Factors influencing engraftment in autologous peripheral hematopoetic stem cell transplantation (PBSCT)

Transfusion and Apheresis Science 36 (2007) 23–29 intl.elsevierhealth.com/journals/tras

Factors inXuencing engraftment in autologous peripheral hematopoetic stem cell transplantation (PBSCT) Ülkü Ergene a,¤, Seçkin Çafirgan b, Mustafa Pehlivan c, Mümtaz Yilmaz d, Murat Tombuloflu b a

Division of Hematology, Medical Faculty, Celal Bayar University, Manisa, Turkey b Division of Hematology, Medical Faculty, Ege University, Ãzmir, Turkey c Department of Hematology, Medical Faculty, Gaziantep University, Antep, Turkey d Department of Internal Medicine, Medical Faculty, Ege University, Ãzmir, Turkey Received 19 May 2006; received in revised form 8 August 2006; accepted 14 August 2006

Abstract Autologous peripheral blood stem cells transplantation (PBSCT) is a therapeutic option which can be used in various hematological neoplastic disorders; and it can prolong disease free survival and total survival and at times it may be curative. In this study, we investigated variables inXuencing PBSCT in 91 patients who had undergone PBSCT between 1998 and 2002 in our center, retrospectively. PBSC collection was performed after mobilization with G-CSF or chemotherapy plus growth factor. Only high dose chemotherapy was used for conditioning regimes. The median number of CD34+ was 11.5 £ 106/kg. Posttransplant neutrophil engraftment (>500/L) was requiring a median of 10 days, it was 13 days for platelet engraftment (>20,000/L). For neutrophil and platelet engraftment, we investigated; sex, age, diagnosis and CD34+ cells, the time interval between diagnosis and transplantation, number of apheresis, conditioning regime, growth factor initiation day as independent variables. In univariate analysis CD34+ cell number (>10 £ 106/kg), time interval more than one year between diagnosis and transplantation and BEAM conditioning was found to be signiWcant for neutrophil engraftment. But in multivariate analysis none of them was found to be signiWcant. For platelet engraftment in univariate analysis CD34+ cell number (>7 £ 106/kg), primary diagnosis of multiple myeloma initiation day of growth factor (>2 day) was found to be signiWcant. In multivariate analyses only CD34+ cell count was found to be signiWcant (p D 0.005). In conclusion, as in previous studies we found that the only predictor of engraftment kinetics was CD34+ cell count. © 2006 Published by Elsevier Ltd. Keywords: Autologous stem cell transplantation; CD34+ cells; Engraftment

1. Introduction

*

Corresponding author. Address: Seferihisar Cad., 366 Sokak Dofakent, Sitesi No: 8, Güzelbahçe, Ãzmir, Turkey. Tel.: +90 505 236 31 47. E-mail address: [email protected] (Ü. Ergene). 1473-0502/$ - see front matter © 2006 Published by Elsevier Ltd. doi:10.1016/j.transci.2006.08.009

Autologous peripheral blood stem cells transplantation is a therapeutic method that is used in various hematological neoplastic disorders. High dose therapy followed by PBSCT is widely used for the treatment of diVerent malignancies. Developments in this

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Weld have dramatically reduced the morbidity and mortality of transplantation. Human hematopoetic stem cells express the antigen CD 34 and also are lineage negative [1–4]. For determining the appropriateness of stem cell product, amount of CD34+ cell/kg acceptable and is a practical method. The optimal cell dose is controversial. However, most transplant centers have observed that stem cell products containing more than 2 £ 106 CD34+ cells/kg result in rapid platelet recovery. The minimum cell dose required for hematopoetic engraftment has not been deWned yet; however, cell doses below 1 £ 106 CD34+ cells/kg are felt to be inadequate [1,5,6]. A number of studies have been made about the factors which are aVecting hematopoetic recovery (HR) after PBSCT. It is important to improve the knowledge of the diVerent factors aVecting HR after PBSCT to further enhance the safety of this procedure. The objective of this study is to identify predictive factors aVecting HR and rapid engraftment, in a series of 91 patients undergoing PBCST.

