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ORIGINAL ARTICLE

Poor mobilization is an independent prognostic factor in patients with malignant lymphomas treated by peripheral blood stem cell transplantation V Pavone1,2, F Gaudio1, G Console3, U Vitolo4, P Iacopino3, A Guarini1, V Liso1, T Perrone1 and A Liso5 1

Hematology Department, University of Bari, Bari, Italy; 2Hematology Department, Hospital ‘C Panico’, Tricase, Italy; Bone Marrow Transplantation Unit, Reggio Calabria, Italy; 4Haematology Department, Turin Hospital, Turin, Italy and 5 Hematology Unit, University of Foggia, Foggia, Italy 3

Haemopoietic stem cell therapy is an increasingly adopted procedure in the treatment of patients with malignant lymphoma. In this retrospective analysis, we evaluated 262 patients, 57 (22%) with Hodgkin’s and 205 (78%) with non-Hodgkin’s lymphomas (NHL), and 665 harvesting procedures in order to assess the impact of poor mobilization on survival and to determine the factors that may be predictive of CD34 þ poor mobilization. The mobilization chemotherapy regimens consisted of highdose cyclophosphamide in 92 patients (35.1%) and a highdose cytarabine-containing regimen (DHAP in 87 patients –(33.2%), MAD in 83 (31.7%)). The incidence of poor mobilizers (o2 106 CD34 þ cells/kg) was 17.9% overall, with a 10% of very poor mobilizers (p1 106/ kg). Refractory disease status and chemotherapeutic load (43 regimens) before mobilization played a negative role and were associated with poor mobilization. Survival analysis of all harvested patients showed an overall survival at 3 years of 71% in good mobilizers vs 33% in poor mobilizers (P ¼ 0.002). The event-free survival at 3 years was 23% in poor mobilizers and 58% in good mobilizers (P ¼ 0.04). We conclude that in NHL patients, poor mobilization status is predictive of survival. Bone Marrow Transplantation (2006) 37, 719–724. doi:10.1038/sj.bmt.1705298; published online 6 March 2006 Keywords: malignant lymphoma; mobilizing regimens; stem cells; CD34 þ cells

Introduction Haemopoietic stem cell (HSC) transplantation has been widely performed to support high-dose chemotherapy in haematological malignancies.1–7 In lymphoid malignancies, autologous stem cell transplantation (ASCT) is the treat-

ment frequently employed in relapsed malignant lymphomas (ML) or in very high-risk ML.2–12 The presence of HSCs in peripheral blood is usually extremely low before mobilizing procedures, and engraftment of CD34 þ peripheral blood stem cells (PBSC) depends on the infusion of an adequate number of CD34 þ stem cells to restore haemopoiesis.13–23 Indeed, the number of CD34 þ cells is commonly used to predict the potential engraftment of harvested HSC.17,19,22,23 A cutoff of 20 CD34 þ cells/ml in the peripheral blood has been arbitrarily defined to predict a successful collection procedure, and an infusion of a minimum of 2.5 106 CD34 þ cells/kg to achieve a safe engraftment.20,21 A good mobilization is mainly achieved by combining chemotherapy and haemopoietic growth factors (HGF). The use of different chemotherapy schedules and various HGF (G-CSF, GM-CSF, stem cell factors, IL-3, etc) to perform HSC collecting procedure has been reported.13–15,24 However, for patients treated with any given chemotherapy regimen, the time to optimal number of CD34 þ cells in peripheral blood varies greatly and different variables need to be considered in order to obtain a reliable prediction of good mobilization.25–29 A total of 10–12% of patients with ML do not reach the minimum threshold of 2 106 CD34 þ collected cells/kg and are considered poor mobilizers.29–32 Data in the literature on poor mobilizers suggest an influence of disease status, bone marrow involvement, number of chemotherapies and of the different kinds of mobilizing regimen, but a reproducible model predictive of poor mobilization is still lacking.25–32 In our retrospective study of 262 consecutive patients with ML, we analysed the impact on survival of poor mobilization expressed as overall survival (OS) and event-free survival (EFS). We also analysed the role of several haematological and clinical variables in the harvest of CD34 HSC.

