table 2 Baseline data and apheresis results. n
Percent (%)
Parameters
Median
Minimum
Maximum
4 22 1 17 10 14 13 1 2 1 1 1 10 1 1 1 1 7 1 14 1 1 1 2 5 1 1
14.8 81.5 3.7 63.0 37.0 51.9 48.1 3.7 7.4 3.7 3.7 3.7 37.0 3.7 3.7 3.7 3.7 25.9 3.7 51.9 3.7 3.7 3.7 7.4 18.5 3.7 3.7
Donor age, years Donor weight, kg Peripheral CD34 × 106 /L Harvest CD34 × 106 /L Patient age, years neutrophil engraftment platelet engraftment by day Hb, g/dL Platelet, x109 /L White blood cell, x109 /L Neutrophil, x109 /L Lymphocyte, x109 /L Monocyte, x109 /L
64 79 54 6.25 64 14 14 13.9 234 6.72 3.98 2.09 0.5
60 57 12 4.04 32 11 9 11 161 3.92 1.41 1.1 0.23
76 100 167 13.61 75 19 25 15.8 328 11.3 2.04 4.07 5.9
BPH: Benign prostate hyperplasia, DM: Diabetes mellitus, HT: Hypertension, OA: Osteoarthritis, CAD: Coronary Artery Disease. ALCL: Anaplastic large cell lymphoma, AML: Acute myeloid leukemia, DLBCL: Diffuse large B cell lymphoma. CML: Chronic myeloid leukemia, LL: Lymphoblastic leukemia, MCL: Mantle cell lymphoma, MDSEB: Myelodysplastic syndrome with excess blast, MM: Multiple myeloma.
analyzed. Data were retrospectively collected from our transplant data base. Patients and donors were matched for HLA A, B, C, DRB1 and DQB1 by low resolution DNA-typing as appropriate. 2.1. Treatment Myeloablative conditioning (MA) regimen consisted of intravenous Busulfan 3,2 mg/kg on days (−7 to −4), and Cyclofosfamide 60 mg/kg (−3,−2). Reduced intensity conditioning (RIC) regimen consisted of Busulfan 3,2 mg/kg on days (−6,−5), Cyclofosfamide 350 mg/m2 (−4 to −2), and Fludarabine 30 mg/m2 (−4 to −2). Graft versus host disease (GVHD) prophylaxis included intravenous Cyclosporine 1 mg/kg from day −1 and Methotrexate 15 mg/m2 on day +1 and 10 mg/m2 on day +3, +6, and +11 in MA regimen. Methotrexate was administered 10 mg/m2 on day +1, +3, and +6 in RIC regimen. Cyclosporine levels in peripheral blood were monitored in order to adjust treatment. As soon as patients tolerate oral cyclosporine, it was administered. 2.2. Statistical analysis The statistical analysis was implemented using SPSS version 20.0 (SPSS, Chicago, IL, USA). CD34 count and donor characteristics were compared by Spearman test and Mann-Whitney test. Survival and progression-free survival (PFS) were calculated by using the method of Kaplan and Meier. HLA matching comparisons were calculated by 2 test, and Mann-Whitney test. CD34 count and venous access were compared by Mann-Whitney test. GVHD associated deaths were compared with variables by Mann-Whitney test. 3. Results Patient and donor characteristics are summarized in Table 1. Among the 27 patients included, diagnosis was Acute Myeloid
Leukemia (AML) in 14 (51.9%), Myelodysplastic Syndrome Excess Blast (MDS-EB) in 5 (18.5%), Mantle Cell Lymphoma in 2 (7.4%). Donor sex was equally balanced. 14 (51.9%) of them were male and 13 (48.1%) of them were female. Patient sex was in favor of male; 17 (63%) versus 10 (37%). 22 (81.5%) donors were sibling. 4 (14.8%) donors were mothers and 1 (3.7%) donor was cousin. Apheresis count was 1 in 16 (59.3%) in donors and 2 in 11 (40.7%) donors. 11 (40.7%) donors required central venous catheter insertion for stem cell collection. Femoral catheter was inserted to only 1 (3.7%) donor. Subclavian catheter was inserted to 10 (37.0%) donors. No side effect occurred during collection period. Table 2 summarizes donor age, baseline hematological counts, CD34 counts, and engraftment. Median donor age was 64 (60–76). Median peripheral CD34 count was 54/mL (12–167). Median CD34+ cell harvest count was 6.25 × 106 /kg. Median patient age was 56 (32–75). The median time to neutrophil and platelet recovery was 14 days for each. 21 (77%) patients died. 11 (52%) of them were transplant related. The leading cause of death were recurrence (23%) and persistent disease (28%). Second cause was acute and chronic GVHD (n = 7, 33%). No significant difference was observed. Kaplan-Meier analysis showed that estimated PFS was 13.2 months (Fig. 1) and estimated OS was 17.9 months (Fig. 2). No significant survival difference was seen between full match and haploidentical donor transplants. Engraftment days did not differ between them, either. An interesting finding was that peripheral venous stem cell harvest was significantly higher than central venous catheter stem cell harvest (p = 0.013). 