Mobilization of peripheral blood stem cells with docetaxel and ... - Nature

Bone Marrow Transplantation, (1999) 23, 421–425  1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt

Mobilization of peripheral blood stem cells with docetaxel and cyclophosphamide (CY) in patients with metastatic breast cancer: a randomized trial of 3 vs 4 g/m2 of CY CH Weaver, LS Schwartzberg, B Zhen, C Franco, M Moore, R Smith Jr, L White, A Van Amburg, B Hazelton and CD Buckner Clinical Research Division of Response Oncology, Inc, Memphis, TN, USA

Summary: The purpose of this study was to develop a regimen of docetaxel, cyclophosphamide (CY) and filgrastim for mobilization of peripheral blood stem cells (PBSC) in patients with metastatic breast cancer (n = 66). A phase I trial of CY 2, 3 or 4 g/m2 with docetaxel 100 mg/m2, in consecutive cohorts of four patients each, did not reveal any dose-limiting toxicities and subsequent patients were randomized to receive 3 or 4 g/m2 of CY. The median yield of CD34ⴙ cells from all patients was 11.06 ⴛ 106/kg (range, 0.03–84.77) from a median of two aphereses (range, 1–7); 6.52 ⴛ 106 CD34ⴙ cells/kg/apheresis (range, 0.01–52.07). Target CD34ⴙ cell doses ⭓2.5 and ⭓5.0 ⴛ 106/kg were achieved in 89% and 79%, respectively. There were no statistically significant differences in CD34ⴙ cell yields or target CD34ⴙ cell doses achieved following 3 or 4 g/m2 of CY. Patients with only one prior chemotherapy regimen yielded a median of 12.82 ⴛ 106 CD34ⴙ cells/kg/ apheresis compared to 5.85 for those receiving ⭓2 regimens (P = 0.03). It was concluded that the combination of docetaxel, 100 mg/m2, CY 3 g/m2 without mesna could be administered with acceptable toxicity with collection of adequate quantities of PBSC from the majority of patients. Keywords: mobilization; docetaxel; cyclophosphamide

The role of HDC with PBSC support for the treatment of patients with breast cancer is controversial1 despite the fact that numerous phase 2 studies2–5 and one prospective randomized trial6 have demonstrated superiority compared to conventional-dose therapies. Patients in complete remission (CR) appear to benefit more from HDC than patients not in CR.4 Thus, one approach to improving outcomes for patients with metastatic breast cancer is to improve the CR rate prior to HDC with PBSC support. Theoretically, chemotherapy administered for mobilization of PBSC can be integrated into the treatment plan of patients scheduled to receive HDC. Previous studies in Correspondence: CD Buckner, Response Oncology, Inc., 600 Broadway, Suite 112, Seattle, Washington 98122, USA Received 23 April 1998; accepted 4 October 1998

patients with metastatic breast cancer have evaluated induction followed by drug combinations including: cyclophosphamide (CY), etoposide,7 CY, etoposide and cisplatin5 and CY and paclitaxel for mobilization of PBSC.8 The taxanes, paclitaxel and docetaxel, are active in the treatment of patients who have failed doxorubicin-based regimens and are increasingly being evaluated in initial treatment regimens.9–17 The administration of paclitaxel or docetaxel prior to HDC with PBSC support is also being evaluated in patients with breast cancer.18,19 In order to incorporate new chemotherapeutic agents into a treatment strategy of induction, mobilization of PBSC and HDC with PBSC support it is important to determine the efficacy of such agents for the mobilization of PBSC. The combination of paclitaxel 200 mg/m2, CY 3 g/m2 and filgrastim can be administered with acceptable toxicity allowing collection of adequate quantities of PBSC from the majority of patients with breast cancer.8,20–22 The purpose of the current study was to determine if regimens of docetaxel and CY were also effective for mobilization of PBSC in patients with metastatic breast cancer and to determine if CY 3 g/m2 could be administered safely with docetaxel 100 mg/m2 without mesna. Patients and methods Between January 1997 and February 1998, 66 patients with metastatic breast cancer meeting protocol eligibility criteria for treatment with HDC were given docetaxel, CY and filgrastim for mobilization of PBSC. Patients were eligible for PBSC mobilization and harvest if they had ECOG performance status of 0–2, age ⬍66 years, and evidence of adequate hepatic, renal and cardiac function.23 All patients signed a protocol-specific informed consent approved by the institutional review board of the hospital where the therapy was administered. Study design This trial evaluated the toxicities of CY 2, 3 or 4 g/m2 when combined with docetaxel 100 mg/m2. If no dose-limiting toxicities (DLT) were experienced at the three dose levels of CY a randomized trial of CY 3 vs 4 g/m2 was to be performed evaluating toxicities and CD34⫹ cell yields. Additional patients were entered at the 2 g/m2 dose level if