Patients and methods Correspondence: Dr V Pavone, Hematology Department, University of Beri, Via LRicchioni 16, 70124 Bari, Italy. E-mail: [email protected] Received 1 April 2005; revised 19 December 2005; accepted 20 December 2005; published online 6 March 2006

Patients characteristics From January 1998 to October 2002, a total of 665 harvesting procedures were performed in 262 patients (120

Poor mobilization in malignant lymphomas V Pavone et al

720

male and 142 female patients, mean age 45 years, range 16– 63) in the participating centres: the Bone Marrow Transplantation Unit of Reggio Calabria, the Haematology Department of Turin Hospital and the Haematology Department of Bari. According to the REAL/WHO classification, there were 62 (23.7%) patients with follicular lymphomas, 143 (54.6%) with diffuse large cell lymphomas (DLCL) and 57 (21.8%) with Hodgkin’s lymphomas (HL); stage III–IV disease was present in 197 patients (75.2%) and 175 patients (66.8%) had bone marrow involvement. Systemic B symptoms were present in 161 patients (61.5%). An age-adjusted international prognostic index (IPI) score X2 was documented in 115 patients (43.9%). At the time of PBSC mobilization, 209 patients (79.8%) were considered to be responsive to chemotherapeutic treatment: 40 patients (15.3%) were in first complete remission, 169 patients (64.5%) in first partial remission and the remaining 53 patients (20.2%) had relapsed or refractory disease (Table 1). Mobilizing procedures. The mobilization chemotherapy regimens were cyclophosphamide (CPM) (5 g/m2) in 92 patients (35.1%), DHAP (cisplatin 100 mg/m2 intravenously (IV) by continuous infusion over 24 h, followed by cytosine arabinoside in two pulses each at a dose of 2 g/m2 given 12 h apart, dexamethasone 40 mg IV given on days 1– 4) in 87 patients (33.2%) and MAD (cytosine arabinoside in two pulses each at a dose of 2 g/m2 given 12 h apart on days 1–4, mitoxantrone 10 mg/m2 on days 3–4, dexamethasone 40 mg IV given on days 1–4) in 83 (31.7%). For all patients, subcutaneous administration of granulocyte colony stimulating factor (G-CSF) (5 mg/kg, once daily) was commenced on day 2 and continued until completion of the PBSC harvest. Stem cell collection. Stem cell collection was performed in all participating centres with a Fenwal CS 3000 (Baxter, USA). Peripheral blood stem cell harvesting was started when a white blood count (WBC) 41 103/ml and 410 CD34 þ cells/ml were reached.33 For every bag harvested, mononuclear cells (MNC)/kg and CD34 þ cells/kg were evaluated at the end of each aphaeresis. Flow cytometry assay for CD34 þ cell estimation. A 20 ml portion of whole blood was incubated for 30 min at 4 1C with 10 ml of fluorescein isothiocyanate (FITC)-conjugated monoclonal antibody HPCA2. The leucocyte population was analysed by acquiring 75 000 events, using a Becton Dickinson FACScan with a 2 W argon ion laser as a light source. Excitation was allowed at 488 nm and fluorescence was measured at 530 nm.

