Docetaxel effectively mobilizes peripheral blood CD34+ cells

Bone Marrow Transplantation (2000) 26, 483–487  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Docetaxel effectively mobilizes peripheral blood CD34ⴙ cells HM Prince1, GC Toner1, JF Seymour1, D Blakey1, P Gates1, S Eerhard1, P Chapple1, D Wall1, M Quinn1, S Juneja1, M Wolf1, EH Januszewicz1, G Richardson2, J Scarlett2, P Briggs2, M Brettell1 and D Rischin1 1 2

Blood and Marrow Transplant Service, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute; and Department of Medical Oncology and Clinical Haematology, Monash Medical Centre, Melbourne, Victoria, Australia

Summary: We prospectively evaluated docetaxel (100 mg/m2) with G-CSF (10 ␮g/kg S.C., daily) for mobilization efficiency in 26 patients with breast cancer. The minimum target yield was ⬎4.5 ⴛ 106 CD34ⴙ cells/kg (optimum = 9 ⴛ 106/kg), sufficient to support the subsequent three cycles of high-dose therapy (HDT). The peak days for peripheral blood (PB) CD34ⴙ cells were day 8 and day 9. Seven collections began on day 7, 16 on day 8 and three on day 9. The median peripheral blood progenitor cell (PBPC) CD34ⴙ cell content ranged from 1.2 to 5.9 ⴛ 106/kg per day during days 7 to 11 with a median CD34ⴙ content of the total 72 PBPC collections of 3.4 ⴛ 106/kg (0.07– 15.6). Fifteen patients obtained a PBPC collection exceeding 5 ⴛ 106/kg on a single day of collection. Following a median 3 days collection for each patient (range 2–4), the median total CD34ⴙ for all individual sets of collections was 9.7 ⴛ 106/kg (range 1.0–28.4). We were able to achieve the minimum CD34ⴙ cell target yield in 22 of 26 patients with one cycle of mobilisation chemotherapy and in two of these patients a second collection yielded sufficient cells. Twenty-two patients have subsequently received repetitive HDT and PBPC transplantation with 57 cycles of HDT having been delivered. For all 57 cycles, the median time to absolute neutrophil count (ANC) ⬎0.5 ⴛ 109/l and 1.0 ⴛ 109/l was 10 days (range 8–22) and 11 days (range 8–23), respectively. The median time to platelets greater than 20 ⴛ 109/l, 50 ⴛ 109/l and 100 ⴛ 109/l was 13 days (range 11–23), 17 days (range 12–53) and 23 days (range 18–70), respectively. We conclude that docetaxel with G-CSF effectively mobilises PBPCs with apheresis needing to be commenced approximately 8 days after docetaxel administration. Bone Marrow Transplantation (2000) 26, 483–487. Keywords: docetaxel; mobilization; stem cells

The efficacy of high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) transplantation for patients with breast cancer remains undefined.1,2 Although the Correspondence: Dr HM Prince, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A’Beckett St, Melbourne 3000, Victoria, Australia Received 31 August 1999; accepted 14 January 2000

results of registry data and phase II studies examining the role of HDT in metastatic breast cancer (MBC) were promising,3–5 the results of the three reported phase III studies are conflicting.6–8 One of the important issues that must be addressed is the relative importance of repeated cycles of HDT. Indeed, we have been interested in developing protocols utilising repetitive cycles of HDT for patients with MBC based on administering three cycles of HDT, with each cycle supported by PBPCs.9–11 An important prerequisite for this mode of therapy is a reliable method of obtaining sufficient PBPCs to ensure rapid and durable engraftment while maintaining patients in at least a stable disease state at the time of commencing the high-dose phase of therapy. In this study, we examined the ability of docetaxel to mobilise PBPCs in pre-treated patients with MBC. We investigated docetaxel because we required an agent that had effective anti-tumour activity in patients who may previously have been exposed to anthracyline, and docetaxel was to be incorporated into our subsequent high-dose regimen. Indeed, docetaxel has reported response rates exceeding 50%.12,13 in patients with MBC with response rates of 29–50% in anthracycline-resistant disease.14–16 Here, we report on the mobilisation of CD34⫹ cells with docetaxel, and examined the ability of these cells to support multiple cycles of HDT.