Docetaxel, filgrastim and blood stem cells CH Weaver et al

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patients at the higher dose levels were still being evaluated for toxicity. Treatment centers Patients were treated in outpatients facilities associated with 26 community cancer centers by 43 practising medical oncologists affiliated with the Clinical Trials Division of Response Oncology Inc. (ROI), Memphis, TN, listed at the end of this manuscript. Administration of chemotherapy and filgrastim Sixty-six patients received docetaxel (Rhoˆne-Poulenc Rorer, Collegeville, PA, USA) 100 mg/m2 and CY 2 (n = 10), 3 (n = 27) or 4 g/m2 (n = 29). Dexamethasone 8 mg p.o. was given twice a day on day 1, docetaxel 100 mg/m2 was administered i.v. on day 2 and CY 2, 3 or 4 g/m2 was administered i.v. on day 3. Docetaxel was diluted in 250–500 ml of normal saline in a glass or polyolefin container and infused over 1 h. Cyclophosphamide was diluted in 500 ml of normal saline and infused over 2– 3 h. Patients receiving CY 4 g/m2 received uroprotection with mesna, administered as a 600 mg/m2 bolus immediately before and after CY and for 24 h as a continuous infusion of 24 mg/m2 or as two fractionated doses over a 24-h period. Mesna was not administered at the two lower dose levels of CY. Filgrastim (Amgen, Thousand Oaks, CA, USA), 6 ␮g/kg/day, was administered subcutaneously from the day after the end of chemotherapy until completion of apheresis. Collection and cryopreservation of PBSC Following the administration of docetaxel, CY and filgrastim PBSC were collected and cryopreserved as previously described.8,23 Measurement of CD34⫹ cells and supportive care procedures have also been previously described.24,25 Toxicity grading All patients were evaluated daily until resolution of signs and symptoms and graded for toxicity using standard criteria.26 A DLT was defined as unresolved grade 4 non-hematologic toxicity according to the common toxicity criteria. Administration of high-dose chemotherapy Sixty-one patients have been infused with PBSC following the administration of cyclophosphamide, thiotepa and carboplatin (n = 25),5 busulfan, melphalan and thiotepa (n = 26)27 or other HDC regimens (n = 10).

of daily PBSC harvests. Continuous variables were anlayzed using the Wilcoxon rank sum test. Differences in proportions between groups were compared using ␹2 or Fisher exact method where appropriate. Results Patient characteristics Table 1 shows patient characteristics. Protocol compliance All patients received the protocol doses of docetaxel, CY and filgrastim and underwent apheresis. Dose escalation of cyclophosphamide The first four patients of each cohort receiving CY 2, 3 or 4 g/m2 did not experience DLT. Six additional patients received CY 2 g/m2 while higher dose levels were being evaluated. Comparison of 3 vs 4 g/m2 of cyclophosphamide Since there were no DLT observed in the phase I study, 48 more patients were randomized between dose level 2, CY 3 g/m2 (n = 23) and dose level 3, CY 4 g/m2 (n = 25). Non-hematologic toxicities: Grade 3–4 non-hematologic toxicities occurring in ⬎5% of patients included nausea (6.1%) and hyperglycemia (9.1%). Grade 3–4 nausea occurred in 3.7% receiving CY 3 g/m2 and in 6.9% receiving CY 4 g/m2 (P = 1.00). Hyperglycemia occurred in 0% receiving CY 3 g/m2 and 6.9% receiving CY 4 g/m2 (P = 0.49). The incidence of grade 1 hematuria was 7.4% for patients receiving CY 3 g/m2 and 13.8% following 4 g/m2 (P = 0.67) with no severe episodes of hemorrhagic cystitis occurring at either dose level. Hematologic toxicities: Grade 3–4 hematologic toxicities occurring in ⬎5% of patients included neutropenia (100%), thrombocytopenia (54%) and anemia (27%). The median duration of neutropenia was 5 days (range, 1–8) for patients receiving CY 3 g/m2 and 5 days (range, 1–8) for patients receiving CY Table 1