Table 1 Patient characteristics at transplantation No. of patients Sex (female/male) Age (years)a Diagnosis Multiple myeloma Non-Hodgkin’s lymphoma Hodgkin disease Acute myelogenous leukemia Acute lymphoblastic leukemia Diagnosis-PBSCT interval (months)a Pretransplant performance scale (ECOG)a Disease stage CR 1

CR 7 2 PR

91 39/52 40 (14–68) 28 25 12 20 6 9 (2.3–84.4)

1 (0–2) 31 (21 acute leukemia, 6 lymphoma, 4 multiple myeloma) 15 (5 acute leukemia, 10 lymphoma) 36 (19 lymphoma, 17 multiple myeloma) 9 (2 lymphoma, 7 multiple myeloma)

2. Patients and methods

Relapse/refractory

2.1. Patients

ECOG: eastern co-operative oncology group; CR: complete remission; PR: partial remission. a Median.

In this study, 91 patients who were undergone PBSCT for various hematological neoplastic disorders between March 1998 and March 2002 in Hematology Department of Medical School of Ege University had been investigated. Also factors that eVect hematological recovery are examined in 91 PBSCT, retrospectively. The general criterion for eligibility of patients was to include a good performance status before the transplant (0–2 according to ECOG’s scale). The patients which were undergone PBSCT (28 with multiple myeloma, MM, 25 with non-Hodgkin’s lymphoma, NHL, 12 with Hodgkin’s disease, HD, 20 with acute myelogenous leukemia, AML, six with acute lymphoblastic leukemia, ALL) includes 39 females and 52 males (median 40 years) (Table 1). The time from diagnosis to transplantation was median 9 (2.3–84.4) months, and median 2 (1–5) diVerent chemotherapeutic regimens was implemented before transplant. Before transplantation, 31 patients were assumed to be in the Wrst complete remission, 15 patients were in second complete remission, 36 patients were in partial remission and nine patients were primary refractory or progressive disease. Clinical properties of the patients are shown in Table 1.

2.2. CD34+ cell counting CD34+ content of collected products is determined by using “ProCount™” Progenitor Cell Enumeration kit, with “CellQuest” program in “FACScan Flow Cytometer (Becton–Dickinson)”. Mononuclear cell (MNC) count was performed using “Cell-Dyn 4000, Abbott” and “Counter (STKS and Gen’s)”. 2.3. Preservation of stem cell products Collected products are diluted with autologous plasma in the cell range of 50,000/L. After collection, the cells were placed in 3% of 10% HES (hydroxyethyl starch, Baxter) and 7.5% of 10% DMSO (dimethylsulfoxide, Sigma) and last stem cell product was achieved. It was frozen to ¡80 °C until use in bags, 100 mL in volume. 2.4. Conditioning regimens High dose busulfan/cyclophosphamide (BUCY) for acute leukemia; carmustine/etoposide/cytara-