4. Discussion Older donor age has been shown to be associated with poorer outcome of unrelated myeloablative transplants [5]. It has also been described that RIC transplantation was better in patients and younger donors [6]. Since RIC is applied to older patients, their donors are older, too. Advanced donor age means loss of function [7], loss of repopulating ability [8], and impaired homing ability [9]. These may explain the high relapse and therapy related mortality rate in our study. Kollman et al. [5] have presented the largest donor group results. Their data set consisted of 6978 unrelated donor bone marrow transplantations facilitated by the NMDP. Their data suggested that survival rates might be improved if younger donors were selected. They described that younger donors overcome deleterious effects of a partial HLA mismatch. In our study we did not see a survival difference between full match and mismatch donors. Their speculation was to lower the upper threshold of age that NDMP accepts as 60 years. It must be kept in mind that patients’ doctors determine the appropriate donor for siblings. This decision may lead to choose a less suitable donor and force a high mortality transplant. When a matched related donor is available, regardless
Please cite this article in press as: Ocakci S, et al. Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors. Transfus Apheresis Sci (2017), https://doi.org/10.1016/j.transci.2017.11.014
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3
Fig. 1. Progression Free Survival.
Fig. 2. Overall Survival.
of the age, this is accepted as donor. Unrelated donors are evaluated by unbound professional medical staff, and that brings out more appropriate donors. As the donor gets older, GVHD incidence rises [10]. For patients older than age of 50 years, the risk of acute and chronic GVHD is higher after matched unrelated donor (MUD) compared with matched sibling donor transplants. The donor source had a greater effect on development of GVHD and non-relapse mortality than donor age [11]. Mobilization failure is expected to increase. Marrow cellularity decreases with age [12]. The incidence of MDS increases with age. In the myeloid series there is a decrease in mean colony formation in response to granulocyte colony stimulating factor (G-CSF) [13]. Kornblau et al. showed that there was no hyporesponsiveness in myeloid cells [14]. In our study we did not see mobilization failure. All CD34+ cell collections were above optimal dose. Alousi et al. have shown that transplantation from an older match related donor was associated with better results compared
to transplant from a younger unrelated donor [15]. 38% of their donors were older than 60 years. Overall mortality and relapse risk were higher in patients transplanted from 67 years or older donors. They concluded that a donor for patients who are age 50 years or older should be a sibling donor age younger than 67 years rather than a younger age MUD. In conclusion, we believe that transplantation from older relative donor is feasible. Adverse event rate is low. Donors tolerate the procedure very well. Good CD34+ cell harvest is possible. Since we do not have large numbers of donors like NMDP, we may use our older relative donors as well. Worse transplant outcomes result from patient’s age and comorbidity; not because of the donor.
References [1] Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 1957;257:491–6.
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[2] Bortin MM, Bach FH, van Bekkum DW, Good RA, van Rood JJ. 25th anniversary of the first successful allogeneic bone marrow transplants. Bone Marrow Transplant 1994;14:211–2. [3] Hansen JA, Clift RA, Thomas ED, Buckner CD, Storb R, Giblett ER. Transplantation of marrow from an unrelated donor to a patient with acute leukemia. N Engl J Med 1980;303:565–7. [4] Current Uses and Outcomes of Hematopoietic Celltransplantation 2016 Summary Slides. http://www.cibmtr.org. [5] Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001;98:2043–51. [6] Mehta J, Gordon LI, Tallman MS, Winter JN, Evens AO, Frankfurt O, et al. Does younger age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially. Bone Marrow Transplant 2006;38:95–100. [7] Kamminga LM, van Os R, Weersing E, Ausema A, Dontje B, Vellenga E, et al. Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. Stem Cells 2005;23:82–92. [8] Harrison DE, Astle CM. Loss of stem cell repopulating ability upon transplantation: effects of donor age, cell number, and transplantation procedure. J Exp Med 1982;156:1767–79. [9] Liang Y, Van Zant G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 2005;106:1479–87.