Patient characteristics

Cyclophosphamide dose

Statistics All data were collected using a custom designed distributed data system, reviewed at a central clinical trials center (ROI) and analyzed using the SAS system (SAS institute, Cary, NC, USA). The number of CD34⫹ cells collected ⫻106/kg/apheresis was calculated by dividing the total number of CD34⫹ cells collected per patient by the number

Number of patients Median age (range) ECOG performance status 0 (%) Prior radiation therapy (%) Prior chemotherapy regimens ⭐1 (%) n = 66.

2 g/m2

3 g/m2

4 g/m2

10 27 29 50 (40–60) 48 (30–59) 49 (36–60) 10 (100) 27 (100) 26 (90) 4 (40) 7 (26) 13 (45) 4 (40) 8 (30) 7 (24)


Table 2

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Results

Cyclophosphamide dose Number of patients Median number of aphereses Median CD34⫹ cells ⫻ 106/kg (range) Median CD34⫹ cells ⫻ 106/kg/apheresis (range) Number achieving ⭓2.5 ⫻ 106 CD34⫹ cells/kg (%) Number achieving ⭓5.0 ⫻ 106 CD34⫹ cells/kg (%) a

2 g/m2

3 g/m2

4 g/m2

10 3 (2–5) 6.80 (2.24–19.33) 1.86 (0.45–9.67)a 9 (90) 7 (70)

27 2 (1–6) 11.98 (0.06–84.77) 7.19 (0.03–47.07) 24 (89) 21 (78)

29 2 (1–7) 17.55 (0.03–52.07) 9.93 (0.01–52.07) 26 (90) 24 (83)

P = 0.02 when comparing CY 2 vs 4 g/m2. All other comparisons were not statistically significant.

4 g/m2. Fifteen of 66 (23%) received a median of 2 (range 1–7) platelet transfusions; seven of 27 (26%) in the CY 3 g/m2 group and seven of 29 (24%) in the CY 4 g/m2 group (P = 1.00). Fourteen of 66 patients (21%) received a median of one (range, 1–2) red blood cell transfusion; five of 27 (19%) in the CY 3 g/m2 and seven of 29 (24%) in the CY 4 g/m2 group (P = 0.75). Seven of 56 patients (12.5%) required admission to the hospital for a median of 3 (range 2–6) days; one of 27 (3.7%) in the CY 3 g/m2 group and six of 29 (21%) in the CY 4 g/m2 group (P = 0.10).

therapy regimen yielded a median of 12.82 ⫻ 106 CD34⫹ cells/kg/apheresis compared to 5.85 for the 41 patients who had received ⭓2 regimens (P = 0.03). Univariate analyses with the number of patients harvesting ⭓2.5 or ⭓5.0 ⫻ 106 CD34⫹ cells/kg as endpoints are shown in Table 4. All 15 patients who had received only one chemotherapy regimen harvested ⭓5.0 ⫻ 106 CD34⫹ cells/kg compared to 73% of 41 patients who had received ⭓2 regimens (P = 0.03). Patients ⭓50 years of age were less likely to harvest ⭓5.0 ⫻ 106 CD34⫹ cells/kg (P = 0.05).