Materials and methods Patient characteristics Patients with histologically and/or cytologically proven metastatic or locally advanced breast cancer were prospectively entered into one of two phase I/II clinical trials utilising either three cycles of high-dose cyclophosphamide, thiotepa and either docetaxel or paclitaxel (see below) with each cycle supported with PBPCs. Sufficient PBPCs to support these three cycles of high-dose therapy were collected prior to any of the cycles of HDT. Patients were excluded if they had a history of ventricular arrhythmia, myocardial infarction within 6 months prior to enrollment, congestive heart failure, sensitivity to any of the study drugs, were pregnant or lactating, had an ECOG performance status ⬎2, life expectancy of less than 2 months, absolute neutrophil count (ANC) ⬍1.5 ⫻ 109/l, platelet count ⬍100 ⫻ 109/l, bilirubin ⬎ upper limit of normal range (ULN), aspartate/alanine transaminase ⬎2.5 ⫻ ULN, alkaline

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phosphatase ⬎5 ⫻ ULN (except if bone metastases in the absence of liver disorder) or creatinine ⬎1.5 ⫻ ULN. Written informed consent was obtained from all patients and the protocol was approved by the Institutional Ethics Committee of Peter MacCallum Cancer Institute. Chemotherapy Patients received one or two cycles of docetaxel (100 mg/m2 on day 1). Dexamethasone (8 mg) was administered for six doses (prior to and after docetaxel). Following the first cycle, for the purpose of mobilising PBPCs, patients also received subcutaneous granulocyte colony-stimulating factor (G-CSF: Neupogen; Amgen Australasia Pty Ltd, Sydney, Australia) at a dose of 10 ␮g/kg commencing 24 h after chemotherapy and continuing until the last day of apheresis. Apheresis procedure Patients had a routine full blood examination on day 7 following mobilisation. Daily CD34⫹ cell enumeration of the peripheral blood (PB) was commenced when the ANC reached 1.0 ⫻ 109/l following the nadir. Apheresis was initiated17 when the PB CD34⫹ cell count exceeded 5 ⫻ 106/l. Apheresis was performed using Hemonetics MCS⫹, CS3000plus (Baxter Healthcare, Deerfield, IL, USA) or Spectra (COBE BCT, Lakewood, CO, USA) cell separators. Blood was collected via a central venous access device or peripheral veins with 1.5–2.5 times estimated blood volume processed. Apheresis was continued until sufficient cells to support the subsequent three separate cycles of HDT therapy had been collected, ie a minimum target of 4.5 ⫻ 106/kg (= three cycles of high-dose therapy, each with a minimum of 1.5 ⫻ 106/kg CD34⫹ cells) with an optimum target yield of 9 ⫻ 106/kg.10 To ensure uniformity, each collection was divided into three separate bags, so that each re-infusion contained PBPCs collected from each day of apheresis. Repeat PBPC collection was performed following an additional cycle of docetaxel if the initial set of collections was deemed inadequate (ie initial total collection ⬍4.5 ⫻ 106/kg). Cell enumeration, processing and cryopreservation Determination of PB and autograft CD34⫹ cells was performed according to ISHAGE guidelines.18 The autograft content of CD34⫹ cells (per/kg) was expressed using the patient’s actual body weight. All collections were cryopreserved in 10% DMSO and stored in vapor-phase liquid nitrogen. High-dose therapy Prior to mobilisation, patients were enrolled in one of two studies for subsequent HDT. In the first study, HDT comprised three cycles of cyclophosphamide (4 g/m2), thiotepa and conventional dose paclitaxel (300 mg/m2) (175 mg/m2/cycle). High-dose therapy was administered according to the following schedule; paclitaxel was admin-