[10] Loren AW, Bunin GR, Boudreau C, Champlin RE, Cnaan A, Horowitz MM, et al. Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006;12(7):758–69. [11] Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996;334(5):281–5. [12] Buckner CD, Clift RA, Sanders JE, Stewart P, Bensinger WI, Doney KC, et al. Marrow harvesting from normal donors. Blood 1984;64:630–4. [13] Chatta GS, Price TH, Allen RC, Dale DC. Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers. Blood 1994;84:2923–9. [14] Kornblau SM, Cohen AC, Soper D, Huang YW, Cesano A. Age-related changes of healthy bone marrow cell signaling in response to growth factors provide insight into low risk MDS. Clin Cytometry 2014;86B:383–96. [15] Alousi AM, Le-Rademacher J, Saliba RM, Appelbaum FR, Artz A, Benjamin J, et al. Who is better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood 2013;121(13):2567–73.
Please cite this article in press as: Ocakci S, et al. Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors. Transfus Apheresis Sci (2017), https://doi.org/10.1016/j.transci.2017.11.014
ARTICLE IN PRESS
TRASCI-2271; No. of Pages 4
Transfusion and Apheresis Science xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors Serkan Ocakci ∗ , Selda Kahraman, Seckin Cagirgan Department of Hematology, Medicalpark Izmir Hospital, Izmir, Turkey
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Donor Age Allogeneic
a b s t r a c t It took several years to succeed safe hematopoietic stem cell transplantations. HLA-matched unrelated donors have become the most common donor source for allogeneic hematopoietic stem cell transplants worldwide. The sibling donor may have more comorbidity and decreased regenerative potential of stem and immune cells. The purpose of this retrospective study was to examine whether aging had any negative effect on aging donor or patient. 27 patients who received a hematopoietic stem cell transplantation (HSCT) from February 2013 to May 2016 and their donors were analyzed. We showed that transplantation from older relative donor was feasible. Adverse event rate was low. Donors tolerated the procedure very well. Good CD34+ cell harvest was possible. © 2017 Elsevier Ltd. All rights reserved.
Contents 1. 2.
3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction In 1957, Thomas ED published the first Bone Marrow Transplantation (BMT) for acute leukemia patients. None of the patients survived [1]. In 1968, three patients suffering from a congenital immune deficiency were successfully transplanted with hematopoietic HLA-matched sibling donor stem cells [2]. In 1979, Hansen and colleagues performed the first successful unrelated donor marrow transplant for an acute leukemia patient [3]. HLA-matched unrelated donors have become the most common donor source for allogeneic hematopoietic cell transplants [4]. The National Marrow Donor Program (NMDP) was established in 1986 to recruit and conduct HLA typing of unrelated donors. Current
NMDP obligation for donor age is 18-60 years. The National Donor Program in Turkey is named as "Türkök” and requires that donors must be between the ages of 18 and 50 years. Turkey is a developing country with limited sources. Recruited unrelated donor count is below NDMP. Unlike United States, patients usually have more than one sibling and the percentage of finding a matched sibling donor is higher. For older-age patients a sibling donor is usually of an age similar to that of the patient. Therefore, the sibling donor may have more comorbidity and decreased regenerative potential of stem and immune cells. The purpose of this retrospective study was to examine whether aging had any negative effect on aging donor or patient. 2. Patients and methods
∗ Corresponding author at: Yeni Girne Blv. 1825 Sokak No: 12 Karsiyaka, Izmir, Turkey. E-mail address: [email protected] (S. Ocakci).