Collection of peripheral blood stem cells The median yield of CD34⫹ cells for all patients was 11.06 ⫻ 106/kg (range, 0.03–84.77), 6.52 ⫻ 106 CD34⫹ cells/kg/apheresis (range, 0.01–52.07), collected in a median of two aphereses (range, 1–7). Target CD34⫹ cell doses ⭓2.5 and ⭓5.0 ⫻ 106/kg were achieved in 89% and 79% of patients, respectively. The median number of CD34⫹ cells ⫻106/kg/apheresis was 1.86 for patients receiving CY 2 g/m2 compared to 9.93 for patients receiving 4 g/m2 (p = 0.02). None of the other comparisons in Table 2 was statistically significant. Univariate analyses with the number of CD34⫹ cells collected/kg/apheresis as the endpoint are shown in Table 3. Fifteen patients who had received only one chemoTable 3 Univariate analysis: Number of CD34⫹ cells collected × 106/kg/apheresis Variable

Number patients

Median

Range

P value

Mobilization regimen Cyclophosphamide 3 g/m2 Cyclophosphamide 4 g/m2

27 29

7.19 9.93

0.03–47.07 0.01–52.07

0.78

Number of chemotherapy regimens 1 ⭓2

15 41

12.82 5.85

3.67–42.39 0.01–52.07

0.03

Prior radiotherapy No Yes

36 20

9.45 5.51

0.01–47.07 0.02–52.07

0.30

31 25

9.38 7.19

0.11–52.07 0.01–26.44

0.47

Age ⬍50 ⭓50 n = 56.

Second attempts to mobilize PBSC Four of seven patients failing to achieve ⭓2.5 ⫻ 106 CD34⫹ cells/kg underwent a second mobilization with filgrastim alone. A median of 1.54 ⫻ 106 CD34⫹ cells/kg (range, 1.01–2.77) were harvested. When the harvests from the first and second mobilizations were combined, one of four achieved the target cell dose ⭓2.5 ⫻ 106 CD34⫹ cells/kg. Thus, 60 of 66 patients (91%) achieved a target CD34⫹ cell dose ⭓2.5 ⫻ 106/kg when first and second collections were combined. Hematopoietic recovery following high-dose chemotherapy Fifty-nine patients (89%) have received HDC followed by the infusion of PBSC. The median number of CD34⫹ cells infused was 7.58 ⫻ 106/kg (range, 2.03–53.01). The median days to recovery of neutrophils to 0.5 ⫻ 109/l and platelets to 20.0 ⫻ 109/l were 10 (range, 8–32) and 11 (range, 0– 60), respectively. CD34⫹ cell doses infused and engraftment patterns were not different for patients who had received CY 2, 3 or 4 g/m2 for mobilization of PBSC. Discussion In this study the toxicities and efficacy of docetaxel, CY and filgrastim for mobilisation of PBSC were evaluated in patients with metastatic breast cancer. The toxicities observed at all three dose levels of CY were minimal. Eighty-nine per cent of 66 patients harvested ⭓2.5 and 79% harvested ⭓5.0 ⫻ 106 CD34⫹ cells/kg with a median of two apheresis procedures. The number of CD34⫹ cells harvested/kg/apheresis was 1.86 ⫻ 106 patients receiving CY 2 g/m2 compared to 9.93 for patients receiving CY 4 g/m2 (P = 0.02) suggesting a dose effect of CY.


424

Table 4

Patients yielding ⭓2.5 or ⭓5 ⫻ 106 CD34⫹ cells/kg Number patients

⭓2.5 ⫻ 106 CD34⫹ cells/kg

P value

⭓5 ⫻ 106 CD34⫹ cells/kg

P value

Mobilization regimen (%) Cyclophosphamide 3 g/m2 Cyclophosphamide 4 g/m2

27 29

24 (89) 26 (90)

1.00

21 (78) 24 (83)

0.74

Prior radiotherapy (%) No Yes

36 20

32 (89) 18 (90)

0.100

28 (78) 17 (85)

0.73

Number of chemotherapeutic regimens (%) 1 ⭓2

15 41

15 (100) 35 (85)

Age (%) ⬍50 ⭓50

31 21

29 (94) 21 (84)