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bine/melphalan (BEAM) or busulphan/etoposide/ cyclophosphamide (BUCYVP) for non-Hodgkin and Hodgkin lymphomas and melphalan for MM patients were applied as conditioning regimens. After 24–48 h following conditioning regimens, hematopoetic stem cell bags were infused by central catheter heated to 37 °C. 2.5. Supportive therapy Patients were followed in standard rooms with no laminar air Xow and no HEPA Wlters. Diphenylhydantoin sodium tablet 400 mg/day was used for patients who were applied high dose busulfan and mesna was used to prevent hemorrhagic cystitis for patients who were applied high dose cyclophosphamide. Supportive care included oral Xuconazole, and prophylactic acyclovir. Growth factor (GCSF, Neupogene, 5 g/kg/day) were routinely used after transplant until neutrophil engraftment. Irradiate and Wltered blood products were given to maintain the hemoglobin level above 8 g/dL and the platelet count above 20,000/L. In cases of neutropenic fever empiric broad-spectrum antibiotic therapy was started immediately. Amphotericin B was added for suspected fungal infections. 2.6. Neutrophil engraftment The Wrst day of the consecutive three days which are posttransplant neutrophil >500 L was taken into account as the day of neutrophil engraftment. 2.7. Platelet engraftment Without posttransplant platelet transfusion for three days, the day when platelet >20,000 L was assumed to be platelet engraftment day. 2.8. Statistical evaluation Sexuality, age, diagnosis, inXuenced CD34+ cell amount, time passed between diagnosis and transplant, conditioning regimens, growing factor, starting day and preservation period are examined in terms of eVecting neutrophil and platelet engraftment. Statistical evaluation was made using Kaplan– Meier and longrank tests with SPSS software (10.0 version) computer program.

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3. Results In 91 autologous hematopoetic stem cell transplantation application, products including median 11.475 (1.14–132.48) £ 106/kg CD34+ cells, were collected with median 3 (1–7) leukopheresis which were applied to patients by reinfusing after 24–48 h than conditioning regimens (Table 2). Amount of infused CD34+ cell was <2.5 £ 106/kg in one patient, 2.5–5 £ 106/kg in 11 patients, 5–10 £ 106/kg in 22 patients and >10 £ 106/kg in 38 patients. Neutrophil engraftment (>500/L) occurred in median 10th (7–19) day and platelet engraftment (>20,000/L) occurred in median 13th (1–104) day. Two NHL patients were discharged from hospital before platelet recovery therefore a deWnite platelet engraftment time could not be determined and be taken into consideration. The eVects of sexuality, age, infused CD34+ cell amount, period between diagnosis-transplant, amount of leukopheresis, preservation time of stem cell products, posttransplant growth factor beginning day, diagnosis and applied conditioning regimens were investigated in terms of hematologic recovery and were given in (Table 3). Because of infused CD34+ cell amount in all patients except one was >2.5 £ 106/kg, to examine the eVects of CD34+ cell amount to engraftment, groups were investigated in 5,7 and 10 £ 106/kg ranges. Neutrophil engraftment occurred in 11th day in 12 patients that infused CD34+ cell amount was 65 £ 106/kg and in 10th day in 60 patients that cell amount was >5 £ 106/kg (p D 0.37). Platelet engraftment occurred in median 15th and 11th day, although the diVerence was not found to be statistical signiWcance (p D 0.67). Table 2 Patient characteristics of transplantation No. of prior chemotherapy regimens (except MM)a Conditioning regimens BUCY M-200 BUCY VP BEAM No. of aphereses per mobilization cyclea Harvest preservation period (day)a Post infusion G-CSF beginning daya CD34+ £ 106/kga

2 (1–5)

26 28 16 21 3 (1–7) 24 (8–141) 1 (1–9) 11.5 (1.14–132.48)

BUCY: busulphan/cyclophosphamide; BUCYVP: busulphan/ cyclophosphamide/etoposide; BEAM: carmustine/etoposide/cytarabine/melphalan; M-200: melphalan – 200 mg. a Median and range.

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Table 3 Factors inXuencing engraftment Neutrophil engraftment

Sex (female/male) Age (>40/640) CD34 £ 106/kg ( >5/65) CD34 £ 106/kg ( >7/67) CD34 £ 106/kg (>10/610) Diagnosis – Tx interval (>1year/61year) No. aphereses (10.2/>2) G-CSF beginning day (10.2/>2) Preservation days (725/<25 ) MM/(AML-ALL) MM/(NHL-HH) (AML-ALL)/(NHL-HH) BUCY/BUCYVP BEAM/BUCYVP BEAM/BUCY

Platelet engraftment

n

Median (day)

Longrank p

n

Median (day)

