Re-mobilization of hematopoietic progenitors for further autografting after prior myelo-ablative high-dose chemotherapy and autologous hematopoietic stem cell transplantation; the role of plerixafor

Salvage high-dose chemotherapy (HDC) and autologous hematopoietic stem cell (HSC) transplantation (ASCT) represents a potentially curative/survival extending treatment option in patients with a variety of chemo-sensitive malignancies, such as Hodgkin lymphoma (HL) and non-Hodgkin B-cell lymphomas (B-NHL), multiple myeloma (MM), germcell tumors (GCTs), and Ewing sarcoma (EWS). However, an appreciable proportion of these patients; 5–30%, fail to mobilize adequate numbers of hematopoietic progenitors to support subsequent ASCT, attributed to extensive prior exposure to bone marrow-damaging intensive chemotherapy. Recently, plerixafor (AMD3100; Genzyme, USA), a small bicyclam molecule CXCR4 antagonist causing mobilization of HSCs by disrupting the SDF-1/CXCR4 axis, has emerged as a novel HSCs mobilizing agent and has demonstrated its efficacy in patients with NHL and MM who had failed previous mobilization with G-CSF in large prospective studies [1,2]. Among solid tumors, plerixafor has been effective in mobilizing adequate HSC numbers in patients with GCTs who are candidates for HDCþASCT and have failed prior mobilization attempts with either G-CSF or chemotherapy followed by G-CSF, as demonstrated by our group and others [3,4]. Similar experience exists in limited numbers of patients with EWS [5]. Limited data exist on remobilization of HSCs in patients who have relapsed after prior HDCþASCT. Herein, we report on five consecutive patients with relapsed solid tumors (GCT and EWS) and hematologic malignancies (B-NHL and MM), who had undergone prior single or tandem HDCþASCT and were expected to derive benefit from further high-dose intensification and ASCT. We explored the feasibility of HSC re-mobilization with plerixaforþG-CSF alone or after appropriate mobilizing chemotherapy, in order to support further cycle(s) of HDC. Patients had to have a WHO performance status of 0–1, adequate hematopoietic, hepatic, renal function, and no major comorbidities. Signed informed consent was obtained from each patient before study entry according to Institutional policies. HSCs mobilization regimens were selected on the basis of prior treatment(s); in NHL, where Rituximab– Ifosfamide–Cisplatin–Etoposide (R-VIP) had been applied as a salvage regimen before the initial HDC regimen (usually BEAM) [6], then Rituximab–Dexamethasone–high dose Cytarabine (Ara-C)–Cisplatin (R-DHAP) was applied as salvage/ mobilizing regimen before the planned second HDC. In EWS, where Etoposide (VP-16)-Ifosfamide-Cisplatin (VIP) was applied as salvage/mobilization therapy before the initial HDC protocol [Melphalan-Etoposide (ME)], then high-dose cyclophosfamide 3.0g/m was applied for further cytoreduction/mobilization before the planned second HDCþASCT regimen [6]. In GCT patients, where Paclitaxel– Ifosfamide–Cisplatin (TIP) had been applied before the initial HDC [high-dose Thiotepa–Etoposide–Carboplatin (TEC) 2], then mobilization was attempted during the third week of bevacizumab–Irinotecan–Paclitaxel (weekly)–Oxaliplatin (bevIPO) salvage chemotherapy [7]. In MM, where high-dose cyclophosfamide (CTX) 3.0 g/m was applied for HSCs mobilization after initial induction before the first high-dose melphalan (HDMel)þASCT, then HSC mobilization with G-CSFþ preemptive plerixafor was attempted, in order to support further HDMelþASCT. Plerixafor was administered in a ‘just-in-time’ strategy, after low CD34þ numbers (<10 10/L) were measured on the first day of anticipated HSC collection in our patients with NHL, GCT and EWS or preemptively in MM. Successful HSCs mobilization was defined as the one that resulted in the collection of 2.0 or 4.0 10 CD34þ/ kg, adequate to support 1–2 cycles of HDC, respectively. Plerixafor was administered at a dose of 240 lg/kg in the evening, 10–12 h before apheresis, when peripheral CD34þ cell count exceeded 5 10/L, while the patient was still receiving G-CSF at 5 lg/kg in the morning before