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istered as a 3 h infusion on day ⫺5. On day ⫺4 patients received mesna (0.8 g/m2 of the mesna over 30 min followed immediately by a 24 h infusion at 4 g/m2 and 2.4 g/m2 for the subsequent 24 h). Thiotepa was administered in equally divided doses on days ⫺4 to ⫺2, inclusive. Patients in whom autograft CD34 exceeded 8 ⫻ 106/kg subsequently had PBPC undergo CD34⫹ cell selection with the Isolex 300i device (Nexell, Irvine, CA, USA).11 The second study was a modification of the above regimen with docetaxel (100–125 mg/m2) substituted for paclitaxel and administered on day ⫺2 (DCT).19 In this study unmanipulated PBPCs were infused. Patients received three cycles of HDT approximately 35 days apart. Following each cycle of HDT, cryopreserved PBPC were thawed and infused on day 0. All patients received G-CSF (5 ␮g/kg/day) subcutaneously from day 1 until the ANC was ⬎1.5 ⫻ 109/l for 3 consecutive days. All patients received prophylactic ciprofloxacin and aciclovir. Statistical analysis Spearman correlation was used to compare daily PB CD34 and daily PBPC CD34 values. All results are expressed as two-sided P values. Statistical analysis was performed using GraphPad Prism Ver 2.01 and GraphPad StatMate Ver 1.00 for Windows 3.1 (GraphPad Software, San Diego, CA, USA). Results Patient characteristics Twenty-six patients were entered in this study and patient characteristics are summarized in Table 1. The median age Table 1

Patient characteristics (n = 26) n

Median age (range) Locally advanced Metastatic Metastatic sites at time of mobilisation bone (bone only) nodal (node only) lung liver skin marrow brain Median number metastatic sites Status prior to mobilization chemotherapy sensitive chemotherapy resistanta untested Median number of prior chemotherapy regimens 0 prior regimens 1 prior regimens 2 prior regimens 3 prior regimens Median number of prior chemotherapy cycles Prior anthracycline Prior cyclophosphamide Number of patients with prior RT for bone mets a

Stable or progressive disease.

43 (37–59) 4 22 16 (4) 12 (0) 11 9 6 5 2 3 (1–4) 3 (12%) 11 (42%) 12 (46%) 1 (0–3) 1 (4%) 15 (58%) 8 (31%) 2 (8%) 6 (0–16) 20 (77%) 24 (92%) 8 (31%)

Docetaxel mobilization in breast cancer HM Prince et al

PBPC CD34 x106/kg

20

r = 0.8643 P < 0.0001

PB CD34 x106/l

All patients who received docetaxel mobilisation were able to proceed to apheresis collection (n = 26). Two patients had an additional mobilisation (with docetaxel again) because of failure to reach the target autograft yield of 4.5 ⫻ 106/kg (see below). The data presented below are for the initial set of collections only (n = 26) with 72 individual apheresis procedures performed. Once the PB ANC exceeded 1.0 ⫻ 109/l (on or after day 7 in all cases) the PB CD34/l was determined. If the PB CD34⫹ cells exceeded 5 ⫻ 106/l on the morning of the planned collection, apheresis was performed on that day. Indeed, we have previously demonstrated the utility of this threshold value for initiating apheresis17,20 and the strong correlation between PB CD34⫹ cell and the autograft CD34⫹ cell content was confirmed in this study (Spearman correlation; r = 0.8643, P ⬍ 0.0001) (Figure 1). The peak days for PB CD34⫹ cells were day 8 and day 9. There was no statistical difference between PB CD34⫹ cell counts on these days (P = 0.6924: Mann–Whitney U test) (Figure 2). By employing this trigger point for initiating daily apheresis, patients underwent harvesting during days 7–11 following docetaxel. For seven collection sets, the first day of apheresis was day 7, 16 collections were initiated on day 8 and three on day 9. The median PBPC CD34⫹ cell content ranged from 0.84 to 5.8 ⫻ 106/kg per day during days 7 to 11 (Figure 3) with a median CD34⫹ content of the total 72 PBPC collections of 3.4 ⫻ 106/kg (0.07–15.6). Following a median of 3 days collection for each patient (range 2–4), the median total CD34⫹ for all 26 individual sets of collections was 9.7 ⫻ 106/kg (range 1.1–28.4). Nine patients required 2 consecutive days of collection, 13 required 3 days and four required 4 days of collection. Of note, 15 patients obtained a PBPC collection exceeding 5 ⫻ 106/kg on a single day of collection. All patients were planned to receive subsequent repetitive HDT. As described, each of three high-dose cycles was

100

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n min median mean max s.e.m.