Longrank p

39/52 44/47 60/12 46/26 38/34 31/60 21/70 72/15 37/42 28/26 28/37 26/37 26/16 21/16 21/26

10/10 (7–19/8–16) 10/10 (7–14/9–19) 10/11 (8–19/9–14) 10/11 (8–19/9–14) 9/11 (8–19/9–16) 10/10 (7–14/8–19) 10/10 (8–19/7–15) 10/10 (7–19/9–12) 10/10 (8–19/7–14) 10/10 (8–14/9–15) 10/9 (8–14/7–19) 10/9 (9–15/7–19) 10/10 (9–15/7–19) 9/10 (8–13/7–19) 9/10 (8–13/9–15)

0.897 0.575 0.374 0.068 0.016 0.041 0.379 0.290 0.829 0.741 0.340 0.354 0.742 0.124 0.033

38/51 43/46 58/12 45/25 37/33 31/58 20/69 71/14 36/42 28/26 28/35 26/35 26/16 19/16 19/26

13/13 (0–62/0–104) 13/12 (0–62/0–104) 11/15 (0–104/10–63) 11/18 (0–62/10–104) 10/18 (0–38/10–104) 13/12 (7–63/0–104) 10/13 (8–62/0–104) 13/10 (0–104/7–20) 13/12 (0–76/0–104) 11 /14 (0–37/8–104) 11/12 (0–37/8–76) 14/12 (8–104/8–76) 14/12 (9–104/8–76) 12/12 (8–47/9–104) 12/14 (8–47/9–104)

0.784 0.542 0.674 0.003 0.000 0.718 0.532 0.037 0.790 0.014 0.057 0.058 0.858 0.237 0.237

n: number of patients longrank; p: bolded numbers are statistically signiWcant.

In 26 patients who were given CD34+ cell less than 7 £ 106/kg, neutrophil engraftment occurred in median 11th day, in 46 patients who were given CD34+ cell >7 £ 106/kg occurred 10th day (p D 0.06). In the patients who were given amount of CD34+ cell 67 £ 106/kg, platelet engraftment occurred in a long period compared to patients given more and it was statistical signiWcance (respectively median 18th and 11th; p D 0.003). In 34 patients who were given 610 £ 106/kg CD34+ cell, neutrophile engraftment occurred in median 11th day and 9th day in 38 patients who were given >10 £ 106/kg CD34+, the diVerence is statistically signiWcant (p D 0.016). In patients who were given >10 £ 106/kg CD34+, platelet engraftment occurred in 10th day. In patients who were given 610 £ 106/kg CD34+ platelet engraftment occurred in 18th day. This formation in a less period of time compared to patients who were given less amounts was statistically signiWcant (p D 0.000). In the patients that diagnosis-transplant period was shorter than one year and longer (60 and 31 patients), neutrophile engraftment occurred in median 10th day. In patients that diagnosis-transplant period was longer than one, statistically signiWcant diVerences were obtained (p D 0.04). Platelet engraftment occurred 12th and 13th day and diVerence was not statistically signiWcant (p D 0.71). Patients that posttransplant growth factor starting day was 1st and 2nd day (n D 72) and after 2nd day (n D 15), were compared. There was no statistical signiWcance for neutrophil engraftment (in

both groups, median 10th days; p D 0.29). The platelet engraftment statistically started earlier in patients that growth factor were applied after 2nd day, respectively, median 10th and 13th days; (p D 0.03). The eVect of diseases diagnoses to engraftment was examined. Multiple myelom, acute leukemia (AML-ALL) and malignant lymphoma (NHL-HL) groups were compared. There was not any diVerence between three groups in terms of neutrophil engraftment median 10th, 10th, 9th days, respectively, (p > 0.05). Platelet engraftment occurred in 11th day in MM patients 14th day in acute leukemia patients, 12th day in malignant lymphoma patients and the diVerence between MM patients and acute leukemia patients was found to be statistically signiWcant (p D 0.01); it was determined that there was statistical signiWcance between MM, malignant lymphoma and malignant lymphoma, acute leukemia groups (p D 0.05). In 21 malignant lymphoma patients who were applied BEAM regimens, neutrophil engraftment occurred in median 9th day, 26 acute leukemia patients who were applied BUCY regimens occurred in 10th day, the diVerence was statistically signiWcant (p D 0.03). Platelet engraftment occurred, respectively, in 12th and 14th day, the diVerence was not statistically signiWcant (p D 0.2). In univariate analysis, the factors which aVect neutrophil engraftment positively were; CD34+ cell amount (>10 £ 106/kg), diagnosis-transplant period (>1 year), conditioning regimens (BEAM regimens