There were also more CD34⫹ cells collected following CY 4 g/m2 than following 3 g/m2 but these differences were small and not statistically significant. There were no statistically significant differences in toxicities between patients receiving 3 or 4 g/m2 of CY although there was a trend toward a lower frequency of hospitalization for the 3 g/m2 (3.7%) compared to the 4 g/m2 group (21%) (P = 0.10). For practical purposes it can be concluded that docetaxel 100 mg/m2 and CY 3 g/m2 can be administered without mesna with tolerable toxicities with adequate CD34⫹ cell yields. In a previous study of CY, 3 g/m2 and paclitaxel 200 mg/m2 in patients with metastatic breast cancer the median number of CD34⫹ cells collected/kg/apheresis was 3.66 compared to 7.12 for patients receiving docetaxel 100 mg/m2 and CY 3 g/m2 in the current study.8 Thus, twice as many CD34⫹ cells/kg/apheresis were collected following docetaxel and CY as following paclitaxel and CY. However, in the previous paclitaxel study 87% of patients yielded ⭓2.5 ⫻ 106 CD34⫹ cells/kg and 73% ⭓5.0 ⫻ 106 CD34⫹ cells/kg which is similar to that achieved in the current study (89% and 79%, respectively).8 Only a randomized trial could determine the relative effectiveness of paclitaxel vs docetaxel for mobilization of PBSC. Patients who had received ⭓2 chemotherapy regimens had fewer CD34⫹ cells harvested (P = 0.03) and were less likely to harvest ⭓5.0 ⫻ 106 CD34⫹ cells/kg (P = 0.03). Patients ⭓50 years of age were less likely to achieve ⭓5.0 ⫻ 106 CD34⫹ cells/kg than younger patients. No other factors were predictive of CD34⫹ cell yields or achievement of target CD34⫹ cell doses. In addition to chemotherapy and age, prior studies have also identified performance status and prior radiation as adverse risk factors for mobilizing CD34⫹ cells.7,8,24,28–32 In the current study, only three patients had an ECOG performance status ⬎0 making this an impossible endpoint to evaluate. Prior radiation was not an adverse risk factor in the current study but this could have been due to the relatively small numbers of patients evaluated. It is evident that PBSC can be harvested after the administration of a variety of chemotherapeutic agents followed

0.18 0.39

15 (100) 26 (73) 28 (90) 17 (68)

0.03 0.05

by a growth factor.7,8,24,29,31–34 It is not clear, however, that any regimen is more optimal than another and at the present time it would seem prudent to utilize chemotherapeutic agents for mobilization of PBSC that are appropriate for the disease being treated. In that context, the combination of docetaxel 100 mg/m2 and CY 3 g/m2 should prove useful for the management of patients with breast cancer receiving HDC. Acknowledgements Many thanks to Pamela Ash for preparing this manuscript. The following physicians participated in this study: L Sanchez, Albuquerque, NM; C Bryan, J Puckett, Asheville, NC; M Moore, R Leff, Atlanta, GA; B Marchello, Billings, MT; R Drapkin, Clearwater, FL; R Smith Jr, S Madden, Columbia, SC; R Rivera, El Paso, TX; R Fleck, Ft Smith AR; S Meyer, Ft Wayne, IN; A Rosenberg, F Wittlin, M Lewis, S Weiss, Hollywood, FL; L Campos, M Crow, Houston, TX; K Pendergrass, Kansas City, MO; A Grossman, J Foster, Knoxville, TN; L Mendelsohn, Little Rock, AR; L Schwartzberg, Memphis, TN; A Feinberg, Miami, FL; D Halverson, Mobile, AL; M Messer, Mt Diablo, CA; A Greco, J Hainsworth, Nashville, TN; L Thomas, New Orleans, LA; C Franco (Northside) Atlanta, GA; J Redmond, P Pickens, Philadelphia, PA; L Lewkow, MK Hagan, Richmond, VA; A Bala, J West, R Goldberg, Savannah, GA; M Hyzinski, R Emanuelso, Scranton, PA; A Van Amburg, B Needles, L White, St Louis, MO; C George, R Blanco, Tampa, FL.

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