D8

D9

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D12

D7 13 6.6 23.6 41.1 158.3 12.6

D8 27 0.1 62.2 76.5 184.8 11.0

D9 26 9.1 55.0 70.0 226.0 10.9

D10 15 8.6 26.8 32.9 108.0 6.6

D11 5 1.9 20.9 18.7 32.5 5.2

D12 1 6.7 6.7 6.7 6.7 0.0

Figure 2 The PB CD34⫹ cell counts (log scale) following mobilisation with docetaxel. Mean values are represented by horizontal lines. Peak days of collection were days 8 and 9; there was no statistical difference between PB CD34⫹ cell counts on these days (P = 0.6924). 100.0

10.0

1.0

0.1

D7

D8

D9

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D12

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n min median mean max s.e.m.

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PBPC CD34 x106/kg

Apheresis collections

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was 43 (range 37–59 years) and the majority of patients had metastatic disease (n = 22) with four patients (15%) having locally advanced disease.

D7 7 0.07 0.84 2.87 7.47 1.20

D8 25 0.40 5.80 5.30 15.64 0.78

D9 27 0.30 3.35 3.80 14.55 0.59

D10 15 0.16 1.58 1.84 4.02 0.32

D11 5 0.11 1.12 1.05 2.08 0.32

D12 -

Figure 3 The PBPC CD34⫹ cell content (log scale) following mobilisation with docetaxel. Mean values are represented by horizontal lines.

0

0

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PB CD34 x106/L Figure 1 Correlation plot of peripheral blood (PB) CD34 ⫻ 106/lvs peripheral blood progenitor cell (PBPC) CD34 content (⫻106/kg) (n = 72 individual days of apheresis).

followed by PBPC support, each with a minimum CD34⫹ cell autograft count of 1.5 ⫻ 106/kg per cycle, thus the goal of the mobilisation prior to this high-dose phase was to achieve a minimum CD34⫹ cell yield of 4.5 ⫻ 106/kg (optimum yield = 9 ⫻ 106/kg) which was divided equally into three separate bags. Utilising the docetaxel regimen we were able to achieve the minimum CD34⫹ cell target yield Bone Marrow Transplantation

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in 22 of 26 patients with one cycle of mobilisation chemotherapy and in two of these patients a second collection obtained sufficient cells (case 1: collection 1 = 3.03, 2 = 3.82; case 2: collection 1 = 2.82, 2 = 3.39) and both patients subsequently proceeded to HDT. In the other two patients, the yield of CD34⫹ cells was well below the target yield of 4.5 ⫻ 106/kg (case 3: 1.02 ⫻ 106/kg and case 4: 1.19 ⫻ 106/kg) and a second collection was not attempted. These two patients did not undergo autotransplant. Toxicity of mobilisation docetaxel The mobilisation therapy was generally well tolerated with no grade 3 or 4 non-haemopoietic toxicities observed. Furthermore, there were no acute allergic reactions, fluid retention or episodes of febrile neutropenia. No patients required red blood cell or platelet transfusions. As daily full blood counts were not routinely performed before day 7, the duration of neutropenia and thrombocytopenia was not determined. High-dose therapy Of the 26 patients undergoing PBPC collections, 22 patients have subsequently received HDT and PBPC transplantation. Of the four patients not undergoing HDT and PBPC transplantation, two did not obtain a sufficient autograft to proceed to transplant (see above) and two were excluded because of detection of asymptomatic brain metastases at pretransplant assessment. The median time from initial diagnosis of breast cancer to HDT was 31 months (range 2.5–169) and the median time from mobilisation chemotherapy to HDT was 25 days (21–59 days). Of the 22 patients undergoing repetitive HDT, 57 cycles of high-dose treatment have been delivered. Eight patients received the combination of cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and paclitaxel (175 mg/m2) with four of these patients receiving CD34-selected PBPCs. Fourteen patients had docetaxel (100–125 mg/m2) substituted for paclitaxel in the HDT regimen and all these patients received unmanipulated cells.19 For all 57 cycles of HDT administered, the median time to ANC⬎0.5 ⫻ 109/l and 1.0 ⫻ 109/l was 10 days (range 8–22) and 11 days (range 8–23), respectively. The median time to platelets greater than 20 ⫻ 109/l, and 50 ⫻ 109/l and 100 ⫻ 109/l was 13 days (range 11–23), 17 days (range 12–53) and 23 days (range 18–70), respectively. Discussion A mobilisation regimen for patients with previously treated MBC should not only mobilise large numbers of CD34⫹ cells into the circulation but also control tumour growth during this phase while having acceptable toxicity that does not prevent or increase toxicity of subsequent HDT. Furthermore, the selection of an appropriate mobilisation agent depends on prior drug exposure. Indeed, with the increased use of anthracycline-containing regimens in the adjuvant setting, the choice of mobilisation regimen for patients entering trials of HDT for MBC is somewhat limited. In