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versus BUCY) and the factors which aVect platelet engraftment positively were CD34+ cell amount (>7 £ 106/kg), diagnosis (multiple myelom compared to acute leukemia), growth factor starting day (>2nd day) (Table 3). In multivariate analysis, the factors that aVect neutrophil engraftment in univariate analysis lost their meaning; only CD34+ cell amount (>7 £ 106/ kg) continued statistically signiWcant for platelet engraftment (p D 0.005). 4. Discussion There are some studies evaluating the parameters eVecting engraftment after PBSCT [7–12]. In one of them, it was found that the cell dose correlated with neutrophil and platelet engraftment. In this study, CD34 cell median 5.10 (0.13–32.65) was used [10]. In an another study, it was indicated that the most important parameter in engraftment was infused progenitor cell dose; it must be at least 2 £ 106/kg CD34+ for engraftment, higher doses, can not ensure high speed engraftment, if <2, than platelet engraftment would be late [13]. In our study, CD34+ cell median 11.5 (1.14–132.48) was used, CD34+ cell dose was found signiWcant in multivariate analysis for platelet engraftment but not for neutrophil engraftment (p D 0.005). In studies of patients with AML, some reports have evaluated the inXuence of the infused progenitor cell dose on engraftment [9,14–19]. Demirer et al. [16] and Martin et al. [18] reported that patients transplanted with >2.5 £ 106/kg CD34+ had a faster recovery of platelet counts, and in another co-operative study, patients transplanted with >12 £ 106/kg CD34+ cells had a more rapid neutrophil and platelet recovery as compared with those receiving <3 £ 106/kg [19]. But these studies include a few patients. In an another study [14] including more patients, higher dose CD34+ were utilized to patients (54 patients) with AML, although a higher dose of CD34+ cells were given, AML patients were lately recovered versus non-myeloid malignancies (NMM) patients. It was emphasised as a result that engraftment period in patients with AML was longer and it was not dependent to cell dose. In that study [14], platelet engraftment in AML patient after autologous stem cell transplant was to be late but when the patients who were early relapsed from working group removed, it was seen that the diVerence between the recovery speed of both diagnosis group was disappeared. In our study, the posttrans-