Statistical analysis We analysed the following variables: age, gender, histology, clinical and laboratory data at mobilization (extranodal site performance status, bulky disease, B symptoms, ageadjusted IPI, abnormal lactate dehydrogenase (LDH), abnormal beta2microglobulin, stage, bone marrow involvement, type of previous chemotherapy, number of previous Bone Marrow Transplantation

Table 1 Patients’ characteristics and association with poor mobilization Total patients 262 Median age at mobilization Sex (M/F) Histology Grade I follicular NHL DLCL Hodgkin’s lymphoma

Second/third line MIME DHAP FC FND IEV Previous rituximab use Disease status at mobilization 1 CR 1 PR Relapse Refractory Mobilizing regimens CPM DHAP MAD Median no. of prior treatment regimens

P

45 120/142

43 99/117

55 21/25

62 143 57

44 122 50

18 21 7

94 81 138 124 85 125 128

16 11 34 37 30 43 29

155

42

132 40

43 22

43 14 79 52 41 33

35 11 65 43 34 27

8 3 14 9 7 6

48 185 18 38 55

39 152 15 31 45

9 33 3 7 10

66

57

9

40 169 28 25

37 160 12 2

3 9 16 23

0.008

92 87 83 3

76 73 66 2

16 14 17 4

0.02

Clinical and laboratory data at mobilization Extranodal sites X2 110 Performance status 2–4 92 Bulky disease 172 B symptoms 161 Age-adjusted IPI 2,3 115 Abnormal LDH 168 Abnormal 157 beta2microglobulin Stage III–IV 197 Bone marrow involvement At diagnosis 175 At mobilization 62 Previous chemotherapy First line ABVD BEACOPP CHOP – CHOP like ProMACE/CytaBOM Mega-CEOP HDS

Good Poor mobilizer mobilizer 215 47

Abbreviations: ABVD ¼ adriamycin, bleomycin, vinblastine, dacarbazine; BEACOPP ¼ bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; CHOP ¼ cyclophosphamide, doxorubicin, vincristine, prednisone; CPM ¼ cyclophosphamide; CR ¼ complete remission; DHAP ¼ dexamethasone, high-dose cytarabine, cisplatinum; DLCL ¼ diffuse large cell lymphoma; FC ¼ fludarabine, cyclophosphamide; FND ¼ fludarabine, mitoxantrone, dexamethasone; HDS ¼ high-dose sequential chemotherapy; IEV ¼ ifosfamide, epirubicin and etoposide; IPI ¼ international prognostic index; MAD ¼ mitoxantrone, high-dose cytarabine, dexamethasone; MEGA-CEOP ¼ cyclophosphamide, epirubicin, vincristine, prednisone; MIME ¼ mitoxantrone, ifosfamide, methotrexate, etoposide; NHL ¼ non-Hodgkin’s lymphoma; PR ¼ partial remission; ProMACE-CytaBOM: cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate prednisone.


721 160 (94.7%)

37 (92.5%)

40

Poor mobilizer Good mobilizer

Number of pts

chemotherapy, disease status at mobilization, mobilizing regimens). Patients were divided into good and poor mobilizer groups. Comparisons between groups were performed using the test. Survival analyses were performed using the Kaplan–Meier method. The log–rank test was used to compare the survival distribution between groups. A Cox proportional hazard regression was performed for multivariate analysis. All P-values reported are two-sided and statistical significance is defined as Po0.05.

30 23 (92%) 16 (57%)

20 9 (5.3%)

10

12 (43%)

3 (7.5%)

Results

The chemotherapeutic load (defined as the number of chemotherapeutic regimen) negatively correlates with CD34 þ cells/kg collected (Table 1). In the group of patients harvested in relapsed or refractory disease, there were a large number of patients defined as poor mobilizers (39 patients (73.6%)), compared with the number of poor mobilizer chemosensitive patients (PR or CR patients; 12 patients (5.7%) (Table 1, Figure 1). No difference was found according to bone marrow involvement at diagnosis and at the harvest procedure. No statistical difference was found in the number of poor mobilizers, according to the type of mobilizing regimen utilized (Table 1). Survival analysis showed an OS at 3 years of 71% in good mobilizers vs 33% in poor mobilizers (HR ¼ 2.12, 95% CI ¼ 0.88–5.32, P ¼ 0.002) (Figure 2); EFS at 3 years was 23% in poor mobilizers and 58% in good mobilizers (HR ¼ 1.16, 95% CI ¼ 0.5–4.12, P ¼ 0.04) (Table 2). Indeed, chemorefractory patients found to be good mobilizers (14 patients) showed a better OS (32 vs 13%, HR ¼ 3.25, 95% CI ¼ 1.01–10.5, P ¼ 0.007) and EFS (23 vs 8%, HR ¼ 5.1, 95% CI ¼ 0.91–6.94, P ¼ 0.014) as compared to poor mobilizers (39 patients).