Bone Marrow Transplantation

this study, we sought to examine the mobilisation efficacy of docetaxel in patients with previously treated MBC. Our prospective study demonstrates that with a single cycle of docetaxel 24 of the 26 (92%) patients obtained sufficient PBPCs for them to be eligible to proceed to repetitive HDT with subsequent rapid platelet and neutrophil recovery. As all patients were planned to proceed directly to HDT, no formal assessment of response was performed but no patient had clinically evident disease progression. Of the total 72 initial sets of collections performed, the median number of CD34⫹ cells collected was 3.4 ⫻ 106/kg/day with 15 of 26 (58%) patients obtaining more than 5 ⫻ 106/kg CD34⫹ cells in a single day’s collection. Furthermore, of the 26 patients, only four patients did not reach the target autograft yield of 4.5 ⫻ 106/kg CD34⫹ cells after the first set of collection and two of these subsequently obtained sufficient cells to proceed to HDT following a second cycle of docetaxel mobilisation. Given the recognised early neutrophil nadir with docetaxel,12 we were particularly interested in examining the kinetics of CD34⫹ cell mobilisation following docetaxel and G-CSF. Having previously demonstrated the value of a morning PB CD34 count in predicting PBPC yield17,20 we found that harvesting was required in some patients as early as day 7 (median time to initiate collection was day 8) with all patients commencing collection between days 7 and 9. In comparison, when we mobilized a similar cohort of patients with ifosfamide with either doxorubicin or paclitaxel with the same G-CSF regimen, the peak days for collection were later (days 10–12).21 Indeed, with docetaxel mobilisation, circulating CD34⫹ had already fallen dramatically by days 10–12. Other investigators have examined the ability of docetaxel to mobilize CD34⫹ cells when used in combination with either cyclophosphamide22 or an anthracycline.23 Taken together, docetaxel-based regimens appear to very effective to mobilise CD34⫹ cells. The relative merits of the various regimens can only be determined by a randomised study. However, our data demonstrate that docetaxel alone is an appropriate choice to mobilise PBPCs for patients with breast cancer who have been previously exposed to anthracyclines or cyclophosphamide. Notably, no patient experienced febrile neutropenia or required platelet transfusions. It may also be of relevance that with intermediate-dose cyclophosphamide/ifosfamide or doxorubincin-based regimens,24–28 PBPCs are mobilised relatively late after the administration of the drugs (10–12 days) and potentially the benefit of the early docetaxel mobilisation of CD34⫹ cells may be reduced when harvesting is not performed until days 10–12. We conclude that docetaxel with G-CSF effectively mobilises PBPC and apheresis should be initiated approximately 8 days after docetaxel administration. Acknowledgements We wish to thank Rhone Poulenc Rhorer, Australia and Amgen, Australia for their generous support of this study, the research nurses, apheresis nurses and nursing staff on the Haematology and Day Wards at Peter MacCallum Cancer Institute for commitment, dedication and expert patient care.

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