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plant patients who died in 3 months were not taken into consideration. Thus, we avoided the contribution of residual leukemia to engraftment delay. Probably, early relapse in their study was because residual leukemia. In that study [14], neutrophil recovery was with further ages in some AML patients. In our study, cut oV values were assumed 40 and 50 years, but it was not found as an important factor. In another study it was found that platelet recovery was slower in patients with acute leukemia than in other diseases and in the multivariate analysis, the conditioning regimens, remained as a signiWcant independent factor inXuencing HR [8]. In our study, progenitor cell dose was high as >2.5 £ 106/kg and cut oV value was assumed to be 65 versus >5 and 67 versus >7 and 610 versus >10. It was investigated that when utilizing 67 £ 106/kg CD34+, platelet engraftment was late (p D 0.005), and it was determined that utilizing >10 £ 106/kg CD34+ was not useful. In our study, patients in which BEAM is used as conditioning regimens, neutrophil engraftment was found statistically signiWcant in univariate analysis versus patients that used BUCY (p D 0.0336). At Wrst this state seems inconsistent with the BEAM protocols myelotoxicity, but it was not found statistically signiWcant in multivariate analysis. Comparing lymphoma patients who received BEAM to those who received BUCYVP, median CD 34+ number was not found similar; respectively, 22.65, 7.7. We thus have not seen any negative eVect of BEAM regimen over CD 34+ number. AML-ALL patients were compared with MM group and found in univariate analysis that it was eVective in platelet engraftment, median 14 versus 11 days (p D 0.0147), but multivariate analysis did not support these results. As to the relation between diagnosis and CD 34+ number, the CD 34+ number of acute leukemia patients was found lower than patients with multiple myeloma and lymphoma. Median CD 34+ was found 7.7 for acute leukemia, 10.175 for multiple myeloma and 17.34 for lymphoma. This diVerence might be explained by; acute leukemia being a stem cell disease, residual leukemia cells preventing hematopoiesis reconstitution and damage in marrow microenvironment caused by prior intensive chemotherapy. We did not use <2.5 £ 106/kg CD34+ cell dose (except one patient who had not any engraftment problem). We had no neutrophil engraftment problem, there was a meaningful delay for platelet

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Ü. Ergene et al. / Transfusion and Apheresis Science 36 (2007) 23–29

engraftment in patients who used <7 £ 106/kg CD34+ (p D 0.003) in univariate and (p D 0.005) in multivariate analysis, <10 £ 106/kg CD34+ cell dose was statistically signiWcant in neutrophil and platelet engraftment for univariate analysis (respectively p D 0.0164 and p D 0.000), but not in multivariate analysis. In our study, we used post infusion G-CSF in all patients, beginning of G-CSF days were diVerent. In univariate analysis, there was a delay of platelet engraftment in patients whose starting day of GCSF were 1st and 2nd, compared to others (p D 0.0371) but it is not found to be statistically signiWcant in multivariate analysis. Ringden et al. said that Bone marrow transplantation and peripheral blood stem cells patients treated with G-CSF had a faster engraftment of absolute neutrophil greater than 0.5 £ 10(9)/L (p < 0.01), but platelet engraftment (>50 £ 10(9)/L) was slower (p < 0.001). This suggests that G-CSF should not be given shortly after BMT [20]. Maybe, further studies on this subject, could result a late application of G-CSF; as an expensive drug. As a result, in PBSCT which is used for various hematological malign diseases, the most diagnostic factor for hematological recovery is infused CD34+ cell levels; infused cell CD34+ of 72.5 £ 106/kg to our patient, is enough for neutrophil and platelet engraftment but above the values of 7 £ 106/kg CD34+ cells could reduce platelet engraftment period. References [1] Beutler E, Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT. Principle of hematopoietic cell transplantation. In: Negrin RS, Blume KG, editors. William Hematol. 7th ed. McGraw-Hill; 2006. p. 301–22. [2] Lee RG, Foerster J, Lukens J, Paraskevas F, Greer PJ, Rodgers MG.Hematol Malignancies. 10th ed. Wintrobe’s Clin Hematol Mass Publishing Co.; 1999. p. 1993–2725. [3] Craig W, Kay R, Cutler RL, Lansdorp PM. Expression of thy-1 on human hematopoietic progenitor cells. J Exp Med 1993;177:1331. [4] Unhida N, Combs J, Chen S, et al. Primitive human hematopoietic cells displaying diVerential eZux of the rhodamine123 dye have distinct biological activities. Blood 1996;88:1297. [5] Bensinger WI, Appelbaum FR, Rowley S, et al. Factors that inXuence collection and engraftment of autologous peripheral blood stem cells. J Clin Oncol 1995;13:2547–55. [6] Schwartzberg L, Birch R, Blanco R, et al. Rapid and sustained hematopoietic reconstitution by peripheral blood stem cell infusion alone following high-dose chemotherapy. Bone Marrow Transpl 1993;11:369–74.

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