27 patients who received hematopoietic stem cell transplantation (HSCT) from February 2013 to May 2016 and their donors were
https://doi.org/10.1016/j.transci.2017.11.014 1473-0502/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ocakci S, et al. Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors. Transfus Apheresis Sci (2017), https://doi.org/10.1016/j.transci.2017.11.014
G Model
ARTICLE IN PRESS
TRASCI-2271; No. of Pages 4
S. Ocakci et al. / Transfusion and Apheresis Science xxx (2017) xxx–xxx
2 Table 1 Patient and donor characteristics. Parameters Relation
Patient sex Donor sex Comorbidity
Type of Disease
Mother Brother Cousin Male Female Male Female BPH DM,HT DM, HT, OA Epilepsy Hypothyroidism HT HT, nephrectomy HT, hypothyroidism HT, CAD Osteoporosis None ALCL AML DLBCL CML LL MCL MDS-EB MM Myelofibrosis
Table 2 Baseline data and apheresis results. n
Percent (%)
Parameters
Median
Minimum
Maximum
4 22 1 17 10 14 13 1 2 1 1 1 10 1 1 1 1 7 1 14 1 1 1 2 5 1 1
14.8 81.5 3.7 63.0 37.0 51.9 48.1 3.7 7.4 3.7 3.7 3.7 37.0 3.7 3.7 3.7 3.7 25.9 3.7 51.9 3.7 3.7 3.7 7.4 18.5 3.7 3.7
Donor age, years Donor weight, kg Peripheral CD34 × 106 /L Harvest CD34 × 106 /L Patient age, years neutrophil engraftment platelet engraftment by day Hb, g/dL Platelet, x109 /L White blood cell, x109 /L Neutrophil, x109 /L Lymphocyte, x109 /L Monocyte, x109 /L
64 79 54 6.25 64 14 14 13.9 234 6.72 3.98 2.09 0.5
60 57 12 4.04 32 11 9 11 161 3.92 1.41 1.1 0.23
76 100 167 13.61 75 19 25 15.8 328 11.3 2.04 4.07 5.9
BPH: Benign prostate hyperplasia, DM: Diabetes mellitus, HT: Hypertension, OA: Osteoarthritis, CAD: Coronary Artery Disease. ALCL: Anaplastic large cell lymphoma, AML: Acute myeloid leukemia, DLBCL: Diffuse large B cell lymphoma. CML: Chronic myeloid leukemia, LL: Lymphoblastic leukemia, MCL: Mantle cell lymphoma, MDSEB: Myelodysplastic syndrome with excess blast, MM: Multiple myeloma.
analyzed. Data were retrospectively collected from our transplant data base. Patients and donors were matched for HLA A, B, C, DRB1 and DQB1 by low resolution DNA-typing as appropriate. 2.1. Treatment Myeloablative conditioning (MA) regimen consisted of intravenous Busulfan 3,2 mg/kg on days (−7 to −4), and Cyclofosfamide 60 mg/kg (−3,−2). Reduced intensity conditioning (RIC) regimen consisted of Busulfan 3,2 mg/kg on days (−6,−5), Cyclofosfamide 350 mg/m2 (−4 to −2), and Fludarabine 30 mg/m2 (−4 to −2). Graft versus host disease (GVHD) prophylaxis included intravenous Cyclosporine 1 mg/kg from day −1 and Methotrexate 15 mg/m2 on day +1 and 10 mg/m2 on day +3, +6, and +11 in MA regimen. Methotrexate was administered 10 mg/m2 on day +1, +3, and +6 in RIC regimen. Cyclosporine levels in peripheral blood were monitored in order to adjust treatment. As soon as patients tolerate oral cyclosporine, it was administered. 2.2. Statistical analysis The statistical analysis was implemented using SPSS version 20.0 (SPSS, Chicago, IL, USA). CD34 count and donor characteristics were compared by Spearman test and Mann-Whitney test. Survival and progression-free survival (PFS) were calculated by using the method of Kaplan and Meier. HLA matching comparisons were calculated by 2 test, and Mann-Whitney test. CD34 count and venous access were compared by Mann-Whitney test. GVHD associated deaths were compared with variables by Mann-Whitney test. 3. Results Patient and donor characteristics are summarized in Table 1. Among the 27 patients included, diagnosis was Acute Myeloid
Leukemia (AML) in 14 (51.9%), Myelodysplastic Syndrome Excess Blast (MDS-EB) in 5 (18.5%), Mantle Cell Lymphoma in 2 (7.4%). Donor sex was equally balanced. 14 (51.9%) of them were male and 13 (48.1%) of them were female. Patient sex was in favor of male; 17 (63%) versus 10 (37%). 22 (81.5%) donors were sibling. 4 (14.8%) donors were mothers and 1 (3.7%) donor was cousin. Apheresis count was 1 in 16 (59.3%) in donors and 2 in 11 (40.7%) donors. 