Mobilization regimen toxicity Grade I (WHO) nausea and vomiting was present in 55 patients (21%), and grade I haemorrhagic cystitis was

CR

PR

REL

REFR

Figure 1 Disease status and CD34 þ mobilization in 262 patients with malignant lymphoma.

1.0

Cumulative survival

A median of 10 l was processed in three centres, with a median of three aphaeretic procedures per patient and a median flow rate of 50 ml/min. A median of 3.2 108 MNC/kg and a median of 28.8 106 CD34 þ cells/kg were harvested. By evaluating the efficacy of CD34 þ cells harvest, 47/ 262 patients (17.9%) were considered as poor mobilizer patients, defined as patients with a collection of o2 106 CD34 þ cells /kg, and a subset (9.9%) as very poor mobilizers (o1 106/kg), 67 patients (25.5%) harvested CD34 þ cells between 2 and 5 106/kg and 148 patients (56.5%) more than 5 106/kg. Stratifying patients by diagnosis, age, disease status, number of chemotherapeutic regimens before mobilization, bone marrow involvement at diagnosis and at harvest, we observed that the following:

0

2 (8%)

0.8

Good (n=215)

0.6 P=0.02 0.4

Poor (n=47)

0.2 0.0

0

5

10

15

20

25 30 Months

35

40

45

50

55

Figure 2 Overall survival in 262 patients with malignant lymphoma: good and poor mobilizers.

observed in 47 patients (18%) in the CPM group. Grade I neurological complaints and grade II acute renal failure occurred in 47 patients (18%) and in 55 patients (21%), respectively, in high-dose Ara-C (DHAP-MAD). These complications reversed within 24–48 h in all cases.

CD34 þ cells infused In the good mobilizers group, a median of 2.4 108 MNC/ kg (range 1.3–3.5) and a median of 5 106 CD34 þ cells/kg (range 2–13) were infused. All patients in poor mobilizer group underwent bone marrow collection, and a median of 1.2 108 MNC/kg (range 0.8–2.1) and of 2.6 106 CD34 þ cells/kg (range 1.8–3.1) were infused. In this group, the CD34 þ cells infused take into account both the PBSC and bone marrow collections. Engraftment. The median time to achieve an ANC X500/ ml was 10 days in the good mobilizer group and 12 days in the poor mobilizer group (P ¼ 0.001). The median time to a platelet count more than 20 103/ml with transfusion independence was 11 days in the good mobilizer group and 14 days in the poor mobilizer group (P ¼ 0.23). Bone Marrow Transplantation


722 Table 2

Univariate and multivariate analysis of prognostic factors for overall survival (OS) and event-free survival (EFS)

Variable

P-value

OS (%) at 3 years Univ.

Age-adjusted IPI Abnormal LDH Refractory disease Poor mobilization status

0–1 2–3 Yes No Yes No Yes No

81 38 67 82 15 78 33 71

Multiv.

0.005

0.006

0.001

0.002

0.04

P-value

EFS (%) at 3 years Univ. 81 55 40 71 10 72 23 58

Multiv.

0.01 0.02 0.02

0.02

0.04

0.04

Abbreviations: IPI ¼ international prognostic index; LDH ¼ lactate dehydrogenase.

Cause of death of poor mobilizer. Disease progression was the major cause of death after transplantation, resulting in 23/48 (48%) deaths. The overall non-progression mortality at 100 days and at 3 years were 8.5 and 19%, respectively; four patients died of infectious causes (three bacterial and one fungal), one patient died of marrow failure, three died for toxicity (pulmonary failure) and one died of secondary malignancy.

