Bone Marrow Transplantation (2006) 37, 719–724 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt 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 1Hematology Department, University of Bari, Bari, Italy; 2Hematology Department, Hospital ‘C Panico’, Tricase, Italy; 3Bone Marrow Transplantation Unit, Reggio Calabria, Italy; 4Haematology Department, Turin Hospital, Turin, Italy and 5Hematology Unit, University of Foggia, Foggia, Italy Haemopoietic stem cell therapy is an increasingly adopted ment frequently employed in relapsed malignant lympho- procedure in the treatment of patients with malignant mas (ML) or in very high-risk ML.2–12 The presence of lymphoma. In this retrospective analysis, we evaluated HSCs in peripheral blood is usually extremely low before 262 patients, 57 (22%) with Hodgkin’s and 205 (78%) mobilizing procedures, and engraftment of CD34 þ per- with non-Hodgkin’s lymphomas (NHL), and 665 harvest- ipheral blood stem cells (PBSC) depends on the infusion of ing procedures in order to assess the impact of poor an adequate number of CD34 þ stem cells to restore mobilization on survival and to determine the factors that haemopoiesis.13–23 Indeed, the number of CD34 þ cells is may be predictive of CD34 þ poor mobilization. The commonly used to predict the potential engraftment of mobilization chemotherapy regimens consisted of high- harvested HSC.17,19,22,23 A cutoff of 20CD34 þ cells/mlin dose cyclophosphamide in 92 patients (35.1%) and a high- the peripheral blood has been arbitrarily defined to predict dose cytarabine-containing regimen (DHAP in 87 patients a successful collection procedure, and an infusion of a –(33.2%), MAD in 83 (31.7%)). The incidence of minimum of 2.5 Â 106 CD34 þ cells/kg to achieve a safe poor mobilizers (o2 Â 106 CD34 þ cells/kg) was 17.9% engraftment.20,21 A good mobilization is mainly achieved overall, with a 10% of very poor mobilizers (p1 Â 106/ by combining chemotherapy and haemopoietic growth kg). Refractory disease status and chemotherapeutic load factors (HGF). (43 regimens) before mobilization played a negative role The use of different chemotherapy schedules and and were associated with poor mobilization. Survival various HGF (G-CSF, GM-CSF, stem cell factors, IL-3, analysis of all harvested patients showed an overall etc) to perform HSC collecting procedure has been survival at 3 years of 71% in good mobilizers vs 33% in reported.13–15,24 However, for patients treated with any poor mobilizers (P ¼ 0.002). The event-free survival at given chemotherapy regimen, the time to optimal number 3 years was 23% in poor mobilizers and 58% in good of CD34 þ cells in peripheral blood varies greatly and mobilizers (P ¼ 0.04). We conclude that in NHL patients, different variables need to be considered in order to obtain poor mobilization status is predictive of survival. a reliable prediction of good mobilization.25–29 A total of Bone Marrow Transplantation (2006) 37, 719–724. 10–12% of patients with ML do not reach the minimum doi:10.1038/sj.bmt.1705298; published online 6 March threshold of 2 Â 106 CD34 þ collected cells/kg and are 2006 considered poor mobilizers.29–32 Data in the literature on Keywords: malignant lymphoma; mobilizing regimens; poor mobilizers suggest an influence of disease status, bone stem cells; CD34 þ cells 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 Introduction ML, we analysed the impact on survival of poor mobiliza- tion expressed as overall survival (OS) and event-free Haemopoietic stem cell (HSC) transplantation has been survival (EFS). We also analysed the role of several widely performed to support high-dose chemotherapy in 1–7 haematological and clinical variables in the harvest of haematological malignancies. In lymphoid malignancies, CD34 HSC. autologous stem cell transplantation (ASCT) is the treat- Patients and methods Correspondence: Dr V Pavone, Hematology Department, University of Beri, Via LRicchioni 16, 70124 Bari, Italy. E-mail: [email protected] Patients characteristics Received 1 April 2005; revised 19 December 2005; accepted 20 December From January 1998 to October 2002, a total of 665 2005; published online 6 March 2006 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– Table 1 Patients’ characteristics and association with poor 63) in the participating centres: the Bone Marrow mobilization Transplantation Unit of Reggio Calabria, the Haemato- Total Good Poor P logy Department of Turin Hospital and the Haematology patients mobilizer mobilizer Department of Bari. According to the REAL/WHO 262 215 47 classification, there were 62 (23.7%) patients with follicular Median age at mobilization 45 43 55 lymphomas, 143 (54.6%) with