11 (40.7%) donors required central venous catheter insertion for stem cell collection. Femoral catheter was inserted to only 1 (3.7%) donor. Subclavian catheter was inserted to 10 (37.0%) donors. No side effect occurred during collection period. Table 2 summarizes donor age, baseline hematological counts, CD34 counts, and engraftment. Median donor age was 64 (60–76). Median peripheral CD34 count was 54/mL (12–167). Median CD34+ cell harvest count was 6.25 × 106 /kg. Median patient age was 56 (32–75). The median time to neutrophil and platelet recovery was 14 days for each. 21 (77%) patients died. 11 (52%) of them were transplant related. The leading cause of death were recurrence (23%) and persistent disease (28%). Second cause was acute and chronic GVHD (n = 7, 33%). No significant difference was observed. Kaplan-Meier analysis showed that estimated PFS was 13.2 months (Fig. 1) and estimated OS was 17.9 months (Fig. 2). No significant survival difference was seen between full match and haploidentical donor transplants. Engraftment days did not differ between them, either. An interesting finding was that peripheral venous stem cell harvest was significantly higher than central venous catheter stem cell harvest (p = 0.013). 4. Discussion Older donor age has been shown to be associated with poorer outcome of unrelated myeloablative transplants [5]. It has also been described that RIC transplantation was better in patients and younger donors [6]. Since RIC is applied to older patients, their donors are older, too. Advanced donor age means loss of function [7], loss of repopulating ability [8], and impaired homing ability [9]. These may explain the high relapse and therapy related mortality rate in our study. Kollman et al. [5] have presented the largest donor group results. Their data set consisted of 6978 unrelated donor bone marrow transplantations facilitated by the NMDP. Their data suggested that survival rates might be improved if younger donors were selected. They described that younger donors overcome deleterious effects of a partial HLA mismatch. In our study we did not see a survival difference between full match and mismatch donors. Their speculation was to lower the upper threshold of age that NDMP accepts as 60 years. It must be kept in mind that patients’ doctors determine the appropriate donor for siblings. This decision may lead to choose a less suitable donor and force a high mortality transplant. When a matched related donor is available, regardless
Please cite this article in press as: Ocakci S, et al. Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors. Transfus Apheresis Sci (2017), https://doi.org/10.1016/j.transci.2017.11.014
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Fig. 1. Progression Free Survival.
Fig. 2. Overall Survival.
of the age, this is accepted as donor. Unrelated donors are evaluated by unbound professional medical staff, and that brings out more appropriate donors. As the donor gets older, GVHD incidence rises [10]. For patients older than age of 50 years, the risk of acute and chronic GVHD is higher after matched unrelated donor (MUD) compared with matched sibling donor transplants. The donor source had a greater effect on development of GVHD and non-relapse mortality than donor age [11]. Mobilization failure is expected to increase. Marrow cellularity decreases with age [12]. The incidence of MDS increases with age. In the myeloid series there is a decrease in mean colony formation in response to granulocyte colony stimulating factor (G-CSF) [13]. Kornblau et al. showed that there was no hyporesponsiveness in myeloid cells [14]. In our study we did not see mobilization failure. All CD34+ cell collections were above optimal dose. Alousi et al. have shown that transplantation from an older match related donor was associated with better results compared
to transplant from a younger unrelated donor [15]. 38% of their donors were older than 60 years. Overall mortality and relapse risk were higher in patients transplanted from 67 years or older donors. They concluded that a donor for patients who are age 50 years or older should be a sibling donor age younger than 67 years rather than a younger age MUD. In conclusion, we believe that transplantation from older relative donor is feasible. Adverse event rate is low. Donors tolerate the procedure very well. Good CD34+ cell harvest is possible. Since we do not have large numbers of donors like NMDP, we may use our older relative donors as well. Worse transplant outcomes result from patient’s age and comorbidity; not because of the donor.
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Please cite this article in press as: Ocakci S, et al. Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors. Transfus Apheresis Sci (2017), https://doi.org/10.1016/j.transci.2017.11.014