Discussion A large number of variables may influence HSC mobilizing, namely the chemotherapeutic load, type of antineoplastic drug (fludarabine, alkylating agents, etc), bone marrow involvement, time from diagnosis to harvest, disease status and so on.25–32 The incidence of poor mobilizer population is variably reported to range from 15 to 40% in different subsets of patients.32,34 In our study, we identified a group of patients (47/262 (17.9%)) defined as poor mobilizers (o2 106 CD34/kg) and a subset (9.9%) of patients of very poor mobilizers (o1 106/kg). Unsuccessful mobilization and collection of HSC (observed in 17.9% of our series) may partially be owing to the increasing use of high-dose chemotherapy procedures or of antineoplastic agents such as fludarabine or high-dose alkylants. In our series of 262 patients, no statistical difference was observed in terms of MNC and CD34 þ cells harvested among the different mobilizing regimens utilized, mainly consisting of high-dose CPM- and highdose ARA-C-containing protocols. These findings are supported by our previous experience,14 but are in contrast with the findings in some other studies.34 Multivariate analysis of the clinical/haematological data of the patients presented in our series and the mobilizing capacity did not reveal any correlation, except for the number of previous chemotherapeutic regimens administered and the disease status at the time of the mobilization procedure (Table 1). The effects of rituximab on HSC mobilization are poorly understood. Some authors have found a trend towards the need for bone marrow harvest to supplement low-yield HSC collections,35 although other authors did not find deleterious effects on HSC mobilization kinetics.36 In our series, with the use of rituximab, we did not find a statistical difference in the number of poor mobilizers. Bone Marrow Transplantation

As in other studies,37,38 poor mobilization status was associated with poor clinical outcome (Table 2; Figure 2). Notably, in our study, chemorefractory patients with good mobilization had better OS (32 vs 13%) and EFS (23 vs 8%) than poor mobilizers. In agreement with Gordan et al.,37 we confirm the role, in multivariate analysis, of refractory disease and number of previous chemotherapy regimens in determining the poor mobilization status. The outcome in terms of EFS and OS was influenced in multivariate analysis by poor mobilization status and refractory disease. The previous study of Gordan et al. described in a group of 90 patients with HD and NHL the impact of 43 chemotherapy regimens, of CD34 þ infused at o2 106/kg, of the elevated LDH and the poor mobilization status, on disease-free survival. Our series of patients (262) represents a larger series. In contrast with the study of Stockerl-Goldstein et al.38 evaluating a series of 172 patients, all with NHL and transplanted with purged PBSC, we did not find the same results in terms of OS and EFS. Nevertheless, in the same study,38 the poor mobilization status identifies a cohort of patients with worse prognosis expressed not as survival but as treatment-related mortality and early (o120 days) deaths, including relapse between poor and good mobilizers patients. However, the CD34 þ cell dose has been reported to influence post transplant morbidity and OS following allogeneic and ASCT.39,40,41 In a previous study40 of 100 unmanipulated identical twin transplants (for leukaemia), it was found that syngeneic marrow dose of 43 108 nucleated cells/kg was independently associated with higher disease-free survival and OS rates. In a study41 of 277 consecutive patients who underwent ASCT for solid tumors, Hodgkin’s and non-Hodgkin’s lymphomas, CD34 þ cell dose of o4 106/kg was associated with both progression and death. In conclusion, our study confirms that a distinct number of variables, lack of response and number of chemotherapeutic regimens are associated in part with a poor mobilizing and collecting procedure and also identify a subset of patients with a worse prognosis and survival who did not mobilize. The optimal strategy to perform collection of HSC in patients at high risk of a poor mobilization procedure remains controversial.


723

Prospective studies are needed to identify patients who will have no benefits from mobilization and collection of HSC. The role of new mobilizing and releasing HSC factors like stem cell factor, pegylated G-CSF, recombinant human growth hormone42 or AMD310043 warrants further investigations.

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