diffuse large cell lymphomas Sex (M/F) 120/142 99/117 21/25 (DLCL) and 57 (21.8%) with Hodgkin’s lymphomas (HL); stage III–IV disease was present in 197 patients (75.2%) Histology and 175 patients (66.8%) had bone marrow involvement. Grade I follicular NHL 62 44 18 Systemic B symptoms were present in 161 patients (61.5%). DLCL 143 122 21 Hodgkin’s lymphoma 57 507 An age-adjusted international prognostic index (IPI) score X2 was documented in 115 patients (43.9%). At the time of Clinical and laboratory data at mobilization PBSC mobilization, 209 patients (79.8%) were considered Extranodal sites X2 11094 16 to be responsive to chemotherapeutic treatment: 40patients Performance status 2–4 92 81 11 Bulky disease 172 138 34 (15.3%) were in first complete remission, 169 patients B symptoms 161 124 37 (64.5%) in first partial remission and the remaining 53 Age-adjusted IPI 2,3 115 85 30 patients (20.2%) had relapsed or refractory disease Abnormal LDH 168 125 43 (Table 1). Abnormal 157 128 29 beta2microglobulin Stage III–IV 197 155 42 Mobilizing procedures. The mobilization chemotherapy Bone marrow involvement regimens were cyclophosphamide (CPM) (5 g/m2)in92 At diagnosis 175 132 43 patients (35.1%), DHAP (cisplatin 100 mg/m2 intrave- At mobilization 62 4022 nously (IV) by continuous infusion over 24 h, followed by 2 Previous chemotherapy cytosine arabinoside in two pulses each at a dose of 2 g/m First line given 12 h apart, dexamethasone 40mg IV given on days 1– ABVD 43 35 8 4) in 87 patients (33.2%) and MAD (cytosine arabinoside BEACOPP 14 11 3 in two pulses each at a dose of 2 g/m2 given 12 h apart on CHOP – CHOP like 79 65 14 2 ProMACE/CytaBOM 52 43 9 days 1–4, mitoxantrone 10mg/m on days 3–4, dexametha- Mega-CEOP 41 34 7 sone 40mg IV given on days 1–4) in 83 (31.7%). For all HDS 33 27 6 patients, subcutaneous administration of granulocyte colony stimulating factor (G-CSF) (5 mg/kg, once daily) Second/third line MIME 48 39 9 was commenced on day 2 and continued until completion DHAP 185 152 33 of the PBSC harvest. FC 18 15 3 FND 38 31 7 Stem cell collection. Stem cell collection was performed in IEV 55 45 10 all participating centres with a Fenwal CS 3000 (Baxter, Previous rituximab use 66 57 9 USA). Peripheral blood stem cell harvesting was started Disease status at mobilization when a white blood count (WBC) 41 Â 103/ml and 410 1 CR 4037 3 CD34 þ cells/ml were reached.33 For every bag harvested, 1 PR 169 1609 Relapse 28 12 16 mononuclear cells (MNC)/kg and CD34 þ cells/kg were Refractory 25 2 23 0.008 evaluated at the end of each aphaeresis. Mobilizing regimens Flow cytometry assay for CD34 þ cell estimation. A20ml CPM 92 76 16 DHAP 87 73 14 portion of whole blood was incubated for 30min at 4 1C MAD 83 66 17 with 10 ml of fluorescein isothiocyanate (FITC)-conjugated Median no. of prior treatment 3 2 4 0.02 monoclonal antibody HPCA2. regimens The leucocyte population was analysed by acquiring 75 000 events, using a Becton Dickinson FACScan with a Abbreviations: ABVD ¼ adriamycin, bleomycin, vinblastine, dacarbazine; BEACOPP ¼ bleomycin, etoposide, doxorubicin, cyclophosphamide, vin- 2 W argon ion laser as a light source. Excitation was cristine, procarbazine, prednisone; CHOP ¼ cyclophosphamide, doxorubi- allowed at 488 nm and fluorescence was measured at cin, vincristine, prednisone; CPM ¼ cyclophosphamide; CR ¼ complete 530nm. remission; DHAP ¼ dexamethasone, high-dose cytarabine, cisplatinum; DLCL ¼ diffuse large cell lymphoma; FC ¼ fludarabine, cyclophos- phamide; FND ¼ fludarabine, mitoxantrone, dexamethasone; HDS ¼ Statistical analysis high-dose sequential chemotherapy; IEV ¼ ifosfamide, epirubicin and We analysed the following variables: age, gender, histology, etoposide; IPI ¼ international prognostic index; MAD ¼ mitoxantrone, clinical and laboratory data at mobilization (extranodal high-dose cytarabine, dexamethasone; MEGA-CEOP ¼ cyclophosphamide, epirubicin, vincristine, prednisone; MIME ¼ mitoxantrone, ifosfamide, site performance status, bulky disease, B symptoms, age- methotrexate, etoposide; NHL ¼ non-Hodgkin’s lymphoma; PR ¼ partial adjusted IPI, abnormal lactate dehydrogenase (LDH), remission; ProMACE-CytaBOM: cyclophosphamide, doxorubicin, etopo- abnormal beta2microglobulin, stage, bone marrow involve- side, cytarabine, bleomycin, vincristine, methotrexate prednisone. ment, type of previous chemotherapy, number of previous Bone Marrow Transplantation Poor mobilization in malignant lymphomas V Pavone et al 721 chemotherapy, disease status at mobilization, mobilizing 160 regimens). (94.7%) Patients were divided into good and poor mobilizer groups. Comparisons between groups were performed 37 40 (92.5%) using the test.